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Ganong’s Review of Medical Physiology A LANGE medical book T W E N T Y F O U R T H E D I T I O N Kim E. Barrett, PhD Professor, Department of Medicine Dean of Graduate Studies University of California, San Diego La Jolla, California Susan M. Barman, PhD Professor, Department of Pharmacology/ Toxicology Michigan State University East Lansing, Michigan Scott Boitano, PhD Associate Professor, Physiology Arizona Respiratory Center Bio5 Collaborative Research Institute University of Arizona Tucson, Arizona Heddwen L. Brooks, PhD Associate Professor, Physiology College of Medicine Bio5 Collaborative Research Institute University of Arizona Tucson, Arizona New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto Copyright © 2012 by Th e McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-178004-9 MHID: 0-07-178004-1 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-178003-2, MHID: 0-07-178003-3. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefi t of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at bulksales@mcgraw-hill.com. Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. Th e authors and the publisher of this work have checked with sources believed to be reliable in their eff orts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confi rm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. Th is recommendation is of particular importance in connection with new or infrequently used drugs. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGraw-Hill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise. CHAPTER 15 Learning, Memory, Language, & Speech 289 of transmission at relevant synaptic junctions so that all the components are brought to consciousness when the memory is recalled. Once long-term memories have been established, they can be recalled or accessed by a large number of diff erent associations. For example, the memory of a vivid scene can be evoked not only by a similar scene but also by a sound or smell associated with the scene and by words such as “scene,” “vivid,” and “view.” Th us, each stored memory must have multiple routes or keys. Furthermore, many memories have an emotional component or “color,” that is, in simplest terms, memories can be pleasant or unpleasant. STRANGENESS & FAMILIARITY It is interesting that stimulation of some parts of the temporal lobes in humans causes a change in interpretation of one’s surroundings. For example, when the stimulus is applied, the subject may feel strange in a familiar place or may feel that what is happening now has happened before. Th e occurrence of a sense of familiarity or a sense of strangeness in appropriate situations probably helps the normal individual adjust to the environment. In strange surroundings, one is alert and on guard, whereas in familiar surroundings, vigilance is relaxed. An inappropriate feeling of familiarity with new events or in new surroundings is known clinically as the déjà vu phenomenon, from the French words meaning “already seen.” Th e phenomenon occurs from time to time in normal individuals, but it also may occur as an aura (a sensation immediately preceding a seizure) in patients with temporal lobe epilepsy. ALZHEIMER DISEASE & SENILE DEMENTIA Alzheimer disease is the most common age-related neurodegenerative disorder. Memory decline initially manifests as a loss of episodic memory, which impedes recollection of recent events. Loss of short-term memory is followed by general loss of cognitive and other brain functions, agitation, depression, the need for constant care, and, eventually, death. Clinical Box 15–3 describes the etiology and therapeutic strategies for the treatment of Alzheimer disease. Figure 15–5 summarizes some of the risk factors, pathogenic processes, and clinical signs linked to cellular CLINICAL BOX 15–3 Alzheimer Disease Alzheimer disease was originally characterized in middle-aged people, and similar deterioration in elderly individuals is technically senile dementia of the alzheimer type, though it is frequently just called Alzheimer disease. Both genetic and environmental factors are thought to contribute to the etiology of the disease. Most cases are sporadic, but a familial form of the disease (accounting for about 5% of the cases) is seen in an early-onset form of the disease. In these cases, the disease is caused by mutations in genes for the amyloid precursor protein on chromosome 21, presenilin I on chromosome 14, or presenilin II on chromosome 1. It is transmitted in an autosomal dominant mode, so off spring in the same generation have a 50/50 chance of developing familial Alzheimer disease if one of their parents is aff ected. Each mutation leads to an overproduction of the β-amyloid protein found in neuritic plaques. Senile dementia can be caused by vascular disease and other disorders, but Alzheimer disease is the most common cause, accounting for 50–60% of the cases. Alzheimer disease is present in 8–17% of the population over the age of 65, with the incidence increasing steadily with age (nearly doubling every 5 years after reaching the age of 60). In those who are 95 years of age and older, the incidence is 40–50%. It is estimated that by the year 2050, up to 16 million people age 65 and older in the US alone will have Alzheimer disease. Although the prevalence of the disease appears to be higher in women, this may be due to their longer life span as the incidence rates are similar for men and women. Alzheimer disease plus the other forms of senile dementia are a major medical problem. THERAPEUTIC HIGHLIGHTS Research is aimed at identifying strategies to prevent the occurrence, delay the onset, slow the progression, or alleviate the symptoms of Alzheimer disease. The use of acetylcholinesterase inhibitors (eg, rivastigmine , donepezil , or galantamine ) in early stages of the disease increases the availability of acetylcholine in the synaptic cleft. It has shown some promise in ameliorating global cognitive dysfunction, but not learning and memory impairments in these patients. These drugs also delay the worsening of symptoms for up to 12 months in about 50% of the cases studied. Antidepressants (eg, paroxetine , imipramine ) have been useful for treating depression in Alzheimer patients. Memantine (an NMDA receptor antagonist) prevents glutamate-induced excitotoxicity in the brain and is used to treat moderate to severe Alzheimer disease. It has been shown to delay the worsening of symptoms in some patients. Drugs used to block the production of β-amyloid proteins are under development. An example is R-fl urbiprofen . Also attempts are underway to develop vaccines that would allow the body’s immune system to produce antibodies to attack these proteins. 290 SECTION II Central and Peripheral Neurophysiology abnormalities that occur in Alzheimer disease. Th e cytopathologic hallmarks of Alzheimer disease are intracellular neurofi brillary tangles, made up in part of hyperphosphorylated forms of the tau protein that normally binds to microtubules, and extracellular senile plaques, which have a core of β-amyloid peptides surrounded by altered nerve fi bers and reactive glial cells. Figure 15–6 compares a normal nerve cell to one showing abnormalities associated with Alzheimer disease. Th e β-amyloid peptides are products of a normal protein, amyloid precursor protein (APP) , a transmembrane protein that projects into the extracellular fl uid (ECF) from all nerve cells. Th is protein is hydrolyzed at three diff erent sites by α-secretase, β-secretase, and γ-secretase, respectively. When APP is hydrolyzed by α-secretase, nontoxic peptide products are produced. However, when it is hydrolyzed by β-secretase and γ-secretase, polypeptides with 40–42 amino acids are produced; the actual length varies because of variation in the site at which γ-secretase cuts the protein chain. Th ese polypeptides are toxic, the most toxic being Aβσ 1–42 . Th e polypeptides form extracellular aggregates, which can stick to AMPA receptors and Ca 2+ ion channels, increasing Ca 2+ infl ux. Th e polypeptides also initiate an infl ammatory response, with production of intracellular tangles. Th e damaged cells eventually die. An interesting fi nding that may well have broad physiologic implications is the observation—now confi rmed in a rigorous prospective study—that frequent eff ortful mental activities, such as doing diffi cult crossword puzzles and playing board games, slow the onset of cognitive dementia due to Alzheimer disease and vascular disease. Th e explanation for this “use it or lose it” phenomenon is as yet unknown, but it certainly suggests that the hippocampus and its connections have plasticity like other parts of the brain and skeletal and cardiac muscles. Risk factors* - Age - Presenilin 1 mutations (chromosome 14) - Presenilin 2 mutations (chromosome 1) - Amyloid precursor protein gene mutations (chromosome 21) - apoE alleles (chromosome 19) - Trisomy 21 * Recently a mutation in the α-2 macroglobulin gene has been implicated in the late-onset disease Vulnerable neurons Monoaminergic systems, basal forebrain cholinergic system, hippocampus, entorhinal cortex, and neocortex Cytopathology Neurofibrillary tangles, neurites, Aβ peptide deposition, other cellular abnormalities End-stage disease Senile plaques, death of neurons, gliosis Pathogenic mechanisms Clinical signs Memory loss, cognitive deficits FIGURE 155 Relationships of risk factors, pathogenic processes, and clinical signs to cellular abnormalities in the brain during Alzheimer disease. (From Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science , 4th ed. McGraw-Hill, 2000.) A Normal Neuropil threads Neurofibrillary tangles B Alzheimer disease Neurites Senile plaque Abnormal membranous organelles Aβ (fibrillar) Paired helical filaments Nerve terminals FIGURE 156 Comparison of a normal neuron and one with abnormalities associated with Alzheimer disease. The cytopathologic hallmarks are intracellular neurofi brillary tangles and extracellular senile plaques that have a core of β-amyloid peptides surrounded by altered nerve fi bers and reactive glial cells. (From Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science , 4th ed. McGraw-Hill, 2000.) CHAPTER 15 Learning, Memory, Language, & Speech 291 LANGUAGE & SPEECH Memory and learning are functions of large parts of the brain, but the centers controlling some of the other “higher functions of the nervous system,” particularly the mechanisms related to language, are more or less localized to the neocortex. Speech and other intellectual functions are especially well developed in humans—the animal species in which the neocortical mantle is most highly developed. COMPLEMENTARY SPECIALIZATION OF THE HEMISPHERES VERSUS “CEREBRAL DOMINANCE” One group of functions localized to the neocortex in humans consists of those related to language; that is, the understanding of the spoken and printed word and expressing ideas in speech and writing. It is a well-established fact that human language functions depend more on one cerebral hemisphere than on the other. Th is hemisphere is concerned with categorization and symbolization and has oft en been called the dominant hemisphere. However, the other hemisphere is not simply less developed or “nondominant;” instead, it is specialized in the area of spatiotemporal relations. It is this hemisphere that is concerned, for example, with the identifi cation of objects by their form and the recognition of musical themes. It also plays a primary role in the recognition of faces. Consequently, the concept of “cerebral dominance” and a dominant and nondominant hemisphere has been replaced by a concept of complementary specialization of the hemispheres, one for sequential-analytic processes (the categorical hemisphere ) and one for visuospatial relations (the representational hemisphere ). Th e categorical hemisphere is concerned with language functions, but hemispheric specialization is also present in monkeys, so it predates the evolution of language. Clinical Box 15–4 describes defi cits that occur in subjects with representational or categorical hemisphere lesions. Hemispheric specialization is related to handedness. Handedness appears to be genetically determined. In 96% of CLINICAL BOX 15–4 Lesions of Representational & Categorical Hemispheres Lesions in the categorical hemisphere produce language disorders, whereas extensive lesions in the representational hemisphere do not. Instead, lesions in the representational hemisphere produce astereognosis— the inability to identify objects by feeling them—and other agnosias. Agnosia is the general term used for the inability to recognize objects by a particular sensory modality even though the sensory modality itself is intact. Lesions producing these defects are generally in the parietal lobe. Especially when they are in the representational hemisphere, lesions of the inferior parietal lobule, a region in the posterior part of the parietal lobe that is close to the occipital lobe, cause unilateral inattention and neglect . Individuals with such lesions do not have any apparent primary visual, auditory, or somatesthetic defects, but they ignore stimuli from the contralateral portion of their bodies or the space around these portions. This leads to failure to care for half their bodies and, in extreme cases, to situations in which individuals shave half their faces, dress half their bodies, or read half of each page. This inability to put together a picture of visual space on one side is due to a shift in visual attention to the side of the brain lesion and can be improved, if not totally corrected, by wearing eyeglasses that contain prisms. Hemispheric specialization extends to other parts of the cortex as well. Patients with lesions in the categorical hemisphere are disturbed about their disability and often depressed, whereas patients with lesions in the representational hemisphere are sometimes unconcerned and even euphoric. Lesions of diff erent parts of the categorical hemisphere produce fl uent , nonfl uent , and anomic aphasias . Although aphasias are produced by lesions of the categorical hemisphere, lesions in the representational hemisphere also have eff ects. For example, they may impair the ability to tell a story or make a joke. They may also impair a subject’s ability to get the point of a joke and, more broadly, to comprehend the meaning of diff erences in infl ection and the “color” of speech. This is one more example of the way the hemispheres are specialized rather than simply being dominant and nondominant. THERAPEUTIC HIGHLIGHTS Treatments for agnosia and aphasia are symptomatic and supportive. Individuals with agnosia can be taught exercises to help them identify objects that are a necessity for independence. Therapy for individuals with aphasia helps them to use remaining language abilities, compensate for language problems, and learn other methods of communicating. Some individuals with aphasia experience recovery but often some disabilities remain. Factors that infl uence the degree of improvement include the cause and extent of the brain damage, the area of the brain that was damaged, and the age and health of the individual. Computer assisted therapies have been shown to improve retrieval of certain parts of speech as well as allowing an alternative way to communicate. 292 SECTION II Central and Peripheral Neurophysiology right-handed individuals, who constitute 91% of the human population, the left hemisphere is the dominant or categorical hemisphere, and in the remaining 4%, the right hemisphere is dominant. In approximately 15% of left -handed individuals, the right hemisphere is the categorical hemisphere and in 15%, there is no clear lateralization. However, in the remaining 70% of left -handers, the left hemisphere is the categorical hemisphere. It is interesting that learning disabilities such as dyslexia (see Clinical Box 15–5 ), an impaired ability to learn to read, are 12 times as common in left -handers as they are in right-handers, possibly because some fundamental abnormality in the left hemisphere led to a switch in handedness early in development. However, the spatial talents of left -handers may be well above average; a disproportionately large number of artists, musicians, and mathematicians are left -handed. For unknown reasons, left -handers have slightly but signifi cantly shorter life spans than right-handers. Some anatomic diff erences between the two hemispheres may correlate with the functional diff erences. Th e planum temporale, an area of the superior temporal gyrus that is involved in language-related auditory processing, is regularly larger on the left side than the right (see Figure 10-13). It is also larger on the left in the brain of chimpanzees, even though language is almost exclusively a human trait. Imaging studies show that other portions of the upper surface of the left temporal lobe are larger in right-handed individuals, the right frontal lobe is normally thicker than the left , and the left occipital lobe is wider and protrudes across the midline. Chemical diff erences also exist between the two sides of the brain. For example, the concentration of dopamine is higher in the nigrostriatal pathway on the left side in right-handed humans but higher on the right in left -handers. Th e physiologic signifi - cance of these diff erences is unknown. In patients with schizophrenia, MRI studies have demonstrated reduced volumes of gray matter on the left side in the anterior hippocampus, amygdala, parahippocampal gyrus, and posterior superior temporal gyrus. Th e degree of reduction in the left superior temporal gyrus correlates with the degree of disordered thinking in the disease. Th ere are also apparent abnormalities of dopaminergic systems and cerebral blood fl ow in this disease. PHYSIOLOGY OF LANGUAGE Language is one of the fundamental bases of human intelligence and a key part of human culture. Th e primary brain areas concerned with language are arrayed along and near the sylvian fi ssure (lateral cerebral sulcus) of the categorical hemisphere. A region at the posterior end of the superior temporal gyrus called Wernicke’s area ( Figure 15–7 ) is concerned with comprehension of auditory and visual information. It projects via the arcuate fasciculus to Broca’s area in the frontal lobe immediately in front of the inferior end of the motor cortex. Broca’s area processes the information received from Wernicke’s area into a detailed and coordinated pattern for vocalization and then projects the pattern via a speech articulation area in the insula to the motor cortex, which initiates the appropriate movements of the lips, tongue, and larynx to produce speech. Th e probable sequence of events that occurs when a subject names a visual object is shown in Figure 15–8 . Th e angular CLINICAL BOX 15–5 Dyslexia Dyslexia , which is a broad term applied to impaired ability to read, is characterized by diffi culties with learning how to decode at the word level, to spell, and to read accurately and fl uently despite having a normal or even higher than normal level of intelligence. It is frequently due to an inherited abnormality that aff ects 5% of the population with a similar incidence in boys and girls. Dyslexia is the most common and prevalent of all known learning disabilities. It often coexists with attention defi cit disorder. Many individuals with dyslexic symptoms also have problems with short-term memory skills and problems processing spoken language. Although its precise cause is unknown, dyslexia is of neurological origin. Acquired dyslexias often occur due to brain damage in the left hemisphere’s key language areas. Also, in many cases, there is a decreased blood fl ow in the angular gyrus in the categorical hemisphere. There are numerous theories to explain the causes of dyslexia. The phonological hypothesis is that dyslexics have a specifi c impairment in the representation, storage, and/or retrieval of speech sounds. The rapid auditory processing theory proposes that the primary defi cit is the perception of short or rapidly varying sounds. The visual theory is that a defect in the magnocellular portion of the visual system slows processing and also leads to phonemic defi cit. More selective speech defects have also been described. For example, lesions limited to the left temporal pole cause inability to retrieve names of places and persons but preserves the ability to retrieve common nouns, that is, the names of nonunique objects. The ability to retrieve verbs and adjectives is also intact. THERAPEUTIC HIGHLIGHTS Treatments for children with dyslexia frequently rely on modifi ed teaching strategies that include the involvement of various senses (hearing, vision, and touch) to improve reading skills. The sooner the diagnosis is made and interventions are applied, the better the prognosis. CHAPTER 15 Learning, Memory, Language, & Speech 293 gyrus behind Wernicke’s area appears to process information from words that are read in such a way that they can be converted into the auditory forms of the words in Wernicke’s area. It is interesting that in individuals who learn a second language in adulthood, fMRI reveals that the portion of Broca’s area concerned with it is adjacent to but separate from the area concerned with the native language. However, in children who learn two languages early in life, only a single area is involved with both. It is well known, of course, that children acquire fl uency in a second language more easily than adults. LANGUAGE DISORDERS Aphasias are abnormalities of language functions that are not due to defects of vision or hearing or to motor paralysis. Th ey are caused by lesions in the categorical hemisphere (see Clinical Box 15–4 ). Th e most common cause is embolism or thrombosis of a cerebral blood vessel. Many diff erent classifi cations of the aphasias have been published, but a convenient classifi cation divides them into nonfl uent , fl uent , and anomic aphasias . In nonfl uent aphasia, the lesion is in Broca’s area. Speech is slow, and words are hard to come by. Patients with severe damage to this area are limited to two or three words with which to express the whole range of meaning and emotion. Sometimes the words retained are those that were being spoken at the time of the injury or vascular accident that caused the aphasia. In one form of fl uent aphasia, the lesion is in Wernicke’s area. In this condition, speech itself is normal and sometimes the patients talk excessively. However, what they say is full of jargon and neologisms that make little sense. Th e patient also fails to comprehend the meaning of spoken or written words, so other aspects of the use of language are compromised. Arcuate fasciculus Angular gyrus Wernicke’s area Broca’s area FIGURE 157 Location of some of the areas in the categorical hemisphere that are concerned with language functions. Wernicke’s area is in the posterior end of the superior temporal gyrus and is concerned with comprehension of auditory and visual information. It projects via the arcuate fasciculus to Broca’s area in the frontal lobe. Broca’s area processes information received from Wernicke’s area into a detailed and coordinated pattern for vocalization and then projects the pattern via a speech articulation area in the insula to the motor cortex, which initiates the appropriate movements of the lips, tongue, and larynx to produce speech. Wernicke’s area (area 22) Angular gyrus (area 39) Higher order visual cortical areas (area 18) Primary visual cortex (area 17) From lateral geniculate nucleus Arcuate fasciculus Facial area of motor cortex (area 4) Broca’s area Left Right 6 5 4 3 2 1 FIGURE 158 Path taken by impulses when a subject identifi es a visual object, projected on a horizontal section of the human brain. Information travels from the lateral geniculate nucleus in the thalamus to the primary visual cortex, to higher order visual critical areas, and to the angular gyrus. Information then travels from Wernicke’s area to Brocas’s area via the arcuate fasciculus. Broca’s area processes the information into a detailed and coordinated pattern for vocalization and then projects the pattern via a speech articulation area in the insula to the motor cortex, which initiates the appropriate movements of the lips, tongue, and larynx to produce speech. Another form of fl uent aphasia is a condition in which patients can speak relatively well and have good auditory comprehension but cannot put parts of words together or conjure up words. Th is is called conduction aphasia because it was thought to be due to lesions of the arcuate fasciculus connecting Wernicke’s and Broca’s areas. However, it now appears that it is due to lesions near the auditory cortex in the posterior perisylvian gyrus. When a lesion damages the angular gyrus in the categorical hemisphere without aff ecting Wernicke’s or Broca’s areas, there is no diffi culty with speech or the understanding of auditory information; instead there is trouble understanding written language or pictures, because visual information is not processed and transmitted to Wernicke’s area. Th e result is a condition called anomic aphasia. Th e isolated lesions that cause the selective defects described above occur in some patients, but brain destruction is oft en more general. Consequently, more than one form of aphasia is oft en present. Frequently, the aphasia is general (global) , involving both receptive and expressive functions. In this situation, speech is scant as well as nonfl uent. Writing is abnormal in all aphasias in which speech is abnormal, but the neural circuits involved are unknown. In addition, deaf subjects who develop a lesion in the categorical hemisphere lose their ability to communicate in sign language. 294 SECTION II Central and Peripheral Neurophysiology Stuttering has been found to be associated with right cerebral dominance and widespread overactivity in the cerebral cortex and cerebellum. Th is includes increased activity of the supplementary motor area. Stimulation of part of this area has been reported to produce laughter , with the duration and intensity of the laughter proportional to the intensity of the stimulus. RECOGNITION OF FACES An important part of the visual input goes to the inferior temporal lobe, where representations of objects, particularly faces, are stored ( Figure 15–9 ). Faces are particularly important in distinguishing friends from foes and the emotional state of those seen. In humans, storage and recognition of faces is more strongly represented in the right inferior temporal lobe in right-handed individuals, though the left lobe is also active. Damage to this area can cause prosopagnosia , the inability to recognize faces. Patients with this abnormality can recognize forms and reproduce them. Th ey can recognize people by their voices, and many of them show autonomic responses when they see familiar as opposed to unfamiliar faces. However, they cannot identify the familiar faces they see. Th e left hemisphere is also involved, but the role of the right hemisphere is primary. Th e presence of an autonomic response to a familiar face in the absence of recognition has been explained by postulating the existence of a separate dorsal pathway for processing information about faces that leads to recognition at only a subconscious level. LOCALIZATION OF OTHER FUNCTIONS Use of fMRI and PET scanning combined with study of patients with strokes and head injuries has provided further insight into the ways serial processing of sensory information Stores biographical information Extracts facial features Connects facial features to biographical information FIGURE 159 Areas in the right cerebral hemisphere, in right-handed individuals, that are concerned with recognition of faces. An important part of the visual input goes to the inferior temporal lobe, where representations of objects, particularly faces, are stored. In humans, storage and recognition of faces is more strongly represented in the right inferior temporal lobe in righthanded individuals, though the left lobe is also active. (Modifi ed from Szpir M: Accustomed to your face. Am Sci 1992;80:539.) produce cognition, reasoning, comprehension, and language. Analysis of the brain regions involved in arithmetic calculations has highlighted two areas. In the inferior portion of the left frontal lobe is an area concerned with number facts and exact calculations. Frontal lobe lesions can cause acalculia , a selective impairment of mathematical ability. Th ere are areas around the intraparietal sulci of both parietal lobes that are concerned with visuospatial representations of numbers and, presumably, fi nger counting. Two right-sided subcortical structures play a role in accurate navigation in humans. One is the right hippocampus, which is concerned with learning where places are located, and the other is the right caudate nucleus, which facilitates movement to the places. Men have larger brains than women and are said to have superior spatial skills and ability to navigate. Other defects seen in patients with localized cortical lesions include, for example, the inability to name animals, though the ability to name other living things and objects is intact. One patient with a left parietal lesion had diffi culty with the second half but not the fi rst half of words. Some patients with parietooccipital lesions write only with consonants and omit vowels. Th e pattern that emerges from studies of this type is one of precise sequential processing of information in localized brain areas. Additional research of this type should greatly expand our understanding of the functions of the neocortex. CHAPTER SUMMARY Memory ■ is divided into explicit (declarative) and implicit (nondeclarative). Explicit is further subdivided into semantic and episodic. Implicit is further subdivided into priming, procedural, associative learning, and nonassociative learning. ■ Declarative memory involves the hippocampus and the medial temporal lobe for retention. Priming is dependent on the neocortex. Procedural memory is processed in the striatum. Associative learning is dependent on the amygdala for its emotional responses and the cerebellum for the motor responses. Nonassociative learning is dependent on various refl ex pathways. ■ Synaptic plasticity is the ability of neural tissue to change as refl ected by LTP (an increased eff ectiveness of synaptic activity) or LTD (a reduced eff ectiveness of synaptic activity) aft er continued use. Habituation is a simple form of learning in which a neutral stimulus is repeated many times. Sensitization is the prolonged occurrence of augmented postsynaptic responses aft er a stimulus to which one has become habituated is paired once or several times with a noxious stimulus. ■ Alzheimer disease is characterized by progressive loss of shortterm memory followed by general loss of cognitive function. Th e cytopathologic hallmarks of Alzheimer disease are intracellular neurofi brillary tangles and extracellular senile plaques. ■ Categorical and representational hemispheres are for sequential-analytic processes and visuospatial relations, respectively. Lesions in the categorical hemisphere produce CHAPTER 15 Learning, Memory, Language, & Speech 295 language disorders, whereas lesions in the representational hemisphere produce astereognosis. Aphasias are abnormalities o ■ f language functions and are caused by lesions in the categorical hemisphere. Th ey are classifi ed as fl uent (Wernicke’s area), nonfl uent (Broca’s area), and anomic (angular gyrus) based on the location of brain lesions. MULTIPLECHOICE QUESTIONS For all questions, select the single best answer unless otherwise directed. 1. A 17-year-old male suff ered a traumatic brain injury as a result of a motor cycle accident. He was unconscious and was rushed to the emergency room of the local hospital. A CT scan was performed and appropriate interventions were taken. About 6 months later he still had memory defi cits. Which of the following is correctly paired to show the relationship between a brain area and a type of memory? A. Hippocampus and implicit memory B. Neocortex and associative learning C. Medial temporal lobe and declarative memory D. Angular gyrus and procedural memory E. Striatum and priming 2. Th e optic chiasm and corpus callosum are sectioned in a dog, and with the right eye covered, the animal is trained to bark when it sees a red square. Th e right eye is then uncovered and the left eye covered. Th e animal will now A. fail to respond to the red square because the square does not produce impulses that reach the right occipital cortex. B. fail to respond to the red square because the animal has bitemporal hemianopia. C. fail to respond to the red square if the posterior commissure is also sectioned. D. respond to the red square only aft er retraining. E. respond promptly to the red square in spite of the lack of input to the left occipital cortex. 3. A 32-year-old male had medial temporal lobe epilepsy for over 10 years. Th is caused bilateral loss of hippocampal function. As a result, this individual might be expected to experience a A. disappearance of remote memories. B. loss of working memory. C. loss of the ability to encode events of the recent past into long-term memory. D. loss of the ability to recall faces and forms but not the ability to recall printed or spoken words. E. production of inappropriate emotional responses when recalling events of the recent past. 4. A 70-year-old woman fell down a fl ight of stairs, hitting her head on the concrete sidewalk. Th e trauma caused a severe intracranial hemorrhage. Th e symptoms she might experience are dependent on the area of the brain most aff ected. Which of the following is incorrectly paired? A. Damage to the parietal lobe of the representational hemisphere : Unilateral inattention and neglect B. Loss of cholinergic neurons in the nucleus basalis of Meynert and related areas of the forebrain : Loss of recent memory C. Damage to the mammillary bodies : Loss of recent memory D. Damage to the angular gyrus in the categorical hemisphere : Nonfl uent aphasia E. Damage to Broca’s area in the categorical hemisphere : Slow speech 5. Th e representational hemisphere is better than the categorical hemisphere at A. language functions. B. recognition of objects by their form. C. understanding printed words. D. understanding spoken words. E. mathematical calculations. 6. A 67-year-old female suff ered a stroke that damaged the posterior end of the superior temporal gyrus . A lesion of Wernicke’s area in the categorical hemisphere causes her to A. lose her short-term memory. B. experience nonfl uent aphasia in which she speaks in a slow, halting voice. C. experience déjà vu. D. talk rapidly but make little sense, which is characteristic of fl uent aphasia. E. lose the ability to recognize faces, which is called prosopagnosia. 7. Which of the following is most likely not involved in production of LTP? A. NO B. Ca 2+ C. NMDA receptors D. Membrane hyperpolarization E. Membrane depolarization 8. An 79-year-old woman has been experiencing diffi culty fi nding her way back home aft er her morning walks. Her husband has also noted that she takes much longer to do routine chores around the home and oft en appears to be confused. He is hoping that this is just due to “old age” but fears it may be a sign of Alzheimer disease. Which of the following is the defi nitive sign of this disease? A. Loss of short-term memory. B. Th e presence of intracellular neurofi brillary tangles and extracellular neuritic plaques with a core of β-amyloid peptides. C. A mutation in genes for amyloid precursor protein (APP) on chromosome 21. D. Rapid reversal of symptoms with the use of acetylcholinesterase inhibitors. E. A loss of cholinergic neurons in the nucleus basalis of Meynert. CHAPTER RESOURCES Aimone JB, Wiles J, Gage FH: Computational infl uence of adult neurogenesis on memory encoding. Neuron 2009;61:187. Andersen P, Morris R, Amaral D, Bliss T, O’Keefe J: Th e Hippocampus Book. Oxford University Press, 2007. Bird CM, Burgess N: Th e hippocampus and memory: Insights from spatial processing. Nature Rev Neurosci 2008;9:182. Eichenbaum H: A cortical-hippocampal system for declarative memory. Nat Neurosci Rev 2000;1:41. 296 SECTION II Central and Peripheral Neurophysiology Goodglass H: Understanding Aphasia. Academic Press, 1993. Ingram VM: Alzheimer’s disease. Am Scientist 2003;91:312. Kandel ER: Th e molecular biology of memory: A dialogue between genes and synapses. Science 2001;294:1028. LaFerla FM, Green KN, Oddo S: Intracellular amyloid-β in Alzheimer’s disease. Nature Rev Neurosci 2007;8:499. Ramus F: Developmental dyslexia: Specifi c phonological defect or general sensorimotor dysfunction. Curr Opin Neurobiol 2003;13:212. Russ MD: Memories are made of this. Science 1998;281:1151. Selkoe DJ: Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 1999;399 (Suppl): A23. Shaywitz S: Dyslexia. N Engl J Med 1998;338:307. Squire LR, Stark CE, Clark RE: Th e medial temporal lobe. Annu Rev Neurosci 2004;27:279. Squire LR, Zola SM: Structure and function of declarative and nondeclarative memory systems. Proc Natl Acad Sci 1996;93:13515. S E C T ION I I I Endocrine and Reproductive Physiology The role of the endocrine system is to maintain whole body homeostasis. This is accomplished via the coordination of hormonal signaling pathways that regulate cellular activity in target organs throughout the body. Endocrine mechanisms are also concerned with the ability of humans to reproduce, and the sexual maturation required for this function. Classic endocrine glands are scattered throughout the body and secrete hormones into the circulatory system, usually via ductless secretion into the interstitial fl uid. Target organs express receptors that bind the specifi c hormone to initiate a cellular response. The endocrine system can be contrasted with the neural regulation of physiological function that was the focus of the previous section. Endocrine eff ectors typically provide “broadcast” regulation of multiple tissues and organs simultaneously, with specifi city provided for by the expression of relevant receptors. A change in environmental conditions, for example, often calls for an integrated response across many organ systems. Neural regulation, on the other hand, is often exquisitely spatially delimited, such as the ability to contract just a single muscle. Nevertheless, both systems must work collaboratively to allow for minuteto- minute as well as longer term stability of the body’s interior milieu. Hormones are the soluble messengers of the endocrine system and are classifi ed into steroids, peptides, and amines (see Chapters 1 and 2 ). Steroid hormones can cross the lipidcontaining plasma membrane of cells and usually bind to intracellular receptors. Peptide and amine hormones bind to cell surface receptors. Steroid hormones are produced by the adrenal cortex ( chapter 20 ), the gonads, testes ( chapter 23 ), and ovaries ( chapter 22 ) in addition to steroid hormones that are made by the placenta during pregnancy ( chapter 22 ). Amine hormones are derivatives of the amino acid tyrosine and are made by the thyroid ( chapter 19 ) and the adrenal medulla ( chapter 20 ). Interestingly, the tyrosinederived thyroid hormone behaves more like a steroid than a peptide hormone by binding to an intracellular receptor. The majority of hormones, however, are peptides and they are usually synthesized as preprohormones before being cleaved fi rst to prohormones in the endoplasmic reticulum and then to the active hormone in secretory vesicles. Diseases of the endocrine system are numerous. Indeed, endocrine and metabolic disorders are among the most common affl ictions in developed countries, particularly when nutrition and access to health care provisions are generous and high risk individuals are identifi ed by regular screening. At least 11 endocrine and metabolic disorders are present in 5% or more of the adult US population, including diabetes mellitus, osteopenia, dyslipidemia, metabolic syndrome, and thyroiditis. For example, type 2 diabetes mellitus is one of the most prevalent endocrine disorders of the 21st century and involves an inability of the body to respond to insulin. The resulting high blood glucose damages many tissues leading to secondary complications (see Chapter 24 ). In large part, the high and increasing prevalence of diabetes and other metabolic disorders rests on the substantial prevalence of obesity in developed countries, with as many as a third of the US adult population now considered to be obese, and two thirds overweight. Indeed, based on a 2009 report, obesity also aff ects 28% of US children aged 12–17, and while the current prevalence of type 2 diabetes in children is quite low, this prevalence is accordingly expected to rise. Further, a number of endocrine disorders are more prevalent in specifi c ethnic groups, or in a particular gender. Overall, the burden of endocrine and metabolic disorders, with their protean manifestations and complications, is a serious public health crisis and even highlights an apparent national shortage of trained endocrinologists. Many endocrine disorders must be managed by primary care physicians as a result. This page intentionally left blank 299 O B J E C T I V E S After studying this chapter, you should be able to: ■ Describe hormones and their contribution to whole body homeostatic mechanisms. ■ Understand the chemical nature of diff erent classes of hormones and how this determines their mechanism of action on target cells. ■ D efi ne how hormones are synthesized and secreted by cells of endocrine glands, including how peptide hormones are cleaved from longer precursors. ■ Explain the relevance of protein carriers in the blood for hydrophobic hormones, and the mechanisms that determine the level of free circulating hormones. ■ Understand the principles of feedback control for hormone release and its relevance for homeostasis. ■ Understand the principles governing disease states that result from over- or under-production of key hormones. Basic Concepts of Endocrine Regulation C H A P T E R 16 INTRODUCTION Th is section of the text deals with the various endocrine glands that control the function of multiple organ systems of the body. In general, endocrine physiology is concerned with the maintenance of various aspects of homeostasis. Th e mediators of such control mechanisms are soluble factors known as hormones. Th e word hormone was derived from the Greek horman, meaning to set in motion. In preparation for specifi c discussions of the various endocrine systems and their hormones, this chapter will address some concepts of endocrine regulation that are common among all systems. Another feature of endocrine physiology to keep in mind is that, unlike other physiological systems that are considered in this text, the endocrine system cannot be cleanly defi ned along anatomic lines. Rather, the endocrine system is a distributed system of glands and circulating messengers that is oft en stimulated by the central nervous system and/or autonomic nervous system. EVOLUTION OF HORMONES AND THEIR ACTIONS ON TARGET CELLS As noted in the introduction to this section, hormones comprise steroids, amines, and peptides. Peptide hormones are by far the most numerous. Many hormones can be grouped into families refl ecting their structural similarities as well as the similarities of the receptors they activate. However, the number of hormones and their diversity increases as one moves from simple to higher life forms, refl ecting the added challenges in providing for homeostasis in more complex organisms. For example, among the peptide hormones, several are heterodimers that share a common α chain, with specifi city being conferred by the β-chain. In the specifi c case of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), there is evidence that the distinctive β-chains arose from a series of duplications of a common ancestral gene. For these and other hormones, moreover, this molecular evolution implies that hormone receptors also needed to evolve to allow for spreading of hormone actions/specifi city. Th is was accomplished Ganong_Ch16_297-306.indd 299 1/4/12 1:01:52 PM 300 SECTION III Endocrine and Reproductive Physiology levels of circulating glucose stimulate the translation of insulin mRNA. Th ese eff ects are mediated by the ability of glucose to increase the interaction of the insulin mRNA with specifi c RNA binding proteins, which increase its stability and enhance its translation. Th e net eff ect is a more precise and timely regulation of insulin levels, and thus energy metabolism, than could be accomplished with transcriptional regulation alone. Th e precursors for peptide hormones are processed through the cellular machinery that handles proteins destined for export, including traffi cking through specifi c vesicles where the propeptide form can be cleaved to the fi nal active hormones. Mature hormones are also subjected to a variety of posttranslational processing steps, such as glycosylation, which can infl uence their ultimate biological activity and/or stability in the circulation. Ultimately, all hormones enter either the constitutive or regulated secretory pathway (see Chapter 2 ). SECRETION Th e secretion of many hormones is via a process of exocytosis of stored granules, as discussed in Chapter 2 . Th e exocytotic machinery is activated when the cell type that synthesizes and stores the hormone in question is activated by a specifi c signal, such as a neurotransmitter or peptide releasing factor. One should, however, contrast the secretion of stored hormones with that of those that are continually released by diff usion (eg, steroids). Control of the secretion of the latter molecules occurs via kinetic infl uences on the synthetic enzymes or carrier proteins involved in hormone production. For example, the steroidogenic acute regulatory protein (StAR) is a labile protein whose expression, activation, and deactivation are regulated by intracellular signaling cascades and their eff ectors, including a variety of protein kinases and phosphatases. StAR traffi cs cholesterol from the outer to the inner membrane leafl et of the mitochondrion. Because this is a rate-limiting fi rst step in the synthesis of the steroid precursor, pregnenolone, this arrangement permits changes in the rate of steroid synthesis, and thus secretion, in response to homeostatic cues such as trophic hormones, cytokines and stress ( Figure 16–1 ). An additional complexity related to hormone secretion relates to the fact that some hormones are secreted in a pulsatile fashion. Secretion rates may peak and ebb relative to circadian rhythms, in response to the timing of meals, or as regulated by other pattern generators whose periodicity may range from milliseconds to years. Pulsatile secretion is oft en related to the activity of oscillators in the hypothalamus that regulate the membrane potential of neurons, in turn secreting bursts of hormone releasing factors into the hypophysial blood fl ow that then cause the release of pituitary and other downstream hormones in a similar pulsatile fashion (see Chapters 17 and 18 ). Th ere is evidence that these hormone pulses convey diff erent information to the target tissues that they act upon than steady exposure to a single concentration of the hormone. Th erapeutically, pulsatile secretion may pose challenges if, due to defi ciency, it proves necessary to replace a particular hormone that is normally secreted in this way. by co-evolution of the basic G-protein coupled receptors (GPCR) and receptor tyrosine kinases that mediate the eff ects of peptide and amine hormones that act at the cell surface (see Chapter 2 ). Th e underlying ancestral relationships sometimes re-emerge, however, in the cross-reactivity that may be seen when hormones rise to unusually high levels (eg, endocrine tumors). Steroids and thyroid hormones are distinguished by their predominantly intracellular sites of action, since they can diffuse freely through the cell membrane. Th ey bind to a family of largely cytoplasmic proteins known as nuclear receptors. Upon ligand binding, the receptor–ligand complex translocates to the nucleus where it either homodimerizes, or associates with a distinct liganded nuclear receptor to form a heterodimer. In either case, the dimer binds to DNA to either increase or decrease gene transcription in the target tissue. Individual members of the nuclear receptor family have a considerable degree of homology, perhaps implying a common ancestral gene, and share many functional domains, such as the zinc fi ngers that permit DNA binding. However, sequence variations allow for ligand specifi city as well as binding to specifi c DNA motifs. In this way, the transcription of distinct genes is regulated by individual hormones. HORMONE SECRETION SYNTHESIS AND PROCESSING Th e regulation of hormone synthesis, of course, depends on their chemical nature. For peptide hormones as well as hormone receptors, synthesis is controlled predominantly at the level of transcription. For amine and steroid hormones, synthesis is controlled indirectly by regulating the production of key synthetic enzymes, as well as by substrate availability. Interestingly, the majority of peptide hormones are synthesized initially as much larger polypeptide chains, and then processed intracellularly by specifi c proteases to yield the fi nal hormone molecule. In some cases, multiple hormones may be derived from the same initial precursor, depending on the specifi c processing steps present in a given cell type. Presumably this provides for a level of genetic “economy.” It is also notable that the hormone precursors themselves are typically inactive. Th is may be a mechanism that provides for an additional measure of regulatory control, or, in the case of thyroid hormones, may dictate the site of highest hormone availability. Th e synthesis of all of the proteins/peptides discussed above is subject to the normal mechanisms of transcriptional control in the cell (see Chapter 2 ). In addition, there is provision for exquisitely specifi c regulation by other hormones, since the regulatory regions of many peptide hormone genes contain binding motifs for the nuclear receptors discussed above. For example, thyroid hormone directly suppresses TSH expression via the thyroid hormone receptor. Th ese specifi c mechanisms to regulate hormone transcription are essential to the function of feedback loops, as will be addressed in greater detail below. In some cases, the abundance of selected hormones may also be regulated via eff ects on translation. For example, elevated CHAPTER 16 Basic Concepts of Endocrine Regulation 301 HORMONE TRANSPORT IN THE BLOOD In addition to the rate of secretion and its nature (steady vs. pulsatile), a number of factors infl uence the circulating levels of hormones. Th ese include the rates of hormone degradation and/or uptake, receptor binding and availability of receptors, and the affi nity of a given hormone for plasma carriers ( Figure 16–2 ). Stability infl uences the circulating half-life of a given hormone and has therapeutic implications for hormone replacement therapy, in addition to those posed by pulsatile secretion as discussed above. Plasma carriers for specifi c hormones have a number of important physiological functions. First, they serve as a reservoir of inactive hormone and thus provide a hormonal reserve. Bound hormones are typically prevented from degradation or uptake. Th us, the bound hormone reservoir can allow fl uctuations in hormonal levels to be smoothed over time. Plasma carriers also restrict the access of the hormone to some sites. Ultimately, plasma carriers may be vital in modulating levels of the free hormone in question. Typically, it is only the free hormone that is biologically active in target tissues or can mediate feedback regulation (see below) since it is the only form able to access the extravascular compartment. Catecholamine and most peptide hormones are soluble in plasma and are transported as such. In contrast steroid Bound (inactive) hormone Plasma carrier Receptor Free (active) hormone Synthesis Secretion Degradation Uptake FIGURE 162 Summary of factors that determine the level of free hormones circulating in the bloodstream. Factors that increase (green upward arrow) or decrease (red downward arrow) hormone levels are shown. Free hormones also equilibrate with the forms bound to either receptors or plasma carrier proteins. Hormones, growth factors, cytokines Cholesterol Pregnenolone Steroids Kinases Transcription factors StAR Cell membrane Mitochondria Nucleus P FIGURE 161 Regulation of steroid biosynthesis by the steroidogenic acute regulatory protein (StAR). Extracellular signals activate intracellular kinases that, in turn, phosphorylate transcription factors that upregulate StAR expression. StAR is activated by phosphorylation, and facilitates transfer of cholesterol from the outer to inner mitochondrial membrane leafl et. This then allows entry of cholesterol into the steroid biosynthetic pathway, beginning with pregnenolone. 302 SECTION III Endocrine and Reproductive Physiology through the pulmonary circulation or the liver. Th is may markedly curtail the temporal window within which a given hormone can act. HORMONE ACTION As we will see in later chapters, hormones exert a wide range of distinctive actions on a huge number of target cells to eff ect changes in metabolism, release of other hormones and regulatory substances, changes in ion channel activity, and cell growth, among others ( Clinical Box 16–1 ). Ultimately, the concerted action of the hormones of the body ensures the maintenance of homeostasis. Indeed, all hormones aff ect homeostasis to some degree. However, a subset of the hormones, as detailed in Table 16–1 , are the key contributors to homeostasis. Th ese include thyroid hormone, cortisol, parathyroid hormone, vasopressin, the mineralocorticoids, and insulin. Detailed information on the precise biological eff ects of these molecules can be found in subsequent chapters. Hydrophilic hormones, including peptides and catecholamines, exert their acute eff ects by binding to cell surface receptors. Most of these are from the GPCR family. Hydrophobic hormones, in the other hand, predominantly exert their actions via nuclear receptors. Th ere are two classes of nuclear receptors that are important in endocrine physiology. Th e fi rst of these provide for direct stimulation of transcription via induction of the binding of a transcriptional co-activator when the hormonal ligand is bound. In the second class, hormone binding triggers simultaneous dislodging of a transcriptional co-repressor and recruitment of a co-activator. Th e latter class of receptor allows for a wider dynamic range of regulation of the genes targeted by the hormone in question. hormones are hydrophobic and are mostly bound to large proteins called steroid binding proteins (SBP), which are synthesized in the liver. As a result, only small amounts of the free hormone are dissolved in the plasma. Specifi cally, sex hormone-binding globulin (SHBG) is a glycoprotein that binds to the sex hormones, testosterone and 17β-estradiol. Progesterone, cortisol, and other corticosteroids are bound by transcortin. Th e SBP-hormone complex and the free hormone are in equilibrium in the plasma, and only the free hormone is able to diff use across cell membranes. SBP have three main functions: they increase the solubility of lipid based hormones in the blood, they reduce the rate of hormone loss in the urine by preventing the hormones from being fi ltered in the kidney, and as mentioned above, they provide a source of hormone in the bloodstream that can release free hormone as the equilibrium changes. It follows that an additional way to regulate the availability of hormones that bind to carrier proteins, such as steroids, is to regulate the expression and secretion of the carrier proteins themselves. Th is is a critical mechanism that regulates the bioavailability of thyroid hormones, for example (see Chapter 19 ). In a pathophysiological setting, some medications can alter levels of binding proteins or displace hormones that are bound to them. In addition, some binding proteins are promiscuous and bind multiple hormones (eg, SHBG). Th ese observations may have clinical implications for endocrine homeostasis, since free hormones are needed to feedback and control their rates of synthesis and secretion (see below). Finally, the anatomic relationship of sites of release and action of hormones may play a key role in their regulation. For example, a number of hormones are destroyed by passage CLINICAL BOX 16–1 Breast Cancer Breast cancer is the most common malignancy of women, with about 1 million new cases diagnosed each year worldwide. The proliferation of more than two-thirds of breast tumors are driven by the ovarian hormone, estrogen, by virtue of the fact that the tumor cells express high levels of posttranslationally modifi ed estrogen receptors (ER). The clinical signifi - cance of these molecular fi ndings has been known for more than 100 years, since the Scottish surgeon, Sir Thomas Beatson, reported delayed disease progression in patients with advanced breast cancer following removal of their ovaries. In modern times, determination of whether a given breast cancer is, or is not, ER-positive is a critical diagnostic test that guides treatment decisions, as well as an important prognosticator. ER-positive tumors are typically of lower grade, and patients with such tumors have improved survival (although the latter is likely due, at least in part, to the availability of excellent treatment options for ER-positive tumors compared with those that are ER-negative—see below). THERAPEUTIC HIGHLIGHTS Estrogen-responsive breast tumors are dependent on the presence of the hormone for growth. In modern times, cells can be deprived of the eff ects of estrogen pharmacologically, rather than resorting to oophorectomy. Tamoxifen and related agents specifi cally inhibit the receptor and may also hasten its degradation. In postmenopausal women, where estrogen is derived from the metabolism of testosterone in extragonadal tissues rather than from the ovaries, aromatase inhibitors inhibit the conversion of androgens to estrogen, and thereby deprive tumor cells of their critical signal for continued proliferation. CHAPTER 16 Basic Concepts of Endocrine Regulation 303 In recent years, it has become apparent that a number of receptors for steroid and other hydrophobic hormones are extranuclear, and some may even be present on the cell surface. Th e characterization of such receptors at a molecular level, their associated signaling pathways, and indeed proof of their existence has been complicated by the ability of hydrophobic hormones to diff use relatively freely into all cellular compartments. Th ese extranuclear receptors, some of which may be structurally related or even identical to the more classical nuclear receptors, are proposed to mediate rapid responses to steroids and other hormones that do not require alterations in gene transcription. Th e physiological eff ects at these receptors may therefore be distinct from those classically associated with a given hormone. Evidence is accumulating, for example, that plasma membrane receptors for estrogen can mediate acute arterial vasodilation as well as reducing cardiac hypertrophy in pathophysiological settings. Functions such as these may account for diff erences in the prevalence of cardiovascular disease in pre and postmenopausal women. In any event, this active area of biomedical investigation is likely to broaden our horizons of the full spectrum of action of steroid hormones. PRINCIPLES OF FEEDBACK CONTROL A fi nal general principle that is critical for endocrine physiology is that of feedback regulation. Th is holds that the responsiveness of target cells to hormonal action subsequently “feeds back” to control the inciting endocrine organ. Feedback can regulate the further release of the hormone in either a negative feedback or (more rarely) a positive feedback loop. Positive feedback relates to the enhancement or continued stimulation TABLE 161 Major hormonal contributors to homeostasis. Hormone Source Action Thyroid hormone Thyroid Controls basal metabolism in most tissues Cortisol Adrenal cortex Energy metabolism; permissive action for other hormones Mineralocorticoids Adrenal cortex Regulate plasma volume via eff ects on serum electrolytes Vasopressin Posterior pituitary Regulates plasma osmolality via eff ects on water excretion Parathyroid hormone Parathyroids Regulates calcium and phosphorus levels Insulin Pancreas Regulates plasma glucose concentration + + Adrenal Gonads Thyroid Hypothalamus CNS Releasing factors Pituitary Trophic hormones Target hormone feedback inhibition FIGURE 163 Summary of feedback loops regulating endocrine axes. CNS, central nervous system. (Reproduced with permission from Jameson JL (editor): Harrison’s Endocrinology 2nd ed. McGraw Hill, 2010. ) of the original release mechanism/stimulus. Such mechanisms are really only seen in settings that need to gather momentum to an eventual outcome, such as parturition. Negative feedback is a far more common control mechanism and involves the inhibition or dampening of the initial hormone release mechanism/stimulus. A general scheme for feedback inhibition of endocrine axes is depicted in Figure 16–3 . In general, the endocrine system uses a network of feedback responses to maintain a steady state. Steady state can be explained using blood osmolality as an example ( Figure 16–4 ). Blood osmolality in humans must be maintained within a physiological range of 275–299 mOsm, and to maintain homeostasis this variable should not exceed that range. To ensure that osmolality does not change in the context of an open system, processes are in place that will add or remove water from the system to ensure a constant osmolality. Th e osmolality of blood will increase with dehydration and decrease with overhydration. If blood osmolality increases outside the ideal range (by 10 mOsm or more), osmoreceptors are activated. Th ese signal release of the peptide hormone, vasopressin, into the circulation (from the pituitary). Vasopressin acts on the renal collecting duct, and increases the permeability of the plasma membrane to water via the insertion of a protein called an aquaporin. Water is then moved from the urine into the circulation via transcellular transport. Th e reabsorption of water from the 304 SECTION III Endocrine and Reproductive Physiology water reabsorption from the urine is reduced. Further details of this collaboration between the kidneys, hypothalamus and pituitary are found in Chapter 38 . Negative feedback control systems such as those described are the most common feedback/homeostatic systems in the body. Other examples include temperature regulation (see Chapter 17 ) and the regulation of blood glucose concentrations (see Chapter 24 ). Feedback control loops also provide for diagnostic strategies in evaluating patients with suspected endocrine disorders. For example, in a patient being evaluated for hypothyroidism, normal levels of TSH (see Chapter 19 ) tend to rule out a primary defect at the level of the thyroid gland itself, and rather suggest that a defect at the level of the anterior pituitary should be sought. Conversely, if TSH is elevated, it suggests that the normal ability of circulating thyroid hormone to suppress TSH synthesis has been lost, likely due to a reduction in the ability of the thyroid gland to synthesize the hormone ( Clinical Box 16–2 ). TYPES OF ENDOCRINE DISORDERS It is pertinent also to discuss briefl y the types of disease states where endocrine physiology can become deranged. Additional details of these disease states can be found in ensuing chapters. HORMONE DEFICIENCY Defi ciencies of particular hormones are most commonly seen in the setting where there is destruction of the glandular structure responsible for their production, oft en as a result of urine to the blood resets the osmolality of the blood to within the physiological range. Th e decrease in blood osmolality then exerts a negative feedback on the cells of the hypothalamus and the pituitary and vasopressin release is inhibited, meaning that CLINICAL BOX 16–2 Approach to the Patient with Suspected Endocrine Disease Unlike many of the disorders of individual organ systems considered elsewhere in this volume, the symptoms of endocrine disease may be protean because of the number of body systems that are impacted by hormonal action. Further, many endocrine glands are relatively inaccessible to direct physical examination. Endocrine disorders must therefore be diagnosed on the basis of the symptoms they produce in concert with appropriate biochemical testing. Radioimmunoassays for specifi c hormones remain the mainstay of diagnostic endocrinolology and can be used to establish steady state concentrations as well as dynamic changes of the hormone in question (the latter requiring repeated blood sampling over time). In addition, the principles of feedback regulation of hormone synthesis and release may allow the physician to pinpoint the likely locus of any defect by comparing the levels of hormones in the same axis. For example, if testosterone levels are low but those of luteinizing hormone (LH) are high, this suggests that the testes are unable to respond to LH. Conversely, if both testosterone and LH are low, the problem is more likely to be at the level of the pituitary. Synthetic hormones can also be administered exogenously to test whether increased basal levels of a given hormone can be suppressed, or abnormally low levels can be stimulated by a relevant upstream agent. An example of applying this type of reasoning to the evaluation of suspected hypothyroidism is provided in Figure 16–5 . THERAPEUTIC HIGHLIGHTS The appropriate treatment of endocrine disorders depends on their underlying basis. For example, if a particular hormone or its releasing factor is defi cient, hormone replacement therapy is often indicated to ameliorate symptoms as well as long-term negative outcomes ( Figure 16–5). Increase in blood osmolality Stimulates osmoreceptors in hypothalamus Activates thirst center in hypothalmus Increases thirst Increases H2O intake Increase in circulating vasopressin Increases permeability of collecting duct H2O reabsorption increases from urine Decrease in blood osmolality FIGURE 164 Feedback loop that ensures homeostasis of blood osmolality. An increase in blood osmolality triggers the thirst mechanism as well as renal conservation of water via the release of vasopressin from the hypothalamus. Both outcomes decrease blood osmolality back towards the normal range, which feeds back to terminate hypothalamic signaling. CHAPTER 16 Basic Concepts of Endocrine Regulation 305 Measure unbound T4 Mild Measure unbound T4 hypothyroidism Measure TSH Elevated Normal Normal Primary hypothyroidism Low Autoimmune hypothyroidism Rule out other causes of hypothyroidism T4 treatment TPOAb or symptomatic TPOAb, no symptoms Annual follow-up T4 treatment TPOAb TPOAb Pituitary disease suspected? No further tests Normal Yes Rule out drug effects, sick euthyroid syndrome, then evaluate anterior pituitary function No further tests No Low Evaluation of Hypothyroidism inappropriate autoimmune attack. For example, in type 1 diabetes mellitus, pancreatic β cells are destroyed leading to an inability to synthesize insulin, oft en from a very young age. Similarly, hormonal defi ciencies arise when there are inherited mutations in the factors responsible for their release or in the receptors for these releasing factors. Defects in the enzymatic machinery needed for hormone production, or a lack of appropriate precursors (eg, iodine defi ciency leads to hypothyroidism) will also reduce the amount of the relevant hormone available for bodily requirements. HORMONE RESISTANCE Many of the consequences of hormone defi ciency can by reproduced in disease states where adequate levels of a given hormone are synthesized and released, but the target tissues become resistant to the hormone’s eff ects. Indeed, there is oft en overproduction of the implicated hormone in these conditions because the feedback loops that normally serve to shut off hormone synthesis and/or secretion are similarly desensitized. Mutations in hormone receptors (especially nuclear receptors) may result in heritable syndromes of hormone resistance. Th ese syndromes, while relatively rare, usually exhibit severe outcomes, and have provided insights into the basic cell biology of hormone signaling. Functional hormone resistance that develops over time is also seen. Resistance arises from a relative failure of receptor signaling to couple effi ciently to downstream intracellular eff ector pathways that normally mediate the eff ects of the hormone. Th e most common example of this is seen in type 2 diabetes mellitus. Target tissues for insulin gradually become more and more resistant to its actions, secondary to reduced activation of phosphatidylinositol 3-kinase and other intracellular signaling pathways. A key factor precipitating this outcome is obesity. In addition, because of excessive insulin secretion, pancreatic β cells become “exhausted” and may eventually fail, necessitating treatment with exogenous insulin. An important therapeutic goal, therefore, is to minimize progression to β cell exhaustion before irreversible insulin resistance sets in, with diet, exercise, and treatment with so-called insulin sensitizers (such as metformin and rosiglitazone). HORMONE EXCESS Th e converse of disorders of hormone defi ciency or resistance is seen in diseases associated with hormone excess and/ or over-stimulation of hormone receptors. A wide variety of endocrine tumors may produce hormones in an excessive and uncontrolled fashion. Note that the secretion of hormones from tumor cells may not be subject to the same types of feedback regulation that are seen for the normal source of that hormone. In the setting of an endocrine tumor, exaggerated eff ects of the hormone are seen. For example, acromegaly, or gigantism, occurs in patients affl icted with an adenoma derived from pituitary somatotropes that secretes excessive quantities of growth hormone (see Chapter 18 ). In addition, other endocrine tumors may secrete hormones other than those characteristic of the cell type or tissue from which they are originally derived. When hormone production is increased FIGURE 165 Summary of a strategy for the laboratory evaluation of hypothyroidism. TSH, thyroid stimulating hormone; T 4 , thyroid hormone; TPOAb + , positive for autoantibodies to thyroid peroxidase; TPOAb – , antiperoxidase antibodies not present. (Reproduced with permission from Jameson JL (editor): Harrison’s Endocrinology 2nd ed. McGraw Hill, 2010. ) 306 SECTION III Endocrine and Reproductive Physiology uptake. Free hydrophobic hormones are also in equilibrium with a form bound to plasma protein carriers, the latter representing a hormone reservoir as well as an additional mechanism to regulate hormone availability. Th e synthesis and r ■ elease of many hormones is subject to regulation by negative feedback loops. ■ Disease states can arise in the setting of both hormone defi ciency and excess. Hormone defi ciencies may be mimicked by inherited defects in their receptors or downstream signaling pathways; hormone excess may be mimicked by autoantibodies that bind to and activate hormone receptors, or by activating mutations of these receptors. CHAPTER RESOURCES Jameson JL (editor): Harrison’s Endocrinology, 2nd ed. McGraw Hill, 2010. Lee EK, Gorospe M: Minireview: Posttranslational regulation of the insulin and insulin-like growth factor systems. Endocrinol 2010;151:1403. Levin ER: Minireview: Extranuclear steroid receptors: Roles in modulation of cell functions. Mol Endocrinol 2011;25:377. Manna PR, Stocco DM: Th e role of specifi c mitogen-activated protein kinase signaling cascades in the regulation of steroidogenesis. J Signal Transduct 2011. Article ID 821615; 13 pp. Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P: Clinical course of genetic diseases of the insulin receptor (Type A and Rabson-Mendenhall syndromes). A 30-year perspective. Medicine 2004;83:209. Walker JJ, Terry JR, Tsaneva-Atanasova K, Armstrong SP, McArdle CA, Lightman SL: Encoding and decoding mechanisms of pulsatile hormone secretion. J Neuroendocrinol 2010;22:1226. in all of these cases, there usually will also be downregulation of upstream releasing factors due to the triggering of negative feedback loops. Disorders of hormone excess can also be mimicked by antibodies that bind to, and activate, the receptor for the hormone. A classic example of such a condition is Graves’ disease, where susceptible individuals generate thyroid-stimulating immunoglobulins (TSIs) that bind to the receptor for TSH. Th is causes a conformational change that elicits receptor activation, and thus secretion of thyroid hormone in the absence of a physiological trigger for this event. Diseases associated with hormone excess can also occur in a heritable fashion secondary to activating mutations of hormone releasing factor receptors or their downstream targets. As seen for endocrine tumors, these pathophysiological triggers of excessive hormone release are of course not subject to dampening by negative feedback loops. CHAPTER SUMMARY ■ Th e endocrine system consists of a distributed set of glands and the chemical messengers that they produce, referred to as hormones. Hormones play a critical role in ensuring the relative stability of body systems, that is homeostasis. ■ Hormones can be grouped into peptide/protein, amine, and steroid categories. Water-soluble hormones (peptides and catecholamines) bind to cell surface receptors; hydrophobic hormones diff use into the cell and activate nuclear receptors to regulate gene transcription. Th e receptors and hormones appear to have evolved in parallel. ■ Hormone availability is dictated by the rate of synthesis, the presence of releasing factors, and rates of degradation or 307 O B J E C T I V E S After reading this chapter you should be able to: ■ Describe the anatomic connections between the hypothalamus and the pituitary gland and the functional signifi cance of each connection. ■ List the factors that control water intake, and outline the way in which they exert their eff ects. ■ Describe the synthesis, processing, storage, and secretion of the hormones of the posterior pituitary. ■ Discuss the eff ects of vasopressin, the receptors on which it acts, and how its secretion is regulated. ■ Discuss the eff ects of oxytocin, the receptors on which it acts, and how its secretion is regulated. ■ Name the hypophysiotropic hormones, and outline the eff ects that each has an anterior pituitary function. ■ List the mechanisms by which heat is produced in and lost from the body, and comment on the diff erences in temperature in the hypothalamus, rectum, oral cavity, and skin. ■ List the temperature-regulating mechanisms, and describe the way in which they are integrated under hypothalamic control to maintain normal body temperature. ■ Discuss the pathophysiology of fever. hypothalamus also functions with the limbic system as a unit that regulates emotional and instinctual behavior. C H A P T E R Hypothalamic Regulation of Hormonal Functions 17 INTRODUCTION Many of the complex autonomic mechanisms that maintain the chemical constancy and temperature of the internal environment are integrated in the hypothalamus. Th e HYPOTHALAMUS: ANATOMIC CONSIDERATIONS Th e hypothalamus ( Figure 17–1 ) is the portion of the anterior end of the diencephalon that lies below the hypothalamic sulcus and in front of the interpeduncular nuclei. It is divided into a variety of nuclei and nuclear areas. AFFERENT & EFFERENT CONNECTIONS OF THE HYPOTHALAMUS Th e principal aff erent and eff erent neural pathways to and from the hypothalamus are mostly unmyelinated. Many connect the hypothalamus to the limbic system. Important connections Ganong_Ch17_307-322.indd 307 1/4/12 1:03:00 PM 308 SECTION III Endocrine and Reproductive Physiology also exist between the hypothalamus and nuclei in the midbrain tegmentum, pons, and hindbrain. Norepinephrine-secreting neurons with their cell bodies in the hindbrain end in many diff erent parts of the hypothalamus (see Figure 7–2). Paraventricular neurons that secrete oxytocin and vasopressin project in turn to the hindbrain and the spinal cord. Neurons that secrete epinephrine have their cell bodies in the hindbrain and end in the ventral hypothalamus. An intrahypothalamic system is comprised of dopaminesecreting neurons that have their cell bodies in the arcuate nucleus and end on or near the capillaries that form the portal vessels in the median eminence. Serotonin-secreting neurons project to the hypothalamus from the raphe nuclei. RELATION TO THE PITUITARY GLAND Th ere are neural connections between the hypothalamus and the posterior lobe of the pituitary gland and vascular connections between the hypothalamus and the anterior lobe. Embryologically, the posterior pituitary arises as an evagination of the fl oor of the third ventricle. It is made up in large part of the endings of axons that arise from cell bodies in the supraoptic and paraventricular nuclei and pass to the posterior pituitary ( Figure 17–2 ) via the hypothalamohypophysial tract. Most of the supraoptic fi bers end in the posterior lobe itself, whereas some of the paraventricular fi bers end in the median eminence. Th e anterior and intermediate lobes of the pituitary arise in the embryo from the Rathke pouch, an evagination from the roof of the pharynx (see Figure 18–1). Sympathetic nerve fi bers Dorsal hypothalamic area Paraventricular nucleus Anterior hypothalamic area Preoptic area Supraoptic nucleus Suprachiasmatic nucleus Arcuate nucleus Optic chiasm Median eminence Superior hypophysial artery Portal hypophysial vessel Anterior lobe Pituitary gland Posterior lobe Primary plexus Posterior hypothalamic nucleus Dorsomedial nucleus Ventromedial nucleus Premamillary nucleus Medial mamillary nucleus Lateral mamillary nucleus Mamillary body FIGURE 171 Human hypothalamus, with a superimposed diagrammatic representation of the portal hypophysial vessels. MB OC PL Supraoptic and paraventricular nuclei Arcuate and other nuclei AL Anterior pituitary hormones Posterior pituitary hormones FIGURE 172 Secretion of hypothalamic hormones. The hormones of the posterior lobe (PL) are released into the general circulation from the endings of supraoptic and paraventricular neurons, whereas hypophysiotropic hormones are secreted into the portal hypophysial circulation from the endings of arcuate and other hypothalamic neurons. AL, anterior lobe; MB, mamillary bodies; OC, optic chiasm. CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 309 reach the anterior lobe from its capsule, and parasympathetic fi bers reach it from the petrosal nerves, but few if any nerve fi bers pass to it from the hypothalamus. However, the portal hypophysial vessels form a direct vascular link between the hypothalamus and the anterior pituitary. Arterial twigs from the carotid arteries and circle of Willis form a network of fenestrated capillaries called the primary plexus on the ventral surface of the hypothalamus ( Figure 17–1 ). Capillary loops also penetrate the median eminence. Th e capillaries drain into the sinusoidal portal hypophysial vessels that carry blood down the pituitary stalk to the capillaries of the anterior pituitary. Th is system begins and ends in capillaries without going through the heart and is therefore a true portal system. In birds and some mammals, including humans, there is no other anterior hypophysial arterial supply other than capsular vessels and anastomotic connections from the capillaries of the posterior pituitary. Th e median eminence is generally defi ned as the portion of the ventral hypothalamus from which the portal vessels arise. Th is region is outside the blood–brain barrier (see Chapter 33 ). HYPOTHALAMIC FUNCTION Th e major functions of the hypothalamus are summarized in Table 17–1 . Some are fairly clear-cut visceral refl exes, and others include complex behavioral and emotional reactions; however, all involve a particular response to a particular stimulus. It is important to keep this in mind in considering hypothalamic function. RELATION TO AUTONOMIC FUNCTION Many years ago, Sherrington called the hypothalamus “the head ganglion of the autonomic system.” Stimulation of the hypothalamus produces autonomic responses, but the hypothalamus does not seem to be concerned with the regulation of visceral function per se. Rather, the autonomic responses triggered in the hypothalamus are part of more complex TABLE 171 Summary of principal hypothalamic regulatory mechanisms. Function Afferents from Integrating Areas Temperature regulation Temperature receptors in the skin, deep tissues, spinal cord, hypothalamus, and other parts of the brain Anterior hypothalamus, response to heat; posterior hypothalamus, response to cold Neuroendocrine control of: Catecholamines Vasopressin Oxytocin Thyroid-stimulating hormone (thyrotropin, TSH) via TRH Adrenocorticotropic hormone (ACTH) and β-lipotropin (β-LPH) via CRH Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via GnRH Prolactin via PIH and PRH Growth hormone via somatostatin and GRH Limbic areas concerned with emotion Osmoreceptors, “volume receptors,” others Touch receptors in breast, uterus, genitalia Temperature receptors in infants, perhaps others Limbic system (emotional stimuli); reticular formation (“systemic” stimuli); hypothalamic and anterior pituitary cells sensitive to circulating blood cortisol level; suprachiasmatic nuclei (diurnal rhythm) Hypothalamic cells sensitive to estrogens, eyes, touch receptors in skin and genitalia of refl ex ovulating species Touch receptors in breasts, other unknown receptors Unknown receptors Dorsal and posterior hypothalamus Supraoptic and paraventricular nuclei Supraoptic and paraventricular nuclei Paraventricular nuclei and neighboring areas Paraventricular nuclei Preoptic area; other areas Arcuate nucleus; other areas (hypothalamus inhibits secretion) Periventricular nucleus, arcuate nucleus “ Appetitive” behavior: Thirst Hunger Sexual behavior Osmoreceptors, probably located in the organum vasculosum of the lamina terminalis; angiotensin II uptake in the subfornical organ Glucostat cells sensitive to rate of glucose utilization; leptin receptors; receptors for other polypeptides Cells sensitive to circulating estrogen and androgen, others Lateral superior hypothalamus Ventromedial, arcuate, and paraventricular nuclei; lateral hypothalamus Anterior ventral hypothalamus plus, in the male, piriform cortex Defensive reactions (fear, rage) Sense organs and neocortex, paths unknown Diff use, in limbic system and hypothalamus Control of body rhythms Retina via retinohypothalamic fi bers Suprachiasmatic nuclei 310 SECTION III Endocrine and Reproductive Physiology phenomena such as eating, and emotions such as rage. For example, stimulation of various parts of the hypothalamus, especially the lateral areas, produces diff use sympathetic discharge and increased adrenal medullary secretion—the mass sympathetic discharge seen in animals exposed to stress (the fl ight or fi ght reaction; see Chapter 13 ). It has been claimed that separate hypothalamic areas control epinephrine and norepinephrine secretion. Diff erential secretion of one or the other of these adrenal medullary catecholamines does occur in certain situations (see Chapter 20 ), but the selective increases are small. Body weight depends on the balance between caloric intake and utilization of calories. Obesity results when the former exceeds the latter. Th e hypothalamus and related parts of the brain play a key role in the regulation of food intake. Obesity is considered in detail in Chapter 26 , and the relation of obesity to diabetes mellitus is discussed in Chapter 24 . Hypothalamic regulation of sleep and circadian rhythms are discussed in Chapter 14 . THIRST Another appetitive mechanism under hypothalamic control is thirst. Drinking is regulated by plasma osmolality and extracellular fl uid (ECF) volume in much the same fashion as vasopressin secretion (see Chapter 38 ). Water intake is increased by increased eff ective osmotic pressure of the plasma ( Figure 17–3 ), by decreases in ECF volume, and by psychologic and other factors. Osmolality acts via osmoreceptors, receptors that sense the osmolality of the body fl uids. Th ese osmoreceptors are located in the anterior hypothalamus. Hypertonicity Osmoreceptors Hypovolemia Hypothalamus Thirst Baroreceptors Angiotensin II FIGURE 174 Diagrammatic representation of the way in which changes in plasma osmolality and changes in ECF volume aff ect thirst by separate pathways. 10 8 6 4 2 0 280 300 320 Plasma osmolality (mosm/kg) Intensity of thirst FIGURE 173 Relation of plasma osmolality to thirst in healthy adult humans during infusion of hypertonic saline. The intensity of thirst is measured on a special analog scale. (Reproduced with permission from Thompson CJ et al: The osmotic thresholds for thirst and vasopressin release are similar in healthy humans. Clin Sci Lond 1986;71:651.) Decreases in ECF volume also stimulate thirst by a pathway independent of that mediating thirst in response to increased plasma osmolality ( Figure 17–4 ). Th us, hemorrhage causes increased drinking even if there is no change in the osmolality of the plasma. Th e eff ect of ECF volume depletion on thirst is mediated in part via the renin–angiotensin system (see Chapter 38 ). Renin secretion is increased by hypovolemia and results in an increase in circulating angiotensin II. Th e angiotensin II acts on the subfornical organ , a specialized receptor area in the diencephalon (see Figure 33–7), to stimulate the neural areas concerned with thirst. Some evidence suggests that it acts on the organum vasculosum of the lamina terminalis (OVLT) as well. Th ese areas are highly permeable and are two of the circumventricular organs located outside the blood–brain barrier (see Chapter 33 ). However, drugs that block the action of angiotensin II do not completely block the thirst response to hypovolemia, and it appears that the baroreceptors in the heart and blood vessels are also involved. Th e intake of liquids is increased during eating (prandial drinking) . Th e increase has been called a learned or habit response, but it has not been investigated in detail. One factor is an increase in plasma osmolality that occurs as food is absorbed. Another may be an action of one or more gastrointestinal hormones on the hypothalamus. When the sensation of thirst is obtunded, either by direct damage to the diencephalon or by depressed or altered states of consciousness, patients stop drinking adequate amounts of fl uid. Dehydration results if appropriate measures are not instituted to maintain water balance. If the protein intake is high, the products of protein metabolism cause an osmotic diuresis (see Chapter 38 ), and the amounts of water required to maintain hydration are large. Most cases of hypernatremia are actually due to simple dehydration in patients with psychoses or hypothalamic disease who do not or cannot increase their water intake when their thirst mechanism is stimulated. Lesions of the anterior communicating artery can also obtund thirst because branches of this artery supply the hypothalamic areas concerned with thirst. CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 311 OTHER FACTORS REGULATING WATER INTAKE A number of other well-established factors contribute to the regulation of water intake. Psychologic and social factors are important. Dryness of the pharyngeal mucous membrane causes a sensation of thirst. Patients in whom fl uid intake must be restricted sometimes get appreciable relief of thirst by sucking ice chips or a wet cloth. Dehydrated dogs, cats, camels, and some other animals rapidly drink just enough water to make up their water defi cit. Th ey stop drinking before the water is absorbed (while their plasma is still hypertonic), so some kind of pharyngeal gastrointestinal “metering” must be involved. Some evidence suggests that humans have a similar metering ability, though it is not well developed. CONTROL OF POSTERIOR PITUITARY SECRETION VASOPRESSIN & OXYTOCIN In most mammals, the hormones secreted by the posterior pituitary gland are arginine vasopressin (AVP) and oxytocin. In hippopotami and most pigs, arginine in the vasopressin molecule is replaced by lysine to form lysine vasopressin . Th e posterior pituitaries of some species of pigs and marsupials contain a mixture of arginine and lysine vasopressin. Th e posterior lobe hormones are nanopeptides with a disulfi de ring at one end ( Figure 17–5 ). BIOSYNTHESIS, INTRANEURONAL TRANSPORT, & SECRETION Th e hormones of the posterior pituitary gland are synthesized in the cell bodies of the magnocellular neurons in the supraoptic and paraventricular nuclei and transported down Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 1 2 3 4 5 6 7 8 9 S S Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 1 2 3 4 5 6 7 8 9 S S Arginine vasopressin Oxytocin FIGURE 175 Arginine vasopressin and oxytocin. the axons of these neurons to their endings in the posterior lobe, where they are secreted in response to electrical activity in the endings. Some of the neurons make oxytocin and others make vasopressin, and oxytocin-containing and vasopressincontaining cells are found in both nuclei. Oxytocin and vasopressin are typical neural hormones , that is, hormones secreted into the circulation by nerve cells. Th is type of neural regulation is compared with other types in Figure 17–6 . Th e term neurosecretion was originally coined to describe the secretion of hormones by neurons, but the term is somewhat misleading because it appears that all neurons secrete chemical messengers (see Chapter 7 ). Like other peptide hormones, the posterior lobe hormones are synthesized as part of larger precursor molecules. Vasopressin and oxytocin each have a characteristic neurophysin associated with them in the granules in the neurons that secrete them— neurophysin I in the case of oxytocin and neurophysin II in the case of vasopressin. Th e neurophysins were originally thought to be binding polypeptides, but it now appears that they are simply parts of the precursor molecules. Th e precursor for AVP, prepropressophysin , contains a 19-amino-acid residue leader sequence followed by AVP, neurophysin II, and a glycopeptide ( Figure 17–7 ). Prepro-oxyphysin, the precursor for oxytocin, is a similar but smaller molecule that lacks the glycopeptide. Acetylcholine Acetylcholine Acetylcholine Acetylcholine Vasopressin General circulation Norepinephrine Epinephrine, norepinephrine ACTH, TSH, GH, FSH, LH, prolactin Norepinephrine or acetylcholine Releasing and inhibiting hormones Portal vessels Motor nerves to skeletal muscle Motor nerves to smooth and cardiac muscle Juxtaglomerular cells Adrenal medulla Anterior pituitary Posterior pituitary Renin FIGURE 176 Neural control mechanisms. In the two situations on the left, neurotransmitters act at nerve endings on muscle; in the two in the middle, neurotransmitters regulate the secretion of endocrine glands; and in the two on the right, neurons secrete hormones into the hypophysial portal or general circulation. 312 SECTION III Endocrine and Reproductive Physiology Th e precursor molecules are synthesized in the ribosomes of the cell bodies of the neurons. Th ey have their leader sequences removed in the endoplasmic reticulum, are packaged into secretory granules in the Golgi apparatus, and are transported down the axons by axoplasmic fl ow to the endings in the posterior pituitary. Th e secretory granules, called Herring bodies, are easy to stain in tissue sections, and they have been extensively studied. Cleavage of the precursor molecules occurs as they are being transported, and the storage granules in the endings contain free vasopressin or oxytocin and the corresponding neurophysin. In the case of vasopressin, the glycopeptide is also present. All these products are secreted, but the functions of the components other than the established posterior pituitary hormones are unknown. Physiological control of vasopressin secretion is described in detail in Chapter 38 . ELECTRICAL ACTIVITY OF MAGNOCELLULAR NEURONS Th e oxytocin-secreting and vasopressin-secreting neurons also generate and conduct action potentials, and action potentials reaching their endings trigger the release of hormones by Ca 2+ -dependent exocytosis. At least in anesthetized rats, these neurons are silent at rest or discharge at low, irregular rates (0.1–3 spikes/s). However, their response to stimulation varies ( Figure 17–8 ). Stimulation of the nipples causes a synchronous, high-frequency discharge of the oxytocin neurons aft er an appreciable latency. Th is discharge causes release of a pulse of oxytocin and consequent milk ejection in postpartum females. On the other hand, stimulation of vasopressinsecreting neurons by a stimulus such as an increase in blood osmolality during dehydration, or loss of blood volume due to hemorrhage, causes an initial steady increase in fi ring rate followed by a prolonged pattern of phasic discharge in which periods of high-frequency discharge alternate with periods of electrical quiescence (phasic bursting) . Th ese phasic Unit Rate Control 5 mL blood removed 5 mL blood removed (+ 20 min) 1 min 10/s ME ME 50/s A HFD B Intramammary pressure FIGURE 178 Responses of magnocellular neurons to stimulation . The tracings show individual extracellularly recorded action potentials, discharge rates, and intramammary duct pressure. A) Response of an oxytocin-secreting neuron. HFD, high-frequency discharge; ME, milk ejection. Stimulation of nipples started before the onset of recording. B) Responses of a vasopressin-secreting neuron, showing no change in the slow fi ring rate in response to stimulation of nipples and a prompt increase in the fi ring rate when 5 mL of blood was drawn, followed by typical phasic discharge. (Modifi ed from Wakerly JB: Hypothalamic neurosecretory function: Insights from electrophysiological studies of the magno-cellular nuclei. IBRO News 1985;4:15.) bursts are generally not synchronous in diff erent vasopressinsecreting neurons. Th ey are well suited to maintain a prolonged increase in the output of vasopressin, as opposed to the synchronous, relatively short, high-frequency discharge of oxytocin-secreting neurons in response to stimulation of the nipples. 1 1 2 3 4 2 3 4 Signal peptide Vasopressin Neurophysin II Glycopeptide 19 aa 9 aa 95 aa 39 aa -Gly-Lys-Arg- -Arg- 1 1 2 3 2 3 Signal peptide Oxytocin Neurophysin I 19 aa 9 aa 93 aa -Gly-Lys-Arg- -Arg/His FIGURE 177 Structure of bovine prepropressophysin (left) and prepro-oxyphysin (right). Gly in the 10 position of both peptides is necessary for amidation of the Gly residue in position 9. aa, amino acid residues. (Reproduced with permission from Richter D: Molecular events in expression of vasopressin and oxytocin and their cognate receptors. Am J Physiol 1988;255:F207.) CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 313 VASOPRESSIN & OXYTOCIN IN OTHER LOCATIONS Vasopressin-secreting neurons are found in the suprachiasmatic nuclei, and vasopressin and oxytocin are also found in the endings of neurons that project from the paraventricular nuclei to the brain stem and spinal cord. Th ese neurons appear to be involved in cardiovascular control. In addition, vasopressin and oxytocin are synthesized in the gonads and the adrenal cortex, and oxytocin is present in the thymus. Th e functions of the peptides in these organs are unsettled. Vasopressin Receptors Th ere are at least three kinds of vasopressin receptors: V 1A , V 1B , and V 2 . All are G protein-coupled. Th e V 1A and V 1B receptors act through phosphatidylinositol hydrolysis to increase intracellular Ca 2+ concentrations. Th e V 2 receptors act through G s to increase cAMP levels. Eff ects of Vasopressin Because one of its principal physiologic eff ects is the retention of water by the kidney, vasopressin is oft en called the antidiuretic hormone (ADH) . It increases the permeability of the collecting ducts of the kidney so that water enters the hypertonic interstitium of the renal pyramids (see Chapter 37 ). Th e urine becomes concentrated and its volume decreases. Th e overall eff ect is therefore retention of water in excess of solute; consequently, the eff ective osmotic pressure of the body fl uids is decreased. In the absence of vasopressin, the urine is hypotonic to plasma, urine volume is increased, and there is a net water loss. Consequently, the osmolality of the body fl uid rises. Eff ects of Oxytocin In humans, oxytocin acts primarily on the breasts and uterus, though it appears to be involved in luteolysis as well (see Chapter 22 ). A G protein-coupled oxytocin receptor has been identifi ed in human myometrium, and a similar or identical receptor is found in mammary tissue and the ovary. It triggers increases in intracellular Ca 2+ levels. The Milk Ejection Refl ex Oxytocin causes contraction of the myoepithelial cells that line the ducts of the breast. Th is squeezes the milk out of the alveoli of the lactating breast into the large ducts (sinuses) and thence out of the nipple (milk ejection) . Many hormones acting in concert are responsible for breast growth and the secretion of milk into the ducts (see Chapter 22 ), but milk ejection in most species requires oxytocin. Milk ejection is normally initiated by a neuroendocrine refl ex. Th e receptors involved are touch receptors, which are plentiful in the breast—especially around the nipple. Impulses generated in these receptors are relayed from the somatic touch pathways to the supraoptic and paraventricular nuclei. Discharge of the oxytocin-containing neurons causes secretion of oxytocin from the posterior pituitary ( Figure 17–8 ). Th e suckling of an infant at the breast stimulates the touch receptors, the nuclei are stimulated, oxytocin is released, and the milk is expressed into the sinuses, ready to fl ow into the mouth of the waiting infant. In lactating women, genital stimulation and emotional stimuli also produce oxytocin secretion, sometimes causing milk to spurt from the breasts. Other Actions of Oxytocin Oxytocin causes contraction of the smooth muscle of the uterus. Th e sensitivity of the uterine musculature to oxytocin is enhanced by estrogen and inhibited by progesterone. Th e inhibitory eff ect of progesterone is due to a direct action of the steroid on uterine oxytocin receptors. In late pregnancy, the uterus becomes very sensitive to oxytocin coincident with a marked increase in the number of oxytocin receptors and oxytocin receptor mRNA (see Chapter 22 ). Oxytocin secretion is then increased during labor. Aft er dilation of the cervix, descent of the fetus down the birth canal initiates impulses in the aff erent nerves that are relayed to the supraoptic and paraventricular nuclei, causing secretion of suffi cient oxytocin to enhance labor (Figure 22–24). Th e amount of oxytocin in plasma is normal at the onset of labor. It is possible that the marked increase in oxytocin receptors at this time allows normal oxytocin levels to initiate contractions, setting up a positive feedback. However, the amount of oxytocin in the uterus is also increased, and locally produced oxytocin may also play a role. Oxytocin may also act on the nonpregnant uterus to facilitate sperm transport. Th e passage of sperm up the female genital tract to the uterine tubes, where fertilization normally takes place, depends not only on the motile powers of the sperm but also, at least in some species, on uterine contractions. Th e genital stimulation involved in coitus releases oxytocin, but whether oxytocin initiates the rather specialized uterine contractions that transport the sperm is as yet unproven. Th e secretion of oxytocin is also increased by stressful stimuli and, like that of vasopressin, is inhibited by alcohol. Circulating oxytocin increases at the time of ejaculation in males, and it is possible that this causes increased contraction of the smooth muscle of the vas deferens, propelling sperm toward the urethra. CONTROL OF ANTERIOR PITUITARY SECRETION ANTERIOR PITUITARY HORMONES Th e anterior pituitary secretes six hormones: adrenocorticotropic hormone (corticotropin, ACTH) , thyroid- stimulating hormone (thyrotropin, TSH) , growth hormone , folliclestimulating hormone (FSH) , luteinizing hormone (LH) , 314 SECTION III Endocrine and Reproductive Physiology and prolactin (PRL) . An additional polypeptide, β-lipotropin (β-LPH), is secreted with ACTH, but its physiologic role is unknown. Th e actions of the anterior pituitary hormones are summarized in Figure 17–9 . Th e hormones are discussed in detail in subsequent chapters. Th e hypothalamus plays an important stimulatory role in regulating the secretion of ACTH, β-LPH, TSH, growth hormone, FSH, and LH. It also regulates prolactin secretion, but its eff ect is predominantly inhibitory rather than stimulatory. NATURE OF HYPOTHALAMIC CONTROL Anterior pituitary secretion is controlled by chemical agents carried in the portal hypophysial vessels from the hypothalamus to the pituitary. Th ese substances used to be called releasing and inhibiting factors, but now they are commonly called hypophysiotropic hormones. Th e latter term seems appropriate since they are secreted into the bloodstream and act at a distance from their site of origin. Small amounts escape into the general circulation, but they are at their highest concentration in portal hypophysial blood. HYPOPHYSIOTROPIC HORMONES Th ere are six established hypothalamic releasing and inhibiting hormones ( Figure 17–10 ): corticotropin-releasing hormone (CRH) ; thyrotropin-releasing hormone (TRH) ; growth hormone-releasing hormone (GRH) ; growth hormoneinhibiting hormone (GIH , now generally called somatostatin); luteinizing hormone-releasing hormone (LHRH , now generally known as gonadotropin-releasing hormone (GnRH)) ; and prolactin-inhibiting hormone (PIH) . In addition, hypothalamic extracts contain prolactin-releasing activity, and a prolactin-releasing hormone (PRH) has been postulated to exist. TRH, VIP, and several other polypeptides found in the hypothalamus stimulate prolactin secretion, but it is uncertain whether one or more of these peptides is the physiologic PRH. Recently, an orphan receptor was isolated from the anterior pituitary, and the search for its ligand led to the isolation of a 31-amino-acid polypeptide from the human Anterior pituitary ACTH TSH FSH LH Prolactin Growth β-LPH hormone ? Breast 17-Hydroxycorticoids Aldosterone, sex hormones Somatomedins Thyroxine Estrogen Progesterone FIGURE 179 Anterior pituitary hormones . In women, FSH and LH act in sequence on the ovary to produce growth of the ovarian follicle, ovulation, and formation and maintenance of the corpus luteum. Prolactin stimulates lactation. In men, FSH and LH control the functions of the testes. Hypothalamus CRH TRH Anterior pituitary GnRH GRH GIH PRH PIH β-LPH ACTH TSH LH FSH Growth Prolactin hormone FIGURE 1710 Eff ects of hypophysiotropic hormones on the secretion of anterior pituitary hormones. CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 315 hypothalamus. Th is polypeptide stimulated prolactin secretion by an action on the anterior pituitary receptor, but additional research is needed to determine if it is the physiologic PRH. GnRH stimulates the secretion of FSH as well as that of LH, and it seems unlikely that a separate FSH-releasing hormone exists. Th e structures of the six established hypophysiotropic hormones are shown in Figure 17–11 . Th e structures of the genes and preprohormones for TRH, GnRH, somatostatin, CRH, and GRH are known. PreproTRH contains six copies of TRH. Several other preprohormones may contain other hormonally active peptides in addition to the hypophysiotropic hormones. Th e area from which the hypothalamic releasing and inhibiting hormones are secreted is the median eminence of the hypothalamus. Th is region contains few nerve cell bodies, but many nerve endings are in close proximity to the capillary loops from which the portal vessels originate. Th e locations of the cell bodies of the neurons that project to the external layer of the median eminence and secrete the hypophysiotropic hormones are shown in Figure 17–12 , which also shows the location of the neurons secreting oxytocin and vasopressin. Th e GnRH-secreting neurons are primarily in the medial preoptic area, the somatostatin-secreting neurons are in the periventricular nuclei, the TRH-secreting and CRH-secreting neurons are in the medial parts of the paraventricular nuclei, and the GRH-secreting (and dopaminesecreting) neurons are in the arcuate nuclei. Most, if not all, of the hypophysiotropic hormones aff ect the secretion of more than one anterior pituitary hormone ( Figure 17–10 ). Th e FSH-stimulating activity of GnRH has been mentioned previously. TRH stimulates the secretion of prolactin as well as TSH. Somatostatin inhibits the secretion of TSH as well as growth hormone. It does not normally inhibit the secretion of the other anterior pituitary hormones, but it inhibits the abnormally elevated secretion of ACTH in patients with Nelson’s syndrome. CRH stimulates the secretion of ACTH and β-LPH. Hypophysiotropic hormones function as neurotransmitters in other parts of the brain, the retina, and the autonomic nervous system (see Chapter 7 ). In addition, somatostatin is TRH (pyro)Glu-His-Pro-NH2 GnRH (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 Somatostatin Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu- Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile-NH2 CRH GRH Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met- Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2 PIH Dopamine S S FIGURE 1711 Structure of hypophysiotropic hormones in humans . Preprosomatostatin is processed to a tetradecapeptide (somatostatin 14, [SS14], shown above) and also to a polypeptide containing 28 amino acid residues (SS28). 0.5 mm Oxytocin Vasopressin SS DA CRH GnRH TRH GRH Peri SO PV ME ARC IC PL IL AL BA PC MC TRH GRH DA FIGURE 1712 Location of cell bodies of hypophysiotropic hormone-secreting neurons projected on a ventral view of the hypothalamus and pituitary of the rat. AL, anterior lobe; ARC, arcuate nucleus; BA, basilar artery; DA, dopamine; IC, internal carotid artery; IL, intermediate lobe; MC, middle cerebral artery; ME, median eminence; PC, posterior cerebral artery; Peri, periventricular nucleus; PL, posterior lobe; PV, paraventricular nucleus; SO, supraoptic nucleus. The names of the hormones are enclosed in boxes. (Courtesy of LW Swanson and ET Cunningham Jr) found in the pancreatic islets (see Chapter 24 ), GRH is secreted by pancreatic tumors, and somatostatin and TRH are found in the gastrointestinal tract (see Chapter 25 ). 316 SECTION III Endocrine and Reproductive Physiology Receptors for most of the hypophysiotropic hormones are coupled to G proteins. Th ere are two human CRH receptors: hCRH-RI and hCRH-RII. Th e physiologic role of hCRH-RII is unsettled, though it is found in many parts of the brain. In addition, a CRH-binding protein in the peripheral circulation inactivates CRH. It is also found in the cytoplasm of corticotropes in the anterior pituitary, and in this location it might play a role in receptor internalization. However, the exact physiologic role of this protein is unknown. Other hypophysiotropic hormones do not have known binding proteins. SIGNIFICANCE & CLINICAL IMPLICATIONS Research delineating the multiple neuroendocrine regulatory functions of the hypothalamus is important because it helps explain how endocrine secretion is matched to the demands of a changing environment. Th e nervous system receives information about changes in the internal and external environment from the sense organs. It brings about adjustments to these changes through eff ector mechanisms that include not only somatic movement but also changes in the rate at which hormones are secreted. Th e manifestations of hypothalamic disease are neurologic defects, endocrine changes, and metabolic abnormalities such as hyperphagia and hyperthermia. Th e relative frequencies of the signs and symptoms of hypothalamic disease in one large series of cases are shown in Table 17–2 . Th e possibility of hypothalamic pathology should be kept in mind in evaluating all patients with pituitary dysfunction, especially those with isolated defi ciencies of single pituitary tropic hormones. A condition of considerable interest in this context is Kallmann syndrome , the combination of hypogonadism due to low levels of circulating gonadotropins (hypogonadotropic hypogonadism) with partial or complete loss of the sense of smell ( hyposmia or anosmia ). Embryologically, GnRH neurons develop in the nose and migrate up the olfactory nerves and then through the brain to the hypothalamus. If this migration is prevented by congenital abnormalities in the olfactory pathways, the GnRH neurons do not reach the hypothalamus and pubertal maturation of the gonads does not occur. Th e syndrome is most common in men, and the cause in many cases is mutation of the KALIG1 gene, a gene on the X chromosome that codes for an adhesion molecule necessary for the normal development of the olfactory nerve. However, the condition also occurs in women and can be due to other genetic abnormalities. TEMPERATURE REGULATION In the body, heat is produced by muscular exercise, assimilation of food, and all the vital processes that contribute to the basal metabolic rate. It is lost from the body by radiation, conduction, and vaporization of water in the respiratory passages TABLE 172 Symptoms and signs in 60 patients with hypothalamic disease. Symptoms and Signs Percentage of Cases Endocrine and metabolic fi ndings Precocious puberty 40 Hypogonadism 32 Diabetes insipidus 35 Obesity 25 Abnormalities of temperature regulation 22 Emaciation 18 Bulimia 8 Anorexia 7 Neurologic fi ndings Eye signs 78 Pyramidal and sensory defi cits 75 Headache 65 Extrapyramidal signs 62 Vomiting 40 Psychic disturbances, rage attacks, etc 35 Somnolence 30 Convulsions 15 Data from Bauer HG: Endocrine and other clinical manifestations of hypothalamic disease. J Clin Endocrinol 1954;14:13. See also Kahana L, et al: Endocrine manifestations of intracranial extrasellar lesions. J Clin Endocrinol 1962;22:304. and on the skin. Small amounts of heat are also removed in the urine and feces. Th e balance between heat production and heat loss determines the body temperature. Because the speed of chemical reactions varies with temperature and because the enzyme systems of the body have narrow temperature ranges in which their function is optimal, normal body function depends on a relatively constant body temperature. Invertebrates generally cannot adjust their body temperatures and so are at the mercy of the environment. In vertebrates, mechanisms for maintaining body temperature by adjusting heat production and heat loss have evolved. In reptiles, amphibians, and fi sh, the adjusting mechanisms are relatively rudimentary, and these species are called “coldblooded” (poikilothermic) because their body temperature fl uctuates over a considerable range. In birds and mammals, the “warm-blooded” (homeothermic) animals, a group of refl ex responses that are primarily integrated in the hypothalamus operate to maintain body temperature within a narrow range in spite of wide fl uctuations in environmental temperature. Th e hibernating mammals are a partial exception. While awake they are homeothermic, but during hibernation their body temperature falls. CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 317 NORMAL BODY TEMPERATURE In homeothermic animals, the actual temperature at which the body is maintained varies from species to species and, to a lesser degree, from individual to individual. In humans, the traditional normal value for the oral temperature is 37°C (98.6°F), but in one large series of normal young adults, the morning oral temperature averaged 36.7°C, with a standard deviation of 0.2°C. Th erefore, 95% of all young adults would be expected to have a morning oral temperature of 36.3–37.1°C (97.3–98.8°F; mean ± 1.96 standard deviations). Various parts of the body are at diff erent temperatures, and the magnitude of the temperature diff erence between the parts varies with the environmental temperature ( Figure 17–13 ). Th e extremities are generally cooler than the rest of the body. Th e temperature of the scrotum is carefully regulated at 32°C. Th e rectal temperature is representative of the temperature at the core of the body and varies least with changes in environmental temperature. Th e oral temperature is normally 0.5°C lower than the rectal temperature, but it is aff ected by many factors, including ingestion of hot or cold fl uids, gum chewing, smoking, and mouth breathing. Th e normal human core temperature undergoes a regular circadian fl uctuation of 0.5–0.7°C. In individuals who sleep at night and are awake during the day (even when hospitalized at bed rest), it is lowest at about 6:00 am and highest in the evenings ( Figure 17–14 ). It is lowest during sleep, is slightly higher in the awake but relaxed state, and rises with activity. In women, an additional monthly cycle of temperature variation is characterized by a rise in basal temperature at the time of ovulation (Figure 22–15). Temperature regulation is less precise in young children and they may normally have 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 23 24 25 26 Feet Hands 27 28 29 30 31 32 33 34 Calorimetric temperature (°C) Temperature (°C) of subject Average skin Trunk Head Rectum FIGURE 1713 Temperatures of various parts of the body of a naked subject at various ambient temperatures in a calorimeter. (Redrawn and reproduced, with permission, from Hardy JD, DuBois EF: Basal heat production and elimination of thirteen normal women at temperatures from 22 degrees C. to 35 degrees C. J Nutr 1938 Oct; 48(2):257–293.) 38 37 36 1 2 3 4 5 Admitted to hospital Days Oral temp (°C) Hyperthyroidism Hypothyroidism Normal FIGURE 1714 Typical temperature chart of a hospitalized patient who does not have a febrile disease. Note the slight rise in temperature, due to excitement and apprehension, at the time of admission to the hospital, and the regular circadian temperature cycle. a temperature that is 0.5°C or so above the established norm for adults. During exercise, the heat produced by muscular contraction accumulates in the body and the rectal temperature normally rises as high as 40°C (104 °F). Th is rise is due in part to the inability of the heat-dissipating mechanisms to handle the greatly increased amount of heat produced, but evidence suggests that during exercise in addition there is an elevation of the body temperature at which the heat-dissipating mechanisms are activated. Body temperature also rises slightly during emotional excitement, probably owing to unconscious tensing of the muscles. It is chronically elevated by as much as 0.5°C when the metabolic rate is high, as in hyperthyroidism, and lowered when the metabolic rate is low, as in hypothyroidism ( Figure 17–14 ). Some apparently normal adults chronically have a temperature above the normal range (constitutional hyperthermia). HEAT PRODUCTION A variety of basic chemical reactions contribute to body heat production at all times. Ingestion of food increases heat production, but the major source of heat is the contraction of skeletal muscle ( Table 17–3 ). Heat production can be varied by endocrine mechanisms in the absence of food intake or muscular exertion. Epinephrine and norepinephrine produce a rapid but short-lived increase in heat production; thyroid hormones produce a slowly developing but prolonged increase. TABLE 173 Body heat production and heat loss. Body heat is produced by: Basic metabolic processes Food intake (specifi c dynamic action) Muscular activity Body heat is lost by: Radiation and conduction Vaporization of sweat Respiration Urination and defecation Percentage of heat lost at 21°C 70 27 2 1 318 SECTION III Endocrine and Reproductive Physiology Furthermore, sympathetic discharge decreases during fasting and is increased by feeding. A source of considerable heat, particularly in infants, is brown fat . Th is fat has a high rate of metabolism and its thermogenic function has been likened to that of an electric blanket. HEAT LOSS Th e processes by which heat is lost from the body when the environmental temperature is below body temperature are listed in Table 17–3 . Conduction is heat exchange between objects or substances at diff erent temperatures that are in contact with one another. A basic characteristic of matter is that its molecules are in motion, with the amount of motion proportional to the temperature. Th ese molecules collide with the molecules in cooler objects, transferring thermal energy to them. Th e amount of heat transferred is proportional to the temperature diff erence between the objects in contact (thermal gradient). Conduction is aided by convection , the movement of molecules away from the area of contact. Th us, for example, an object in contact with air at a diff erent temperature changes the specifi c gravity of the air, and because warm air rises and cool air falls, a new supply of air is brought into contact with the object. Of course, convection is greatly aided if the object moves about in the medium or the medium moves past the object, for example, if a subject swims through water or a fan blows air through a room. Radiation is the transfer of heat by infrared electromagnetic radiation from one object to another at a diff erent temperature with which it is not in contact. When an individual is in a cold environment, heat is lost by conduction to the surrounding air and by radiation to cool objects in the vicinity. Conversely, of course, heat is transferred to an individual and the heat load is increased by these processes when the environmental temperature is above body temperature. Note that because of radiation, an individual can feel chilly in a room with cold walls even though the room is relatively warm. On a cold but sunny day, the heat of the sun refl ected off bright objects exerts an appreciable warming eff ect. It is the heat refl ected from the snow, for example, that in part makes it possible to ski in fairly light clothes even though the air temperature is below freezing. Because conduction occurs from the surface of one object to the surface of another, the temperature of the skin determines to a large extent the degree to which body heat is lost or gained. Th e amount of heat reaching the skin from the deep tissues can be varied by changing the blood fl ow to the skin. When the cutaneous vessels are dilated, warm blood wells into the skin, whereas in the maximally vasoconstricted state, heat is held centrally in the body. Th e rate at which heat is transferred from the deep tissues to the skin is called the tissue conductance . Further, birds have a layer of feathers next to the skin, and most mammals have a signifi cant layer of hair or fur. Heat is conducted from the skin to the air trapped in this layer and from the trapped air to the exterior. When the thickness of the trapped layer is increased by fl uffi ng the feathers or erection of the hairs (horripilation), heat transfer across the layer is reduced and heat losses (or, in a hot environment, heat gains) are decreased. “Goose pimples” are the result of horripilation in humans; they are the visible manifestation of cold-induced contraction of the piloerector muscles attached to the rather meager hair supply. Humans usually supplement this layer of hair with one or more layers of clothes. Heat is conducted from the skin to the layer of air trapped by the clothes, from the inside of the clothes to the outside, and from the outside of the clothes to the exterior. Th e magnitude of the heat transfer across the clothing, a function of its texture and thickness, is the most important determinant of how warm or cool the clothes feel, but other factors, especially the size of the trapped layer of warm air, are also important. Dark clothes absorb radiated heat and light-colored clothes refl ect it back to the exterior. Th e other major process transferring heat from the body in humans and other animals that sweat is vaporization of water on the skin and mucous membranes of the mouth and respiratory passages. Vaporization of 1 g of water removes about 0.6 kcal of heat. A certain amount of water is vaporized at all times. Th is insensible water loss amounts to 50 mL/h in humans. When sweat secretion is increased, the degree to which the sweat vaporizes depends on the humidity of the environment. It is common knowledge that one feels hotter on a humid day. Th is is due in part to the decreased vaporization of sweat, but even under conditions in which vaporization of sweat is complete, an individual in a humid environment feels warmer than an individual in a dry environment. Th e reason for this diff erence is unknown, but it seems related to the fact that in the humid environment sweat spreads over a greater area of skin before it evaporates. During muscular exertion in a hot environment, sweat secretion reaches values as high as 1600 mL/h, and in a dry atmosphere, most of this sweat is vaporized. Heat loss by vaporization of water therefore varies from 30 to over 900 kcal/h. Some mammals lose heat by panting . Th is rapid, shallow breathing greatly increases the amount of water vaporization in the mouth and respiratory passages and therefore the amount of heat lost. Because the breathing is shallow, it produces relatively little change in the composition of alveolar air (see Chapter 34 ). Th e relative contribution of each of the processes that transfer heat away from the body ( Table 17–3 ) varies with the environmental temperature. At 21°C, vaporization is a minor component in humans at rest. As the environmental temperature approaches body temperature, radiation losses decline and vaporization losses increase. TEMPERATUREREGULATING MECHANISMS Th e refl ex and semirefl ex thermoregulatory responses in humans are listed in Table 17–4 . Th ey include autonomic, somatic, endocrine, and behavioral changes. One group of CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 319 responses increases heat loss and decreases heat production; the other decreases heat loss and increases heat production. In general, exposure to heat stimulates the former group of responses and inhibits the latter, whereas exposure to cold does the opposite. Curling up “in a ball” is a common reaction to cold in animals and has a counterpart in the position some people assume on climbing into a cold bed. Curling up decreases the body surface exposed to the environment. Shivering is an involuntary response of the skeletal muscles, but cold also causes a semiconscious general increase in motor activity. Examples include foot stamping and dancing up and down on a cold day. Increased catecholamine secretion is an important endocrine response to cold. Mice unable to make norepinephrine and epinephrine because their dopamine β-hydroxylase gene is knocked out do not tolerate cold; they have defi cient vasoconstriction and are unable to increase thermogenesis in brown adipose tissue through UCP 1. TSH secretion is increased by cold and decreased by heat in laboratory animals, but the change in TSH secretion produced by cold in adult humans is small and of questionable signifi cance. It is common knowledge that activity is decreased in hot weather—the “it’s too hot to move” reaction. Th ermoregulatory adjustments involve local responses as well as more general refl ex responses. When cutaneous blood vessels are cooled they become more sensitive to catecholamines and the arterioles and venules constrict. Th is local eff ect of cold directs blood away from the skin. Another heat-conserving mechanism that is important in animals living in cold water is heat transfer from arterial to venous blood in the limbs. Th e deep veins (venae comitantes) run alongside the arteries supplying the limbs and heat is transferred from the warm arterial blood going to the limbs to the cold venous blood coming from the extremities ( countercurrent exchange ; see Chapter 37 ). Th is limits the ability to maintain heat in the tips of the extremities but conserves body heat. Th e refl ex responses activated by cold are controlled from the posterior hypothalamus. Th ose activated by warmth are controlled primarily from the anterior hypothalamus, although some thermoregulation against heat still occurs aft er decerebration at the level of the rostral midbrain. Stimulation of the anterior hypothalamus causes cutaneous vasodilation and sweating, and lesions in this region cause hyperthermia, with rectal temperatures sometimes reaching 43°C (109.4°F). Posterior hypothalamic stimulation causes shivering, and the body temperature of animals with posterior hypothalamic lesions falls toward that of the environment. AFFERENTS Th e hypothalamus is said to integrate body temperature information from sensory receptors (primarily cold receptors) in the skin, deep tissues, spinal cord, extrahypothalamic portions of the brain, and the hypothalamus itself. Each of these fi ve inputs contributes about 20% of the information that is integrated. Th ere are threshold core temperatures for each of the main temperature-regulating responses and when the threshold is reached the response begins. Th e threshold is 37°C for sweating and vasodilation, 36.8°C for vasoconstriction, 36°C for nonshivering thermogenesis, and 35.5°C for shivering. FEVER Fever is perhaps the oldest and most universally known hallmark of disease. It occurs not only in mammals but also in birds, reptiles, amphibia, and fi sh. When it occurs in homeothermic animals, the thermoregulatory mechanisms behave as if they were adjusted to maintain body temperature at a higher than normal level, that is, “as if the thermostat had been reset” to a new point above 37°C. Th e temperature receptors then signal that the actual temperature is below the new set point, and the temperature-raising mechanisms are activated. Th is usually produces chilly sensations due to cutaneous vasoconstriction and occasionally enough shivering to produce a shaking chill. However, the nature of the response depends on the ambient temperature. Th e temperature rise in experimental animals injected with a pyrogen is due mostly to increased heat production if they are in a cold environment and mostly to decreased heat loss if they are in a warm environment. Th e pathogenesis of fever is summarized in Figure 17–15 . Toxins from bacteria, such as endotoxin, act on monocytes, macrophages, and Kupff er cells to produce cytokines that act as endogenous pyrogens (EPs) . Th ere is good evidence that TABLE 174 Temperature-regulating mechanisms. Mechanisms activated by cold Shivering Hunger Increased voluntary activity Increased secretion of norepinephrine and epinephrine Decreased heat loss Cutaneous vasoconstriction Curling up Horripilation Mechanisms activated by heat Increased heat loss Cutaneous vasodilation Sweating Increased respiration Decreased heat production Anorexia Apathy and inertia 320 SECTION III Endocrine and Reproductive Physiology IL-1β, IL-6, IFN-β, IFN-γ, and TNF-α (see Chapter 3 ) can act independently to produce fever. Th ese circulating cytokines are polypeptides and it is unlikely that they penetrate the brain. Instead, evidence suggests that they act on the OVLT, one of the circumventricular organs (see Chapter 33 ). Th is in turn activates the preoptic area of the hypothalamus. Cytokines are also produced by cells in the central nervous system (CNS) when these are stimulated by infection, and these may act directly on the thermoregulatory centers. Th e fever produced by cytokines is probably due to local release of prostaglandins in the hypothalamus. Intrahypothalamic injection of prostaglandins produces fever. In addition, the antipyretic eff ect of aspirin is exerted directly on the hypothalamus, and aspirin inhibits prostaglandin synthesis. PGE 2 is one of the prostaglandins that causes fever. It acts on four sub-types of prostaglandin receptors—EP 1 , EP 2 , EP 3 , and EP 4 —and knockout of the EP 3 receptor impairs the febrile response to PGE 2 , IL-1β, and endotoxin, or bacterial lipopolysaccharide (LPS). Th e benefi t of fever to the organism is uncertain. A benefi - cial eff ect is assumed because fever has evolved and persisted as a response to infections and other diseases. Many microorganisms grow best within a relatively narrow temperature range and a rise in temperature inhibits their growth. In addition, antibody production is increased when body temperature is elevated. Before the advent of antibiotics, fevers were artifi cially induced for the treatment of neurosyphilis and proved to be benefi cial. Hyperthermia also benefi ts individuals infected with anthrax, pneumococcal pneumonia, leprosy, and various fungal, rickettsial, and viral diseases. Hyperthermia also slows the growth of some tumors. However, very high temperatures are harmful. A rectal temperature over 41°C (106°F) for prolonged periods results in some permanent brain damage. When the temperature is over 43°C, heat stroke develops and death is common. Endotoxin Inflammation Other pyrogenic stimuli Monocytes Macrophages Kupffer cells Cytokines Preoptic area of hypothalamus Prostaglandins Raise temperature set point Fever FIGURE 1715 Pathogenesis of fever. In malignant hyperthermia, various mutations of the gene coding for the ryanodine receptor (see Chapter 5 ) lead to excess Ca 2+ release during muscle contraction triggered by stress. Th is in turn leads to contractures of the muscles, increased muscle metabolism, and a great increase in heat production in muscle. Th e increased heat production causes a marked rise in body temperature that is fatal if not treated. Periodic fevers also occur in humans with mutations in the gene for pyrin, a protein found in neutrophils; the gene for mevalonate kinase, an enzyme involved in cholesterol synthesis; and the gene for the type 1 TNF receptor, which is involved in infl ammatory responses. However, how any of these three mutant gene products cause fever is unknown. HYPOTHERMIA In hibernating mammals, body temperature drops to low levels without causing any demonstrable ill eff ects on subsequent arousal. Th is observation led to experiments on induced hypothermia. When the skin or the blood is cooled enough to lower the body temperature in nonhibernating animals or in humans, metabolic and physiologic processes slow down. Respiration and heart rate are very slow, blood pressure is low, and consciousness is lost. At rectal temperatures of about 28°C, the ability to spontaneously return the temperature to normal is lost, but the individual continues to survive and, if rewarmed with external heat, returns to a normal state. If care is taken to prevent the formation of ice crystals in the tissues, the body temperature of experimental animals can be lowered to subfreezing levels without producing any detectable damage aft er subsequent rewarming. Humans tolerate body temperatures of 21–24°C (70– 75°F) without permanent ill eff ects, and induced hypothermia has been used in surgery. On the other hand, accidental hypothermia due to prolonged exposure to cold air or cold water is a serious condition and requires careful monitoring and prompt rewarming. CHAPTER SUMMARY Neural connections ■ run between the hypothalamus and the posterior lobe of the pituitary gland, and vascular connections between the hypothalamus and the anterior lobe of the pituitary. ■ In most mammals, the hormones secreted by the posterior pituitary gland are vasopressin and oxytocin. Vasopressin increases the permeability of the collecting ducts of the kidney to water, thus concentrating the urine. Oxytocin acts on the breasts (lactation) and the uterus (contraction). ■ Th e anterior pituitary secretes six hormones: adrenocorticotropic hormone (corticotropin, ACTH), thyroidstimulating hormone (thyrotropin, TSH), growth hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL). ■ Other complex autonomic mechanisms that maintain the chemical constancy and temperature of the internal environment are integrated in the hypothalamus. CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 321 MULTIPLECHOICE QUESTIONS For all questions, select the single best answer unless otherwise directed. 1. Th irst is stimulated by increases in p A. lasma osmolality and volume. B. an increase in plasma osmolality and a decrease in plasma volume. C. a decrease in plasma osmolality and an increase in plasma volume. D. decreases in plasma osmolality and volume. E. injection of vasopressin into the hypothalamus. 2. When an individual is naked in a room in which the air temperature is 21°C (69.8°F) and the humidity 80%, the greatest amount of heat is lost from the body by A. elevated metabolism. B. respiration. C. urination. D. vaporization of sweat. E. radiation and conduction. In questions 3–8, select A if the item is associated with (a) below, B if the item is associated with (b) below, C if the item is associated with both (a) and (b), and D if the item is associated with neither (a) nor (b). (a) V 1A vasopressin receptors (b) V 2 vasopressin receptors 3. Activation of G s 4. Vasoconstriction 5. Increase in intracellular inositol triphosphate 6. Movement of aquaporin 7. Proteinuria 8. Milk ejection CHAPTER RESOURCES Brunton PJ, Russell JA, Douglas AJ: Adaptive responses of the maternal hypothalamic-pituitary-adrenal axis during pregnancy and lactation. J Neuroendocrinol 2008; 20:764. Lamberts SWJ, Hofl and LJ, Nobels FRE: Neuroendocrine tumor markers. Front Neuroendocrinol 2001;22:309. Loh JA, Verbalis JG: Disorders of water and salt metabolism associated with pituitary disease. Endocrinol Metab Clin 2008;37:213. McKinley MS, Johnson AK: Th e physiologic regulation of thirst and fl uid intake. News Physiol Sci 2004;19:1. This page intentionally left blank 323 O B J E C T I V E S After studying this chapter, you should be able to : ■ Describe the structure of the pituitary gland and how it relates to its function. ■ D efi ne the cell types present in the anterior pituitary and understand how their numbers are controlled in response to physiologic demands. ■ Understand the function of hormones derived from proopiomelanocortin in humans, and how they are involved in regulating pigmentation in humans, other mammals, and lower vertebrates. ■ D efi ne the eff ects of the growth hormone in growth and metabolic function, and how insulin-like growth factor I (IGF-I) may mediate some of its actions in the periphery. ■ List the stimuli that regulate growth hormone secretion and defi ne their underlying mechanisms. ■ Understand the relevance of pituitary secretion of gonadotropins and prolactin, and how these are regulated. ■ Understand the basis of conditions where pituitary function and growth hormone secretion and function are abnormal, and how they can be treated. C H A P T E R The Pituitary Gland 18 INTRODUCTION Th e pituitary gland, or hypophysis, lies in a pocket of the sphenoid bone at the base of the brain. It is a coordinating center for control of many downstream endocrine glands, some of which are discussed in subsequent chapters. In many ways, it can be considered to consist of at least two (and in some species, three) separate endocrine organs that contain a plethora of hormonally active substances. Th e anterior pituitary secretes thyroid-stimulating hormone (TSH, thyrotropin), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), folliclestimulating hormone (FSH), prolactin , and growth hormone (see Figure 17–9 ), and receives almost all of its blood supply from the portal hypophysial vessels that pass initially through the median eminence, a structure immediately below the hypothalamus. Th is vascular arrangement positions the cells of the anterior pituitary to respond effi ciently to regulatory factors released from the hypothalamus. Of the listed hormones, prolactin acts on the breast. Th e remaining fi ve are, at least in part, tropic hormones ; that is, they stimulate secretion of hormonally active substances by other endocrine glands or, in the case of growth hormone, the liver and other tissues (see below). Th e tropic hormones for some endocrine glands are discussed in the chapter on that gland: TSH in Chapter 19 ; and ACTH in Chapter 20 . However, the gonadotropins FSH and LH, along with prolactin, are covered here. Th e posterior pituitary in mammals consists predominantly of nerves that have their cell bodies in the hypothalamus, and stores oxytocin and vasopressin in the termini of these neurons, to be released into the bloodstream. Th e secretion of these hormones, as well as a discussion of the overall role of the hypothalamus and median eminence in regulating both the anterior and posterior pituitary, was covered in Chapter 17 . In some species, there is also a well-developed intermediate lobe of the pituitary, whereas in humans it is rudimentary. Nevertheless, the intermediate Ganong_Ch18_323-338.indd 323 1/4/12 1:03:56 PM 324 SECTION III Endocrine and Reproductive Physiology MORPHOLOGY GROSS ANATOMY Th e anatomy of the pituitary gland is summarized in Figure 18–1 and discussed in detail in Chapter 17 . Th e posterior pituitary is made up largely of the endings of axons from the supraoptic and paraventricular nuclei of the hypothalamus and arises initially as an extension of this structure. Th e anterior pituitary, on the other hand, contains endocrine cells that store its characteristic hormones and arises embryologically as an invagination of the pharynx ( Rathke’s pouch ). In species where it is well developed, the intermediate lobe is formed in the embryo from the dorsal half of Rathke’s pouch, but is closely adherent to the posterior lobe in the adult. It is separated from the anterior lobe by the remains of the cavity in Rathke’s pouch, the residual cleft . HISTOLOGY In the posterior lobe, the endings of the supraoptic and paraventricular axons can be observed in close relation to blood vessels. Pituicytes , stellate cells that are modifi ed astrocytes, are also present. As noted above, the intermediate lobe is rudimentary in humans and a few other mammalian species. In these species, most of its cells are incorporated in the anterior lobe. Along the residual cleft are small thyroid-like follicles, some containing a little colloid (see Chapter 19 ). Th e function of the colloid, if any, is unknown. Th e anterior pituitary is made up of interlacing cell cords and an extensive network of sinusoidal capillaries. Th e endothelium of the capillaries is fenestrated, like that in other endocrine organs. Th e cells contain granules of stored hormone that are extruded from the cells by exocytosis. Th eir constituents then enter the capillaries to be conveyed to target tissues. CELL TYPES IN THE ANTERIOR PITUITARY Five types of secretory cells have been identifi ed in the anterior pituitary by immunocytochemistry and electron microscopy. Th e cell types are the somatotropes, which secrete growth hormone; the lactotropes (also called mammotropes), which secrete prolactin; the corticotropes, which secrete ACTH; the thyrotropes, which secrete TSH; and the gonadotropes, which secrete FSH and LH. Th e characteristics of these cells are summarized in Table 18–1 . Some cells may contain two or more hormones. It is also notable that the three pituitary glycoprotein hormones, FSH, LH, and TSH, while being made up of two subunits, all share a common α subunit that is the product of a single gene and has the same amino acid composition in each hormone, although their carbohydrate residues vary. Th e α subunit must be combined with a β subunit characteristic of each hormone for maximal physiologic activity. Th e β subunits, which are produced by separate genes and diff er in structure, confer hormonal specifi city (see Chapter 16 ). Th e α subunits are remarkably interchangeable and hybrid molecules can be created. In addition, the placental glycoprotein gonadotropin human chorionic gonadotropin (hCG) has α and β subunits (see Chapter 22 ). Th e anterior pituitary also contains folliculostellate cells that send processes between the granulated secretory Pars tuberalis Anterior lobe Posterior lobe Rathke’s pouch Intermediate lobe Third ventricle Third ventricle FIGURE 181 Diagrammatic outline of the formation of the pituitary (left) and the various parts of the organ in the adult (right). TABLE 181 Hormone-secreting cells of the human anterior pituitary gland. Cell Type Hormones Secreted Percentage of Total Secretory Cells Somatotrope Growth hormone 50 Lactotrope Prolactin 10–30 Corticotrope ACTH 10 Thyrotrope TSH 5 Gonadotrope FSH, LH 20 lobe, as well as the anterior pituitary, contains hormonally active derivatives of the proopiomelanocortin (POMC) molecule that regulate skin pigmentation, among other functions (see below). To avoid redundancy, this chapter will focus predominantly on growth hormone and its role in growth and facilitating the activity of other hormones, along with a number of general considerations about the pituitary. Th e melanocyte-stimulating hormones (MSHs) of the intermediate lobe of the pituitary, α-MSH and β-MSH, will also be touched upon. CHAPTER 18 The Pituitary Gland 325 cells. Th ese cells produce paracrine factors that regulate the growth and function of the secretory cells discussed above. Indeed, the anterior pituitary can adjust the relative proportion of secretory cell types to meet varying requirements for diff erent hormones at diff erent life stages. Th is plasticity has recently been ascribed to the presence of a small number of pluripotent stem cells that persist in the adult gland. PROOPIOMELANOCORTIN & DERIVATIVES BIOSYNTHESIS Intermediate-lobe cells, if present, and corticotropes of the anterior lobe both synthesize a large precursor protein that is cleaved to form a family of hormones. Aft er removal of the signal peptide, this prohormone is known as proopiomelanocortin (POMC) . Th is molecule is also synthesized in the hypothalamus, the lungs, the gastrointestinal tract, and the placenta. Th e structure of POMC, as well as its derivatives, is shown in Figure 18–2 . In corticotropes, it is hydrolyzed to ACTH and β-lipotropin (LPH), plus a small amount of β-endorphin, and these substances are secreted. In the intermediate lobe cells, POMC is hydrolyzed to corticotropin-like intermediate-lobe peptide (CLIP), γ-LPH, and appreciable quantities of β-endorphin. Th e functions, if any, of CLIP and γ-LPH are unknown, whereas β-endorphin is an opioid peptide (see Chapter 7 ) that has the fi ve amino acid residues of met-enkephalin at its amino terminal end. Th e melanotropins α- and β-MSH are also formed. However, the intermediate lobe in humans is rudimentary, and it appears that neither α-MSH nor β-MSH is secreted in adults. In some species, however, the melanotropins have important physiological functions, as discussed below. CONTROL OF SKIN COLORATION & PIGMENT ABNORMALITIES Fish, reptiles, and amphibia change the color of their skin for thermoregulation, camoufl age, and behavioral displays. Th ey do this in part by moving black or brown granules into or out of the periphery of pigment cells called melanophores. Th e granules are made up of melanins, which are synthesized from dopamine (see Chapter 7 ) and dopaquinone. Th e movement of these granules is controlled by a variety of hormones and neurotransmitters, including α- and β-MSH, melaninconcentrating hormone, melatonin, and catecholamines. Mammals have no melanophores containing pigment granules that disperse and aggregate, but they do have melanocytes, which have multiple processes containing melanin granules. Melanocytes express melanotropin-1 receptors. Treatment with MSHs accelerates melanin synthesis, causing readily detectable darkening of the skin in humans in 24 h. As noted above, α- and β-MSH do not circulate in adult humans, and their function is unknown. However, ACTH binds to melanotropin-1 receptors. Indeed, the pigmentary changes in several human endocrine diseases are due to changes in circulating ACTH. For example, abnormal pallor is a hallmark of hypopituitarism. Hyperpigmentation occurs in patients with adrenal insuffi ciency due to primary adrenal disease. Indeed, the presence of hyperpigmentation in association with adrenal insuffi ciency rules out the possibility that the insuffi ciency is secondary to pituitary or hypothalamic disease because in these conditions, plasma ACTH is not increased (see Chapter 20 ). Other disorders of pigmentation result from peripheral mechanisms. Th us, albinos have a congenital inability to synthesize melanin. Th is can result from a variety of diff erent genetic defects in the pathways for melanin synthesis. Piebaldism is characterized by patches of skin that lack melanin as a result of congenital defects in the migration of pigment cell precursors from the Signal peptide (–131) γ−MSH (–55 to –44) β-LPH (42–134) β-LPH ACTH (1–39) AL and IL γ−MSH α-MSH (1–13) β-MSH (84–101) Met-enkephalin (104–108) γ-LPH (42–101) β-Endorphin (104–134) CLIP (18–39) Arg-Lys Arg-Arg Lys-Arg Lys-Arg Lys-Arg Lys-Arg Lys-Lys Lys-Lys Lys-Lys Arg-Arg Fast in IL Slow in AL ACTH AL and IL IL only Amino terminal fragment FIGURE 182 Schematic representation of the preproopiomelanocortin molecule formed in pituitary cells, neurons, and other tissues . The numbers in parentheses identify the amino acid sequences in each of the polypeptide fragments. For convenience, the amino acid sequences are numbered from the amino terminal of ACTH and read toward the carboxyl terminal portion of the parent molecule, whereas the amino acid sequences in the other portion of the molecule read to the left to – 131, the amino terminal of the parent molecule. The locations of Lys–Arg and other pairs of basic amino acids residues are also indicated; these are the sites of proteolytic cleavage in the formation of the smaller fragments of the parent molecule. AL, anterior lobe; IL, intermediate lobe. 326 SECTION III Endocrine and Reproductive Physiology neural crest during embryonic development. Not only the condition but also the precise pattern of the loss is passed from one generation to the next. Vitiligo involves a similar patchy loss of melanin, but the loss develops progressively aft er birth secondary to an autoimmune process that targets melanocytes. GROWTH HORMONE BIOSYNTHESIS & CHEMISTRY Th e long arm of human chromosome 17 contains the growth hormone-hCS cluster that contains fi ve genes: one, hGH-N , codes for the most abundant (“normal”) form of growth hormone; a second, hGH-V , codes for the variant form of growth hormone (see below); two code for human chorionic somatomammotropin (hCS) (see Chapter 22 ); and the fi ft h is probably an hCS pseudogene. Growth hormone that is secreted into the circulation by the pituitary gland consists of a complex mixture of hGH-N, peptides derived from this molecule with varying degrees of posttranslational modifi cations, such as glycosylation, and a splice variant of hGH-N that lacks amino acids 32–46. Th e physiologic signifi cance of this complex array of hormones has yet to be fully understood, particularly since their structural similarities make it diffi cult to assay for each species separately. Nevertheless, there is emerging evidence that, while the various peptides share a broad range of functions, they may occasionally exert actions in opposition to one another. hGH-V and hCS, on the other hand, are primarily products of the placenta, and as a consequence are only found in appreciable quantities in the circulation during pregnancy (see Chapter 22 ). SPECIES SPECIFICITY Th e structure of growth hormone varies considerably from one species to another. Porcine and simian growth hormones have only a transient eff ect in the guinea pig. In monkeys and humans, bovine and porcine growth hormones do not even have a transient eff ect on growth, although monkey and human growth hormones are fully active in both monkeys and humans. Th ese facts are relevant to public health discussions surrounding the presence of bovine growth hormones (used to increase milk production) in dairy products, as well as the popularity of growth hormone supplements, marketed via the Internet, with body builders. Controversially, recombinant human growth hormone has also been given to children who are short in stature, but otherwise healthy (ie, without growth hormone defi ciency), with apparently limited results. PLASMA LEVELS, BINDING, & METABOLISM A portion of circulating growth hormone is bound to a plasma protein that is a large fragment of the extracellular domain of the growth hormone receptor (see below). It appears to be produced by cleavage of receptors in humans, and its concentration is an index of the number of growth hormone receptors in the tissues. Approximately 50% of the circulating pool of growth hormone activity is in the bound form, providing a reservoir of the hormone to compensate for the wide fl uctuations that occur in secretion (see below). Th e basal plasma growth hormone level measured by radioimmunoassay in adult humans is normally less than 3 ng/mL. Th is represents both the protein-bound and free forms. Growth hormone is metabolized rapidly, at least in part in the liver. Th e half-life of circulating growth hormone in humans is 6–20 min, and the daily growth hormone output has been calculated to be 0.2–1.0 mg/d in adults. GROWTH HORMONE RECEPTORS Th e growth hormone receptor is a 620-amino-acid protein with a large extracellular portion, a transmembrane domain, and a large cytoplasmic portion. It is a member of the cytokine receptor superfamily, which is discussed in Chapter 3 . Growth hormone has two domains that can bind to its receptor, and when it binds to one receptor, the second binding site attracts another, producing a homodimer ( Figure 18–3 ). Dimerization is essential for receptor activation. Growth hormone has widespread eff ects in the body (see below), so even though it is not yet possible precisely to correlate intracellular and whole body eff ects, it is not surprising that, like insulin, growth hormone activates many diff erent intracellular signaling cascades ( Figure 18–3 ). Of particular note is its activation of the JAK2–STAT pathway. JAK2 is a member of the Janus family of cytoplasmic tyrosine kinases. STATs (for signal transducers and activators of transcription) are a family of cytoplasmic transcription factors that, upon phosphorylation by JAK kinases, migrate to the nucleus where they activate various genes. JAK–STAT pathways are known also to mediate the eff ects of prolactin and various other growth factors. EFFECTS ON GROWTH In young animals in which the epiphyses have not yet fused to the long bones (see Chapter 21 ), growth is inhibited by hypophysectomy and stimulated by growth hormone. Chondrogenesis is accelerated, and as the cartilaginous epiphysial plates widen, they lay down more bone matrix at the ends of long bones. In this way, stature is increased. Prolonged treatment of animals with growth hormone leads to gigantism. When the epiphyses are closed, linear growth is no longer possible. In this case, an overabundance of growth hormone produces the pattern of bone and soft tissue deformities known in humans as acromegaly . Th e sizes of most of the viscera are increased. Th e protein content of the body is increased, and the fat content is decreased (see Clinical Box 18–1 ). CHAPTER 18 The Pituitary Gland 327 EFFECTS ON PROTEIN & ELECTROLYTE HOMEOSTASIS Growth hormone is a protein anabolic hormone and produces a positive nitrogen and phosphorus balance, a rise in plasma phosphorus, and a fall in blood urea nitrogen and amino acid levels. In adults with growth hormone defi ciency, recombinant human growth hormone produces an increase in lean body mass and a decrease in body fat, along with an increase in metabolic rate and a fall in plasma cholesterol. Gastrointestinal absorption of Ca 2+ is increased. Na + and K + excretion is reduced by an action independent of the adrenal glands, probably because these electrolytes are diverted from the kidneys to the growing tissues. On the other hand, excretion of the amino acid 4-hydroxyproline is increased during this growth, refl ective of the ability of growth hormone to stimulate the synthesis of soluble collagen. EFFECTS ON CARBOHYDRATE & FAT METABOLISM Th e actions of growth hormone on carbohydrate metabolism are discussed in Chapter 24 . At least some forms of growth hormone are diabetogenic because they increase hepatic glucose output and exert an anti-insulin eff ect in muscle. Growth hormone is also ketogenic and increases circulating free fatty acid (FFA) levels. Th e increase in plasma FFA, which takes several hours to develop, provides a ready source of energy for the tissues during hypoglycemia, fasting, and stressful stimuli. Growth hormone does not stimulate β cells of the pancreas directly, but it increases the ability of the pancreas to respond to insulinogenic stimuli such as arginine and glucose. Th is is an additional way growth hormone promotes growth, since insulin has a protein anabolic eff ect (see Chapter 24 ). SOMATOMEDINS Th e eff ects of growth hormone on growth, cartilage, and protein metabolism depend on an interaction between growth hormone and somatomedins , which are polypeptide growth factors secreted by the liver and other tissues. Th e fi rst of these factors isolated was called sulfation factor because it stimulated the incorporation of sulfate into cartilage. However, it also stimulated collagen formation, and its name was changed to somatomedin. It then became clear that there are a variety of diff erent somatomedins and that they are members of an increasingly large family of growth factors that aff ect many diff erent tissues and organs. Th e principal (and in humans probably the only) circulating somatomedins are insulin-like growth factor I (IGF-I, somatomedin C) and IGF-II . Th ese factors are closely related to insulin, except that their C chains are not P P P P P P P P GH GHR JAK2 IRS P P SHC DAG PKC P MAP K Grb2 STATs STAT5 STAT1 STAT3 SRF SRF TCF PLC p90RSK PLA2 GLE-2 P450-3A10 GLE-1 Spi 2.1 SIE SRE c-fos STAT5 Ca2+ FIGURE 183 Some of the principal signaling pathways activated by the dimerized growth hormone receptor (GHR) . Solid arrows indicate established pathways; dashed arrows indicate probable pathways. The details of the PLC pathway and the pathway from Grb2 to MAP K are discussed in Chapter 2 . The small uppercase letter P’s in yellow hexagons represent phosphorylation of the factor indicated. GLE-1 and GLE-2, interferon γ-activated response elements; IRS, insulin receptor substrate; p90 RSK , an S6 kinase; PLA 2 , phospholipase A 2 ; SIE, Sis-induced element; SRE, serum response element; SRF, serum response factor; TCF, ternary complex factor. 328 SECTION III Endocrine and Reproductive Physiology separated ( Figure 18–4 ) and they have an extension of the A chain called the D domain. Th e hormone relaxin (see Chapter 22 ) is also a member of this family. Humans have two related relaxin isoforms, and both resemble IGF-II. In humans a variant form of IGF-I lacking three amino terminal amino acid residues has been found in the brain, and there are several variant forms of human IGF-II ( Figure 18–4 ). Th e mRNAs for IGF-I and IGF-II are found in the liver, in GPETLCGAELVDALQFVCGDRGFYFNKPTGYGSSSRRAPQTGIVDECCFRSCDLRRLEMYCAPLKPAKSA AYRPSETLCGGELVDTLQFVCGDRGFYFSRPA--SRVSRRSR--GIVEECCFRSCDLALLETYCAT--PAKSE FVNQHLCGSHLVEALYLVCGERGFFYTPKT GIVEQCCTSICSLYQLENYCN hlGF-I hlGF-II h ins I II II II I B C A D C C C G C D C E E E L L P P P P L A A A A A K S E 21 1 T T V I T Y Y C Q C G G G G G G E E S S S S R R R R R R R R S Y L L V L V V D D D T L F F F F R S FIGURE 184 Structure of human IGF-I, IGF-II, and insulin (ins) (top) . The lower panel shows the structure of human IGF-II with its disulfi de bonds, as well as three variant structures shown: a 21-aa extension of the C-terminus, a tetrapeptide substitution at Ser-29, and a tripeptide substitution of Ser-33. CLINICAL BOX 18–1 Gigantism & Acromegaly Tumors of the somatotropes of the anterior pituitary (pituitary adenoma) secrete large amounts of growth hormone, leading to gigantism in children and to acromegaly in adults. If the tumor arises before puberty, the individual may grow to an extraordinary height. After linear growth is no longer possible, on the other hand, the characteristic features of acromegaly arise, including greatly enlarged hands and feet, vertebral changes attributable to osteoarthritis, soft tissue swelling, hirsutism, and protrusion of the brow and jaw. Abnormal growth of internal organs may eventually impair their function such that the condition, which has an insidious onset, can prove fatal if left untreated. Hypersecretion of growth hormone is accompanied by hypersecretion of prolactin in 20–40% of patients with acromegaly. About 25% of patients have abnormal glucose tolerance tests, and 4% develop lactation in the absence of pregnancy. Acromegaly can be caused by extra-pituitary as well as intrapituitary growth hormone-secreting tumors and by hypothalamic tumors that secrete GHRH, but the latter are rare. THERAPEUTIC HIGHLIGHTS The mainstay of therapy for acromegaly remains the use of somatostatin analogues that inhibit the secretion of growth hormone. A growth hormone receptor antagonist has recently become available and has been found to reduce plasma IGF-I and produce clinical improvement in cases of acromegaly that fail to respond to other treatments. Surgical removal of the pituitary tumor is also helpful in both acromegaly and gigantism, but sometimes challenging to perform due to the tumor’s often invasive nature. In any case, adjuvant pharmacological therapy must often be continued after surgery to control ongoing symptoms. CHAPTER 18 The Pituitary Gland 329 cartilage, and in many other tissues, indicating that they are likely synthesized in these tissues. Th e properties of IGF-I, IGF-II, and insulin are compared in Table 18–2 . Both IGF-I and IGF-II are tightly bound to proteins in the plasma, and, at least for IGF-I, this prolongs their half-life in the circulation. Six diff erent IGF-binding proteins, with diff erent patterns of distribution in various tissues, have been identifi ed. All are present in plasma, with IGF-binding protein-3 (IGFBP-3) accounting for 95% of the binding in the circulation. Th e contribution of the IGFs to the insulinlike activity in blood is discussed in Chapter 24 . Th e IGF-I receptor is very similar to the insulin receptor and probably uses similar or identical intracellular signaling pathways. Th e IGF-II receptor has a distinct structure (see Figure 24–5 ) and TABLE 182 Comparison of insulin and the insulin-like growth factors. Insulin IGF-I IGF-II Other names … Somatomedin C Multiplicationstimulating activity (MSA) Number of amino acids 51 70 67 Source Pancreatic B cells Liver and other tissues Diverse tissues Level regulated by Glucose Growth hormone after birth, nutritional status Unknown Plasma levels 0.3–2 ng/mL 10–700 ng/ mL; peaks at puberty 300–800 ng/mL Plasmabinding proteins No Yes Yes Major physiologic role Control of metabolism Skeletal and cartilage growth Growth during fetal development is involved in the intracellular targeting of acid hydrolases and other proteins to intracellular organelles. Secretion of IGF-I is independent of growth hormone before birth but is stimulated by growth hormone aft er birth, and it has pronounced growth-stimulating activity. Its concentration in plasma rises during childhood and peaks at the time of puberty, then declines to low levels in old age. IGF-II is largely independent of growth hormone and plays a role in the growth of the fetus before birth. In human fetuses in which it is overexpressed, several organs, especially the tongue, other muscles, kidneys, heart, and liver, develop out of proportion to the rest of the body. In adults, the gene for IGF-II is expressed only in the choroid plexus and meninges. DIRECT & INDIRECT ACTIONS OF GROWTH HORMONE Our understanding of the mechanism of action of growth hormone has evolved. It was originally thought to produce growth by a direct action on tissues, and then later was believed to act solely through its ability to induce somatomedins. However, if growth hormone is injected into one proximal tibial epiphysis, a unilateral increase in cartilage width is produced, and cartilage, like other tissues, makes IGF-I. A current hypothesis to explain these results holds that growth hormone acts on cartilage to convert stem cells into cells that respond to IGF-I. Locally produced as well as circulating IGF-I then makes the cartilage grow. However, the independent role of circulating IGF-I remains important, since infusion of IGF-I in hypophysectomized rats restores bone and body growth. Overall, it seems that growth hormone and somatomedins can act both in cooperation and independently to stimulate pathways that lead to growth. Th e situation is almost certainly complicated further by the existence of multiple forms of growth hormone in the circulation that can, in some situations, have opposing actions. Figure 18–5 is a summary of current views of the other actions of growth hormone and IGF-I. However, growth hormone probably combines with circulating and locally produced IGF-I in various proportions to produce at least some of the latter eff ects. GH Na+ retention Decreased insulin sensitivity Lipolysis Protein synthesis Epiphysial growth IGF-I Insulin-like activity Antilipolytic activity Protein synthesis Epiphysial growth FIGURE 185 Direct and indirect actions of growth hormone (GH). The latter are mediated by the ability of growth hormone to induce production of IGF-I. (Courtesy of R Clark and N Gesundheit.) 330 SECTION III Endocrine and Reproductive Physiology HYPOTHALAMIC & PERIPHERAL CONTROL OF GROWTH HORMONE SECRETION Th e secretion of growth hormone is not stable over time. Adolescents have the highest circulating levels of growth hormone, followed by children and fi nally adults. Levels decline in old age, and there has been considerable interest in injecting growth hormone to counterbalance the eff ects of aging. Th e hormone increases lean body mass and decreases body fat, but it does not produce statistically signifi cant increases in muscle strength or mental status. Th ere are also diurnal variations in growth hormone secretion superimposed on these developmental stages. Growth hormone is found at relatively low levels during the day, unless specifi c triggers for its release are present (see below). During sleep, on the other hand, large pulsatile bursts of growth hormone secretion occur. Th erefore, it is not surprising that the secretion of growth hormone is under hypothalamic control. Th e hypothalamus controls growth hormone production by secreting growth hormone-releasing hormone (GHRH) as well as somatostatin, which inhibits growth hormone release (see Chapter 17 ). Th us, the balance between the eff ects of these hypothalamic factors on the pituitary will determine the level of growth hormone release. Th e stimuli of growth hormone secretion can therefore act by increasing hypothalamic secretion of GHRH, decreasing secretion of somatostatin, or both. A third regulator of growth hormone secretion is ghrelin . Th e main site of ghrelin synthesis and secretion is the stomach, but it is also produced in the hypothalamus and has marked growth hormone-stimulating activity. In addition, it appears to be involved in the regulation of food intake (see Chapter 26 ). Growth hormone secretion is under feedback control (see Chapter 16 ), like the secretion of other anterior pituitary hormones. It acts on the hypothalamus to antagonize GHRH release. Growth hormone also increases circulating IGF-I, and IGF-I in turn exerts a direct inhibitory action on growth hormone secretion from the pituitary. It also stimulates somatostatin secretion ( Figure 18–6 ). Stimuli Aff ecting Growth Hormone Secretion Th e basal plasma growth hormone concentration ranges from 0 to 3 ng/mL in normal adults. However, secretory rates cannot be estimated from single values because of their irregular nature. Th us, average values over 24 h (see below) and peak values may be more meaningful, albeit diffi cult to assess in the clinical setting. Th e stimuli that increase growth hormone secretion are summarized in Table 18–3 . Most of them fall into three general categories: (1) conditions such as hypoglycemia and/or fasting in which there is an actual or threatened decrease in the substrate for energy production in cells, (2) conditions in which the amounts of certain SS Anterior pituitary Liver (and other organs) GH Tissues IGF-I GHRH Hypothalamus Ghrelin FIGURE 186 Feedback control of growth hormone secretion . Solid arrows represent positive eff ects and dashed arrows represent inhibition. GH, growth hormone; GHRH, growth hormone releasing hormone; IGF-I, insulin-like growth factor-I; SS, somatostatin. TABLE 183 Stimuli that affect growth hormone secretion in humans. Stimuli that increase secretion Hypoglycemia 2-Deoxyglucose Exercise Fasting Increase in circulating levels of certain amino acids Protein meal Infusion of arginine and some other amino acids Glucagon Stressful stimuli Pyrogen Lysine vasopressin Various psychologic stresses Going to sleep L -Dopa and α-adrenergic agonists that penetrate the brain Apomorphine and other dopamine receptor agonists Estrogens and androgens Stimuli that decrease secretion REM sleep Glucose Cortisol FFA Medroxyprogesterone Growth hormone and IGF-I amino acids are increased in the plasma, and (3) stressful stimuli. Th e response to glucagon has been used as a test of growth hormone reserve. Growth hormone secretion is also increased in subjects deprived of rapid eye movement CHAPTER 18 The Pituitary Gland 331 (REM) sleep (see Chapter 14 ) and inhibited during normal REM sleep. Glucose infusions lower plasma growth hormone levels and inhibit the response to exercise. Th e increase produced by 2-deoxyglucose is presumably due to intracellular glucose defi ciency, since this compound blocks the catabolism of glucose 6-phosphate. Sex hormones induce growth hormone secretion, increase growth hormone responses to provocative stimuli such as arginine and insulin, and also serve as permissive factors for the action of growth hormone in the periphery. Th is likely contributes to the relatively high levels of circulating growth hormone and associated growth spurt in puberty. Growth hormone secretion is also induced by thyroid hormones. Growth hormone secretion is inhibited, on the other hand, by cortisol, FFA, and medroxyprogesterone. Growth hormone secretion is increased by l -dopa, which increases the release of dopamine and norepinephrine in the brain, and by the dopamine receptor agonist apomorphine. PHYSIOLOGY OF GROWTH Growth hormone, while being essentially unimportant for fetal development, is the most important hormone for postnatal growth. However, growth overall is a complex phenomenon that is aff ected not only by growth hormone and somatomedins, but also, as would be predicted by the previous discussion, by thyroid hormones, androgens, estrogens, glucocorticoids, and insulin. It is also aff ected, of course, by genetic factors, and it depends on adequate nutrition. It is normally accompanied by an orderly sequence of maturational changes, and it involves accretion of protein and an increase in length and size, not just an increase in weight (which could refl ect the formation of fat or retention of salt and water rather than growth per se). ROLE OF NUTRITION Th e food supply is the most important extrinsic factor aff ecting growth. Th e diet must be adequate not only in protein content but also in essential vitamins and minerals (see Chapter 26 ) and in calories, so that ingested protein is not burned for energy. However, the age at which a dietary defi ciency occurs appears to be an important consideration. For example, once the pubertal growth spurt has commenced, considerable linear growth continues even if caloric intake is reduced. Injury and disease, on the other hand, stunt growth because they increase protein catabolism. GROWTH PERIODS Patterns of growth vary somewhat from species to species. Rats continue to grow, although at a declining rate, throughout life. In humans, two periods of rapid growth occur ( Figure 18–7 ): the fi rst in infancy and the second in late puberty just before 10 12 14 16 18 20 Girls Height gain (cm/yr) Boys Age in years 2 4 6 8 0 5.1 10.2 15.2 20.3 25.4 FIGURE 187 Rate of growth in boys and girls from birth to age 20. 10 12 14 16 18 20 Brain and head Percent of size at age 20 Body and most visceral organs Age in years 0 2 4 6 8 20 40 60 80 100 120 140 160 180 200 Lymphoid tissue Reproductive organs FIGURE 188 Growth of diff erent tissues at various ages as a percentage of size at age 20 . The curves are composites that include data for both boys and girls. growth stops. Th e fi rst period of accelerated growth is partly a continuation of the fetal growth period. Th e second growth spurt, at the time of puberty, is due to growth hormone, androgens, and estrogens, and the subsequent cessation of growth is due in large part to closure of the epiphyses in the long bones by estrogens (see Chapter 21 ). Aft er this time, further increases in height are not possible. Because girls mature earlier than boys, this growth spurt appears earlier in girls. Of course, in both sexes the rate of growth of individual tissues varies ( Figure 18–8 ). 332 SECTION III Endocrine and Reproductive Physiology It is interesting that at least during infancy, growth is not a continuous process but is episodic or saltatory. Increases in length of human infants of 0.5–2.5 cm in a few days are separated by periods of 2–63 days during which no measurable growth can be detected. Th e cause of the episodic growth is unknown. HORMONAL EFFECTS Th e contributions of hormones to growth aft er birth are shown diagrammatically in Figure 18–9 . Plasma growth hormone is elevated in newborns. Subsequently, average resting levels fall but the spikes of growth hormone secretion are larger, especially during puberty, so the mean plasma level over 24 h is increased; it is 2–4 ng/mL in normal adults, but 5–8 ng/mL in children. One of the factors stimulating IGF-I secretion is growth hormone, and plasma IGF-I levels rise during childhood, reaching a peak at 13–17 years of age. In contrast, IGF-II levels are constant throughout postnatal growth. Th e growth spurt that occurs at the time of puberty ( Figure 18–7 ) is due in part to the protein anabolic eff ect of androgens, and the secretion of adrenal androgens increases at this time in both sexes; however, it is also due to an interaction among sex steroids, growth hormone, and IGF-I. Treatment with estrogens and androgens increases the secretion of growth hormone in response to various stimuli and increases plasma IGF-I secondary to this increase in circulating growth hormone. Th is, in turn, causes growth. Although androgens and estrogens initially stimulate growth, estrogens ultimately terminate growth by causing the epiphyses to fuse to the long bones (epiphysial closure). Once the epiphyses have closed, linear growth ceases (see Chapter 21 ). Th is is why patients with sexual precocity are apt to be dwarfed. On the other hand, men who were castrated before puberty tend to be tall because their estrogen production is decreased and their epiphyses remain open, allowing some growth to continue past the normal age of puberty. Birth 2 4 6 8 10 12 14 16 18 20 Thyroid hormones Growth hormone Androgens and estrogens Age (years) FIGURE 189 Relative importance of hormones in human growth at various ages . (Courtesy of Fisher DA.) In hypophysectomized animals, growth hormone increases growth but this eff ect is potentiated by thyroid hormones, which by themselves have no eff ect on growth. Th e action of thyroid hormones in this situation is therefore permissive to that of growth hormone, possibly via potentiation of the actions of somatomedins. Th yroid hormones also oft en appear to be necessary for the normal rate of growth hormone secretion; basal growth hormone levels are normal in hypothyroidism, but the response to hypoglycemia is frequently blunted. Th yroid hormones have widespread eff ects on the ossifi cation of cartilage, the growth of teeth, the contours of the face, and the proportions of the body. Hypothyroid dwarfs (also known as cretins ) therefore have infantile features ( Figure 18–10 ). Patients who are dwarfed because of panhypopituitarism have features consistent with their chronologic age until puberty, but since they do not mature sexually, they have juvenile features in adulthood ( Clinical Box 18–2 ). Th e eff ect of insulin on growth is discussed in Chapter 24 . Diabetic animals fail to grow, and insulin causes growth in hypophysectomized animals. However, the growth is appreciable only when large amounts of carbohydrate and protein are supplied with the insulin. Adrenocortical hormones other than androgens exert a permissive action on growth in the sense that adrenalectomized animals fail to grow unless their blood pressures and circulations are maintained by replacement therapy. On the other hand, glucocorticoids are potent inhibitors of growth because of their direct action on cells, and treatment of children with pharmacologic doses of steroids slows or stops growth for as long as the treatment is continued. CATCHUP GROWTH Following illness or starvation in children, a period of catchup growth ( Figure 18–11 ) takes place during which the growth rate is greater than normal. Th e accelerated growth usually continues until the previous growth curve is reached, then slows to normal. Th e mechanisms that bring about and control catch-up growth are unknown. PITUITARY GONADOTROPINS & PROLACTIN CHEMISTRY FSH and LH are each made up of an α and a β subunit. Th ey are glycoproteins that contain the hexoses mannose and galactose, the hexosamines N-acetylgalactosamine and N-acetylglycosamine, and the methylpentose fucose. Th ey also contain sialic acid. Th e carbohydrate in the gonadotropin molecules increases their potency by markedly slowing their metabolism. Th e half-life of human FSH is about 170 min; the half-life of LH is about 60 min. Loss-of-function CHAPTER 18 The Pituitary Gland 333 mutations in the FSH receptor cause hypogonadism. Gainof- function mutations cause a spontaneous form of ovarian hyperstimulation syndrome , a condition in which many follicles are stimulated and cytokines are released from the ovary, causing increased vascular permeability and shock. Human pituitary prolactin contains 199 amino acid residues and three disulfi de bridges and has considerable structural similarity to human growth hormone and human chorionic somatomammotropin (hCS). Th e half-life of prolactin, like that of growth hormone, is about 20 min. Structurally similar prolactins are secreted by the endometrium and by the placenta. RECEPTORS Th e receptors for FSH and LH are G-protein coupled receptors coupled to adenylyl cyclase through a stimulatory G protein (G s ; see Chapter 2 ). In addition, each has an extended, glycosylated extracellular domain. Th e human prolactin receptor resembles the growth hormone receptor and is one of the superfamily of receptors that includes the growth hormone receptor and receptors for many cytokines and hematopoietic growth factors (see Chapters 2 and 3 ). It dimerizes and activates the Janus kinase/signal transducers and activators of transcription (JAK–STAT) pathway and other intracellular enzyme cascades ( Figure 18–3 ). ACTIONS Th e testes and ovaries become atrophic when the pituitary is removed or destroyed. Th e actions of prolactin and the gonadotropins FSH and LH, as well as those of the gonadotropin secreted by the placenta, are described in detail in Chapters 22 and 23 . In brief, FSH helps maintain the spermatogenic epithelium by stimulating Sertoli cells in the male and is responsible for the early growth of ovarian follicles in the female. LH is tropic for the Leydig cells and, in females, is responsible for the fi nal maturation of the ovarian follicles and estrogen secretion from them. It is also responsible for ovulation, the initial formation of the corpus luteum, and secretion of progesterone. Prolactin causes milk secretion from the breast aft er estrogen and progesterone priming. Its eff ect on the breast involves increasing mRNA levels and subsequent production of casein and lactalbumin. However, the action of the hormone is not exerted on the cell nucleus and is prevented by inhibitors of microtubules. Prolactin also inhibits the eff ects of Level of symphysis Normal 2 years Normal 8 years Hypothyroid 8 years Dwarf–not hypothyroid 8 years Inches Centimeters 60 55 50 45 40 35 30 25 20 15 10 5 0 0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 FIGURE 1810 Normal and abnormal growth . Hypothyroid dwarfs (cretins) retain their infantile proportions, whereas dwarfs of the constitutional type and, to a lesser extent, of the hypopituitary type have proportions characteristic of their chronologic age. See also Clinical Box 18–2 . (Reproduced, with permission, from Wilkins L: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence , 3rd ed. Thomas, 1966.) 334 SECTION III Endocrine and Reproductive Physiology gonadotropins, possibly by an action at the level of the ovary. It also prevents ovulation in lactating women. Th e function of prolactin in normal males is unsettled, but excess prolactin secreted by tumors causes impotence. REGULATION OF PROLACTIN SECRETION Th e regulatory factors for prolactin secretion by the pituitary overlap, in part, with those causing secretion of growth hormone, but there are important diff erences, and some stimuli increase prolactin secretion while decreasing that of growth hormone (and vice versa) ( Table 18–4 ). Th e normal plasma prolactin concentration is approximately 5 ng/mL in men and 8 ng/mL in women. Secretion is tonically inhibited by the hypothalamus, and section of the pituitary stalk leads to an increase in circulating prolactin. Th us, the eff ect of the hypothalamic prolactin-inhibiting hormone, dopamine, must normally be greater than the eff ects of the various hypothalamic peptides with prolactin-releasing activity. In humans, prolactin secretion is increased by exercise, surgical and psychologic stresses, and stimulation of the nipple ( Table 18–4 ). Th e plasma prolactin level rises during sleep, the rise starting aft er the onset of sleep and persisting throughout the sleep period. Secretion is increased during pregnancy, reaching a peak at the time of parturition. Aft er delivery, the plasma concentration falls to nonpregnant levels in about 8 days. Suckling produces a prompt increase in secretion, but the magnitude of this rise gradually declines aft er a woman has been nursing for more than 3 months. With prolonged lactation, milk secretion occurs with prolactin levels that are in the normal range. l -Dopa decreases prolactin secretion by increasing the formation of dopamine; bromocriptine, and other dopamine agonists inhibit secretion because they stimulate dopamine receptors. Chlorpromazine and related drugs that block dopamine receptors increase prolactin secretion. Th yrotropin-releasing hormone (TRH) stimulates the secretion of prolactin in addition to TSH, and additional polypeptides with prolactin-releasing activity are present in hypothalamic tissue. Estrogens produce a slowly developing increase in prolactin secretion as a result of a direct action on the lactotropes. It has now been established that prolactin facilitates the secretion of dopamine in the median eminence. Th us, CLINICAL BOX 18–2 Dwarfi sm The accompanying discussion of growth control should suggest several possible etiologies of short stature. It can be due to GHRH defi ciency, growth hormone defi ciency, or defi cient secretion of IGF-I. Isolated growth hormone defi ciency is often due to GHRH defi ciency, and in these instances, the growth hormone response to GHRH is normal. However, some patients with isolated growth hormone defi ciency have abnormalities of their growth hormone secreting cells. In another group of dwarfed children, the plasma growth hormone concentration is normal or elevated but their growth hormone receptors are unresponsive as a result of loss-of-function mutations. The resulting condition is known as growth hormone insensitivity or Laron dwarfi sm . Plasma IGF-I is markedly reduced, along with IGFBP 3, which is also growth hormone-dependent. African pygmies have normal plasma growth hormone levels and a modest reduction in the plasma level of growth hormone-binding protein. However, their plasma IGF-I concentration fails to increase at the time of puberty and they experience less growth than nonpygmy controls throughout the prepubertal period. Short stature may also be caused by mechanisms independent of specifi c defects in the growth hormone axis. It is characteristic of childhood hypothyroidism (cretinism) and occurs in patients with precocious puberty. It is also part of the syndrome of gonadal dysgenesis seen in patients who have an XO chromosomal pattern instead of an XX or XY pattern (see Chapter 22 ). Various bone and metabolic diseases also cause stunted growth, and in many cases there is no known cause (“constitutional delayed growth”). Chronic abuse and neglect can also cause dwarfi sm in children, independent of malnutrition. This condition is known as psychosocial dwarfi sm or the Kaspar Hauser syndrome , named for the patient with the fi rst reported case. Finally, achondroplasia , the most common form of dwarfi sm in humans, is characterized by short limbs with a normal trunk. It is an autosomal dominant condition caused by a mutation in the gene that codes for fi broblast growth factor receptor 3 (FGFR3) . This member of the fi broblast growth receptor family is normally expressed in cartilage and the brain. THERAPEUTIC HIGHLIGHTS The treatment of dwarfi sm is dictated by its underlying cause. If treatment to replace the relevant hormone is commenced promptly in appropriate childhood cases, almost normal stature can often be attained. Thus, the availability of recombinant forms of growth hormone and IGF-I has greatly improved treatment in cases where these hormones are defi cient. CHAPTER 18 The Pituitary Gland 335 INSULIN SENSITIVITY Hypophysectomized animals have a tendency to become hypoglycemic, especially when fasted. Hypophysectomy ameliorates diabetes mellitus (see Chapter 24 ) and markedly increases the hypoglycemic eff ect of insulin. Th is is due in part to the defi ciency of adrenocortical hormones, but hypophysectomized animals are more sensitive to insulin than adrenalectomized animals because they also lack the anti-insulin eff ect of growth hormone. WATER METABOLISM Although selective destruction of the supraoptic–posterior pituitary causes diabetes insipidus (see Chapter 17 ), removal of both the anterior and posterior pituitary usually causes no more than a transient polyuria. In the past, there was speculation that the anterior pituitary secreted a “diuretic hormone,” but the amelioration of the diabetes insipidus is actually TABLE 184 Comparison of factors affecting the secretion of human prolactin and growth hormone. Factor Prolactin Growth Hormone Sleep I+ I+ Nursing I++ N Breast stimulation in nonlactating women I N Stress I+ I+ Hypoglycemia I I+ Strenuous exercise I I Sexual intercourse in women I N Pregnancy I++ N Estrogens I I Hypothyroidism I N TRH I+ N Phenothiazines, butyrophenones I+ N Opioids I I Glucose N D Somatostatin N D+ L -Dopa D+ I+ Apomorphine D+ I+ Bromocriptine and related ergot derivatives D+ I I, moderate increase; I+, marked increase; I++, very marked increase; N, no change; D, moderate decrease; D+, marked decrease; TRH, thyrotropin-releasing hormone. prolactin acts in the hypothalamus in a negative feedback fashion to inhibit its own secretion. EFFECTS OF PITUITARY INSUFFICIENCY CHANGES IN OTHER ENDOCRINE GLANDS Th e widespread changes that develop when the pituitary is removed surgically or destroyed by disease in humans or animals are predictable in terms of the known hormonal functions of the gland. In hypopituitarism, the adrenal cortex atrophies, and the secretion of adrenal glucocorticoids and sex hormones falls to low levels. Stress induced increases in aldosterone secretion are absent, but basal aldosterone secretion and increases induced by salt depletion are normal, at least for some time. Since no mineralocorticoid defi ciency is present, salt loss and hypovolemic shock do not develop, but the inability to increase glucocorticoid secretion makes patients with pituitary insuffi ciency sensitive to stress. Th e development of salt loss in long-standing hypopituitarism is discussed in Chapter 20 . Growth is inhibited (see above). Th yroid function is depressed to low levels, and cold is tolerated poorly. Th e gonads atrophy, sexual cycles stop, and some of the secondary sex characteristics disappear. 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 1 2 3 4 5 6 7 8 9 10111213141516171819 Age (y) Height (cm) Illness Catch-up growth FIGURE 1811 Growth curve for a normal boy who had an illness beginning at age 5 and ending at age 7 . The shaded area shows the range of normal heights for a given age. The red line shows actual growth of the boy studied. Catch-up growth eventually returned his height to his previous normal growth curve. (Modifi ed from Boersma B, Wit JM: Catch-up growth. Endocr Rev 1997;18:646.) 336 SECTION III Endocrine and Reproductive Physiology explained by a decrease in the osmotic load presented for excretion. Osmotically active particles hold water in the renal tubules (see Chapter 38 ). Because of the ACTH defi ciency, the rate of protein catabolism is decreased in hypophysectomized animals. Because of the TSH defi ciency, the metabolic rate is low. Consequently, fewer osmotically active products of catabolism are fi ltered and urine volume declines, even in the absence of vasopressin. Growth hormone defi ciency contributes to the depression of the glomerular fi ltration rate in hypophysectomized animals, and growth hormone increases the glomerular fi ltration rate and renal plasma fl ow in humans. Finally, because of the glucocorticoid defi ciency, there is the same defective excretion of a water load that is seen in adrenalectomized animals. Th e “diuretic” activity of the anterior pituitary can thus be explained in terms of the actions of ACTH, TSH, and growth hormone. OTHER DEFECTS When growth hormone defi ciency develops in adulthood, it is usually accompanied by defi ciencies in other anterior pituitary hormones. Th e defi ciency of ACTH and other pituitary hormones with MSH activity may be responsible for the pallor of the skin in patients with hypopituitarism. Th ere may be some loss of protein in adults, but wasting is not a feature of hypopituitarism in humans, and most patients with pituitary insuffi ciency are well nourished. CAUSES OF PITUITARY INSUFFICIENCY IN HUMANS Tumors of the anterior pituitary cause pituitary insuffi ciency. Suprasellar cysts, remnants of Rathke’s pouch that enlarge and compress the pituitary, are another cause of hypopituitarism. In women who have an episode of shock due to postpartum hemorrhage, the pituitary may become infarcted, with the subsequent development of postpartum necrosis (Sheehan syndrome). Th e blood supply to the anterior lobe is vulnerable because it descends on the pituitary stalk through the rigid diaphragma sellae, and during pregnancy the pituitary is enlarged. Pituitary infarction is usually extremely rare in men. CHAPTER SUMMARY Th e pituitary ■ gland plays a critical role in regulating the function of downstream glands, and also exerts independent endocrine actions on a wide variety of peripheral organs and tissues. It consists of two functional sections in humans: the anterior pituitary, which secretes mainly tropic hormones; and the posterior pituitary, which contains nerve endings that release oxytocin and vasopressin. Th e intermediate lobe is prominent in lower vertebrates but not in humans or other mammals. ■ Corticotropes of the anterior lobe synthesize proopiomelanocortin, which is the precursor of ACTH, endorphins, and melanotropins. Th e latter have a critical role in the control of skin coloration in fi sh, amphibians, and reptiles, whereas ACTH is a primary regulator of skin pigmentation in mammals. ■ Growth hormone is synthesized by somatotropes. It is secreted in an episodic fashion in response to hypothalamic factors, and secretion is subject to feedback inhibition. A portion of the circulating pool is protein-bound. ■ Growth hormone activates growth and infl uences protein, carbohydrate, and fat metabolism to react to stressful conditions. Many, but not all, of the peripheral actions of growth hormone can be attributed to its ability to stimulate production of IGF-I. ■ Growth reflects a complex interplay of growth hormone, IGF-I, and many other hormones as well as extrinsic influences and genetic factors. The consequences of over- or underproduction of such influences depends on whether this occurs before or after puberty. Deficiencies in components of the growth hormone pathway in childhood lead to dwarfism; overproduction results in gigantism, acromegaly, or both. ■ Th e pituitary also supplies hormones that regulate reproductive tissues and lactation—follicle-stimulating hormone, luteinizing hormone, and prolactin. Prolactin, in particular, is regulated by many of the factors that also regulate growth hormone secretion, although specifi c regulators may have opposing eff ects. MULTIPLECHOICE QUESTIONS For all questions, select the single best answer unless otherwise directed . 1. A neuroscientist is studying communication between the hypothalamus and pituitary in a rat model. She interrupts blood fl ow through the median eminence and then measures circulating levels of pituitary hormones following appropriate physiological stimulation. Secretion of which of the following hormones will be unaff ected by the experimental manipulation? A. Growth hormone B. Prolactin C. Th yroid stimulating hormone D. Follicle-stimulating hormone E. Vasopressin 2. Which of the following pituitary hormones is an opioid peptide? A. α-melanocyte-stimulating hormone (α-MSH) B. β-MSH C. ACTH D. Growth hormone E. β-endorphin 3. During childbirth, a woman suff ers a serious hemorrhage and goes into shock. Aft er she recovers, she displays symptoms of hypopituitarism. Which of the following will not be expected in this patient? A. Cachexia B. Infertility C. Pallor D. Low basal metabolic rate E. Intolerance to stress CHAPTER 18 The Pituitary Gland 337 4. A scientist fi nds that infusion of growth hormone into the median eminence of the hypothalamus in experimental animals inhibits the secretion of growth hormone and concludes that this proves that growth hormone feeds back to inhibit GHRH secretion. Do you accept this conclusion? No, because growth A. hormone does not cross the blood– brain barrier. B. No, because the infused growth hormone could be stimulating dopamine secretion. C. No, because substances placed in the median eminence could be transported to the anterior pituitary. D. Yes, because systemically administered growth hormone inhibits growth hormone secretion. E. Yes, because growth hormone binds GHRH, inactivating it. 5. Th e growth hormone receptor A. activates G s . B. requires dimerization to exert its eff ects. C. must be internalized to exert its eff ects. D. resembles the IGF-I receptor. E. resembles the ACTH receptor. CHAPTER RESOURCES Ayuk J, Sheppard MC: Growth hormone and its disorders. Postgrad Med J 2006;82:24. Boissy RE, Nordlund JJ: Molecular basis of congenital hypopigmentary disorders in humans: A review. Pigment Cell Res 1997;10:12. Brooks AJ, Waters MJ: Th e growth hormone receptor: mechanism of activation and clinical implications. Nat Rev Endocrinol 2010;6:515. Buzi F, Mella P, Pilotta A, Prandi E, Lanfranchi F, Carapella T: Growth hormone receptor polymorphisms. Endocr Dev 2007;11:28. Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson ICAF: SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc Natl Acad Sci USA 2008;105:2907. Hindmarsh PC, Dattani MT: Use of growth hormone in children. Nat Clin Pract Endocrinol Metab 2006;2:260. This page intentionally left blank 339 O B J E C T I V E S After studying this chapter, you should be able to: The Thyroid Gland C H A P T E R 19 INTRODUCTION Th e thyroid gland is one of the larger endocrine glands of the body. Th e gland has two primary functions. Th e fi rst is to secrete the thyroid hormones, which maintain the level of metabolism in the tissues that is optimal for their normal function. Th yroid hormones stimulate O 2 consumption by most of the cells in the body, help to regulate lipid and carbohydrate metabolism, and thereby infl uence body mass and mentation. Consequences of thyroid gland dysfunction depend on the life stage at which they occur. Th e thyroid is not essential for life, but its absence or hypofunction during fetal and neonatal life results in severe mental retardation and dwarfi sm. In adults, hypothyroidism is accompanied by mental and physical slowing and poor resistance to cold. Conversely, excess thyroid secretion leads to body wasting, nervousness, tachycardia, tremor, and excess heat production. Th yroid function is controlled by the thyroid-stimulating hormone (TSH, thyrotropin) of the anterior pituitary. Th e secretion of this hormone is in turn increased by thyrotropin-releasing hormone (TRH) from the hypothalamus and is also subject to negative feedback control by high circulating levels of thyroid hormones acting on the anterior pituitary and the hypothalamus. Th e second function of the thyroid gland is to secrete calcitonin, a hormone that regulates circulating levels of calcium. Th is function of the thyroid gland is discussed in Chapter 21 in the broader context of whole body calcium homeostasis. ANATOMIC CONSIDERATIONS Th e thyroid is a butterfl y-shaped gland that straddles the trachea in the front of the neck. It develops from an evagination of the fl oor of the pharynx, and a thyroglossal duct marking the path of the thyroid from the tongue to the neck sometimes persists in the adult. Th e two lobes of the human thyroid are ■ Describe the structure of the thyroid gland and how it relates to its function. ■ D efi ne the chemical nature of the thyroid hormones and how they are synthesized. ■ Understand the critical role of iodine in the thyroid gland and how its transport is controlled. ■ Describe the role of protein binding in the transport of thyroid hormones and peripheral metabolism. ■ Identify the role of the hypothalamus and pituitary in regulating thyroid function. ■ D efi ne the eff ects of the thyroid hormones in homeostasis and development. ■ Understand the basis of conditions where thyroid function is abnormal and how they can be treated. connected by a bridge of tissue, the thyroid isthmus , and there is sometimes a pyramidal lobe arising from the isthmus in front of the larynx ( Figure 19–1 ). Th e gland is well vascularized, and the thyroid has one of the highest rates of blood fl ow per gram of tissue of any organ in the body. Th e portion of the thyroid concerned with the production of thyroid hormone consists of multiple acini Ganong_Ch19_339-352.indd 339 1/5/12 7:25:10 340 SECTION III Endocrine and Reproductive Physiology reticulum is prominent, a feature common to most glandular cells, and secretory granules containing thyroglobulin are seen ( Figure 19–3 ). Th e individual thyroid cells rest on a basal lamina that separates them from the adjacent capillaries. Th e capillaries are fenestrated, like those of other endocrine glands (see Chapter 31). FORMATION & SECRETION OF THYROID HORMONES CHEMISTRY Th e primary hormone secreted by the thyroid is thyroxine (T 4 ), along with much lesser amounts of triiodothyronine (T 3 ). T 3 has much greater biological activity than T 4 and is specifi cally generated at its site of action in peripheral tissues by deiodination of T 4 (see below). Both hormones are iodinecontaining amino acids ( Figure 19–4 ). Small amounts of reverse triiodothyronine (3,3′,5′-triiodothyronine, RT 3 ) and other compounds are also found in thyroid venous blood. RT 3 is not biologically active. IODINE HOMEOSTASIS Iodine is an essential raw material for thyroid hormone synthesis. Dietary iodide is absorbed by the intestine and enters the circulation; its subsequent fate is summarized in Figure 19–5 . (follicles) . Each spherical follicle is surrounded by a single layer of polarized epithelial cells and fi lled with pink-staining proteinaceous material called colloid. Colloid consists predominantly of the glycoprotein, thyroglobulin. When the gland is inactive, the colloid is abundant, the follicles are large, and the cells lining them are fl at. When the gland is active, the follicles are small, the cells are cuboid or columnar, and areas where the colloid is being actively reabsorbed into the thyrocytes are visible as “reabsorption lacunae” ( Figure 19–2 ). Microvilli project into the colloid from the apexes of the thyroid cells and canaliculi extend into them. Th e endoplasmic Left lobe Right lobe Larynx Pyramidal lobe Hyoid bone FIGURE 191 The human thyroid. Inactive Active Colloid Reabsorption lacunae Parafollicular cells FIGURE 192 Thyroid histology. The appearance of the gland when it is inactive (left) and actively secreting (right) is shown. Note the small, punched-out “reabsorption lacunae” in the colloid next to the cells in the active gland. Secretory droplets Lumen of follicle Uptake of colloid by endocytosis Lysosome coalescing with endocytotic vacuole Golgi apparatus Capillary endothelium Normal TSH-stimulated Capillary basal lamina Cell basal lamina FIGURE 193 Thyroid cell. Left: Normal pattern. Right: After TSH stimulation. The arrows on the right show the secretion of thyroglobulin into the colloid. On the right, endocytosis of the colloid and merging of a colloid-containing vacuole with a lysosome are also shown. The cell rests on a capillary with gaps (fenestrations) in the endothelial wall. CHAPTER 19 The Thyroid Gland 341 IODIDE TRANSPORT ACROSS THYROCYTES Th e basolateral membranes of thyrocytes facing the capillaries contain a symporter that transports two Na + ions and one I – ion into the cell with each cycle, against the electrochemical gradient for I – . Th is Na + /I – symporter (NIS) is capable of producing intracellular I – concentrations that are 20–40 times as great as the concentration in plasma. Th e process involved is secondary active transport (see Chapter 2), with the energy provided by active transport of Na + out of thyroid cells by Na, K ATPase. NIS is regulated both by transcriptional means and by active traffi cking into and out of the thyrocyte basolateral membrane; in particular, thyroid stimulating hormone (TSH; see below) induces both NIS expression and the retention of NIS in the basolateral membrane, where it can mediate sustained iodide uptake. Iodide must also exit the thyrocyte across the apical membrane to access the colloid, where the initial steps of thyroid hormone synthesis occur. Th is transport step is believed to be mediated, at least in part, by a Cl – /I – exchanger known as pendrin. Th is protein was fi rst identifi ed as the product of the gene responsible for the Pendred syndrome, whose patients suffer from thyroid dysfunction and deafness. Pendrin (SLC26A4) is one member of the larger family of SLC26 anion exchangers. Th e relation of thyroid function to iodide is unique. As discussed in more detail below, iodide is essential for normal thyroid function, but iodide defi ciency and iodide excess both inhibit thyroid function. Th e salivary glands, the gastric mucosa, the placenta, the ciliary body of the eye, the choroid plexus, the mammary glands, and certain cancers derived from these tissues also express NIS and can transport iodide against a concentration gradient, but the transporter in these tissues is not aff ected by TSH. Th e physiologic signifi cance of all these extrathyroidal iodide-concentrating mechanisms is obscure, but they may provide pathways for radioablation of NIS-expressing cancer cells using iodide radioisotopes. Th is approach is also useful for the ablation of thyroid cancers. THYROID HORMONE SYNTHESIS & SECRETION At the interface between the thyrocyte and the colloid, iodide undergoes a process referred to as organifi cation. First, it is oxidized to iodine, and then incorporated into the carbon 3 position of tyrosine residues that are part of the thyroglobulin molecule in the colloid ( Figure 19–6 ). Th yroglobulin is a glycoprotein made up of two subunits and has a molecular weight of 660 kDa. It contains 10% carbohydrate by weight. It also contains 123 tyrosine residues, but only 4–8 of these are normally incorporated into thyroid hormones. Th yroglobulin is synthesized in the thyroid cells and secreted into the colloid by exocytosis of granules. Th e oxidation and reaction of iodide with the secreted thyroglobulin is mediated by thyroid Th e minimum daily iodine intake that will maintain normal thyroid function is 150 μg in adults. In most developed countries, supplementation of table salt means that the average dietary intake is approximately 500 μg/d. Th e principal organs that take up circulating I – are the thyroid, which uses it to make thyroid hormones, and the kidneys, which excrete it in the urine. About 120 μg/d enter the thyroid at normal rates of thyroid hormone synthesis and secretion. Th e thyroid secretes 80 μg/d in the form of T 3 and T 4 , while 40 μg/d diff uses back into the extracellular fl uid (ECF). Circulating T 3 and T 4 are metabolized in the liver and other tissues, with the release of a further 60 μg of I – per day into the ECF. Some thyroid hormone derivatives are excreted in the bile, and some of the iodine in them is reabsorbed (enterohepatic circulation), but there is a net loss of I – in the stool of approximately 20 μg/d. Th e total amount of I – entering the ECF is thus 500 + 40 + 60, or 600 μg/d; 20% of this I – enters the thyroid, whereas 80% is excreted in the urine. HO O CH2 CH NH2 C OH O Ι Ι Ι Ι 3' 5' 3 5 3,5,3',5',-Tetraiodothyronine (thyroxine, T4) HO O CH2 CH NH2 C OH O Ι Ι Ι 3,5,3',-Triiodothyronine (T3) FIGURE 194 Thyroid hormones. The numbers in the rings in the T 4 formula indicate the number of positions in the molecule. RT 3 is 3,3′,5′-triiodothyronine. Liver and other tissues Thyroid 120 μg I− 40 μg I− 60 μg I− Extracellular fluid 500 μg I− in diet 480 μg I− in urine 20 μg I− in stool 80 μg in T3, T4 Bile FIGURE 195 Iodine metabolism. The fi gure shows the movement of iodide amongst various body compartments on a daily basis. 342 SECTION III Endocrine and Reproductive Physiology One holds that the coupling occurs with both DIT molecules attached to thyroglobulin (intramolecular coupling). Th e other holds that the DIT that forms the outer ring is fi rst detached from thyroglobulin (intermolecular coupling). In either case, thyroid peroxidase is involved in coupling as well as iodination. T 3 is formed by condensation of MIT with DIT. A small amount of RT 3 is also formed, probably by condensation of DIT with MIT. In the normal human thyroid, the average distribution of iodinated compounds is 3% MIT, 33% DIT, 35% T 4 , and 7% T 3 . Only traces of RT 3 and other components are present. Th e human thyroid secretes about 80 μg (103 nmol) of T 4 , 4 μg (7 nmol) of T 3 , and 2 μg (3.5 nmol) of RT 3 per day ( Figure 19–7 ). MIT and DIT are not secreted. Th ese iodinated tyrosines are deiodinated by a microsomal iodotyrosine deiodinase. Th is represents a mechanism to recover iodine and bound tyrosines and recycle them for additional rounds of hormone synthesis. Th e iodine liberated by deiodination of MIT and DIT is reutilized in the gland and normally provides about twice as much iodide for hormone synthesis as NIS does. In patients with congenital absence of the iodotyrosine deiodinase, MIT and DIT appear in the urine and there are symptoms of iodine defi ciency (see below). Iodinated thyronines are resistant to the activity of iodotyrosine deiodinase, thus allowing T 4 and T 3 to pass into the circulation. peroxidase, a membrane-bound enzyme found in the thyrocyte apical membrane. Th e thyroid hormones so produced remain part of the thyroglobulin molecule until needed. As such, colloid represents a reservoir of thyroid hormones, and humans can ingest a diet completely devoid of iodide for up to 2 months before a decline in circulating thyroid hormone levels is seen. When there is a need for thyroid hormone secretion, colloid is internalized by the thyrocytes by endocytosis, and directed toward lysosomal degradation. Th us, the peptide bonds of thyroglobulin are hydrolyzed, and free T 4 and T 3 are discharged into cytosol and thence to the capillaries (see below). Th yrocytes thus have four functions: Th ey collect and transport iodine, they synthesize thyroglobulin and secrete it into the colloid, they fi x iodine to the thyroglobulin to generate thyroid hormones, and they remove the thyroid hormones from thyroglobulin and secrete them into the circulation. Th yroid hormone synthesis is a multistep process. Th yroid peroxidase generates reactive iodine species that can attack thyroglobulin. Th e fi rst product is monoiodotyrosine (MIT). MIT is next iodinated on the carbon 5 position to form diiodotyrosine (DIT). Two DIT molecules then undergo an oxidative condensation to form T 4 with the elimination of the alanine side chain from the molecule that forms the outer ring. Th ere are two theories of how this coupling reaction occurs. HO CH2− CH CH CH HO CH2− Tyrosine Ι Ι − Ι− (Iodide) Ι (Iodine) HO CH2− Ι Ι O CH2− CH Ι Ι DIT + DIT Alanine + HO Ι Ι 3-Monoiodotyrosine (MIT) 3,5-Diiodotyrosine (DIT) Ι− Ι− Ι MIT + DIT Alanine + 3,5,3'-Triiodothyronine (T3) DIT + MIT Alanine + 3,3',5'-Triiodothyronine (reverse T3) Thyroxine (T4) THYROID CELL Active transport PLASMA COLLOID THYROGLOBULIN MOLECULE FIGURE 196 Outline of thyroid hormone biosynthesis. Iodide is transported from the plasma across the cells of the thyroid gland by both secondary active and passive transport. The iodide is converted to iodine, which reacts with tyrosine residues exposed on the surface of thyroglobulin molecules resident in the colloid. Iodination of tyrosine takes place at the apical border of the thyroid cells while the molecules are bound in peptide linkage in thyroglobulin. CHAPTER 19 The Thyroid Gland 343 T 4 and T 3 can both be measured by radioimmunoassay. Th ere are also direct assays that specifi cally measure only the free forms of the hormones. Th e latter are the more clinically relevant measures given that these are the active forms, and also due to both acquired and congenital variations in the concentrations of binding proteins between individuals. Th e plasma proteins that bind thyroid hormones are albumin , a prealbumin called transthyretin (formerly called thyroxine-binding prealbumin) , and a globulin known as thyroxine-binding globulin (TBG) . Of the three proteins, albumin has the largest capacity to bind T 4 (ie, it can bind the most T 4 before becoming saturated) and TBG has the smallest capacity. However, the affi nities of the proteins for T 4 (ie, the avidity with which they bind T 4 under physiologic conditions) are such that most of the circulating T 4 is bound to TBG ( Table 19–1 ), with over a third of the binding sites on the protein occupied. Smaller amounts of T 4 are bound to transthyretin and albumin. Th e half-life of transthyretin is 2 days, that of TBG is 5 days, and that of albumin is 13 days. Normally, 99.98% of the T 4 in plasma is bound; the free T 4 level is only about 2 ng/dL. Th ere is very little T 4 in the urine. Its biologic half-life is long (about 6–7 days), and its volume of distribution is less than that of ECF (10 L, or about 15% of body weight). All of these properties are characteristic of a substance that is strongly bound to protein. T 3 is not bound to quite as great an extent; of the 0.15 μg/ dL normally found in plasma, 0.2% (0.3 ng/dL) is free. Th e remaining 99.8% is protein-bound, 46% to TBG and most of the remainder to albumin, with very little binding to transthyretin ( Table 19–1 ). Th e lesser binding of T 3 correlates with the facts that T 3 has a shorter half-life than T 4 and that its action on the tissues is much more rapid. RT 3 also binds to TBG. FLUCTUATIONS IN BINDING When a sudden, sustained increase in the concentration of thyroid-binding proteins in the plasma takes place, the concentration of free thyroid hormones falls. Th is change is temporary, however, because the decrease in the concentration of free thyroid hormones in the circulation stimulates TSH secretion, which in turn causes an increase in the production of free thyroid hormones. A new equilibrium is eventually reached at TRANSPORT & METABOLISM OF THYROID HORMONES PROTEIN BINDING Th e normal total plasma T 4 level in adults is approximately 8 μg/dL (103 nmol/L), and the plasma T 3 level is approximately 0.15 μg/dL (2.3 nmol/L). T 4 and T 3 are relatively lipophilic; thus, their free forms in plasma are in equilibrium with a much larger pool of protein-bound thyroid hormones in plasma and in tissues. Free thyroid hormones are added to the circulating pool by the thyroid. It is the free thyroid hormones in plasma that are physiologically active and that feed back to inhibit pituitary secretion of TSH ( Figure 19–8 ). Th e function of proteinbinding appears to be maintenance of a large pool of hormone that can readily be mobilized as needed. In addition, at least for T 3 , hormone binding prevents excess uptake by the fi rst cells encountered and promotes uniform tissue distribution. Total Conjugates, etc Thyroid Secretion Interconversion Metabolism and Excretion 4 80 27 36 2 17 RT3 38 μg T4 80 μg T3 31 μg FIGURE 197 Secretion and interconversion of thyroid hormones in normal adult humans . Figures are in micrograms per day. Note that most of the T 3 and RT 3 are formed from T 4 deiodination in the tissues and only small amounts are secreted by the thyroid. T 4 is also conjugated for subsequent excretion from the body. Pituitary TSH Free T4 0.002 μg/dL Plasma protein-bound T4 8 μg/dL Tissue protein-bound T4 Thyroid T4 FIGURE 198 Regulation of thyroid hormone synthesis. T4 is secreted by the thyroid in response to TSH. Free T 4 secreted by the thyroid into the circulation is in equilibrium with T 4 bound to both plasma and tissue proteins. Free T 4 also feeds back to inhibit TSH secretion by the pituitary. TABLE 19–1 Binding of thyroid hormones to plasma proteins in normal adult humans . Protein Plasma Concentration (mg/dL) Amount of Circulating Hormone Bound (%) T 4 T 3 Thyroxine-binding globulin (TBG) 2 67 46 Transthyretin (thyroxine-binding prealbumin, TBPA) 15 20 1 Albumin 3500 13 53 344 SECTION III Endocrine and Reproductive Physiology is essential for their enzymatic activity. D 1 is present in high concentrations in the liver, kidneys, thyroid, and pituitary. It appears primarily to be responsible for maintaining the formation of T 3 from T 4 in the periphery. D 2 is present in the brain, pituitary, and brown fat. It also contributes to the formation of T 3 . In the brain, it is located in astroglia and produces a supply of T 3 to neurons. D 3 is also present in the brain and in reproductive tissues. It acts only on the 5 position of T 4 and T 3 and is probably the main source of RT 3 in the blood and tissues. Overall, the deiodinases appear to be responsible for maintaining diff erences in T 3 /T 4 ratios in the various tissues in the body. In the brain, in particular, high levels of deiodinase activity ensure an ample supply of active T 3 . Some of the T 4 and T 3 is further converted to deiodotyrosines by deiodinases. T 4 and T 3 are also conjugated in the liver to form sulfates and glucuronides. Th ese conjugates enter the bile and pass into the intestine. Th e thyroid conjugates are hydrolyzed, and some are thereaft er reabsorbed (enterohepatic circulation), but others are excreted in the stool. In addition, some T 4 and T 3 passes directly from the circulation to the intestinal lumen. Th e iodide lost by these routes amounts to about 4% of the total daily iodide loss. FLUCTUATIONS IN DEIODINATION Much more RT 3 and much less T 3 are formed during fetal life, and the ratio shift s to that of adults about 6 weeks aft er birth. Various drugs inhibit deiodinases, producing a fall in plasma T 3 levels and a reciprocal rise in RT 3 . Selenium defi ciency has the same eff ect. A wide variety of nonthyroidal illnesses also suppress deiodinases. Th ese include burns, trauma, advanced cancer, cirrhosis, renal failure, myocardial infarction, and febrile states. Th e low-T 3 state produced by these conditions disappears with recovery. It is diffi cult to decide whether individuals with the low-T 3 state produced by drugs and illness have mild hypothyroidism. Diet also has a clear-cut eff ect on conversion of T 4 to T 3 . In fasted individuals, plasma T 3 is reduced by 10–20% within 24 h and by about 50% in 3–7 days, with a corresponding rise in RT 3 ( Figure 19–9 ). Free and bound T 4 levels remain essentially normal. During more prolonged starvation, RT 3 returns which the total quantity of thyroid hormones in the blood is elevated but the concentration of free hormones, the rate of their metabolism, and the rate of TSH secretion are normal. Corresponding changes in the opposite direction occur when the concentration of thyroid-binding protein is reduced. Consequently, patients with elevated or decreased concentrations of binding proteins, particularly TBG, are typically neither hyper- nor hypothyroid; that is, they are euthyroid . TBG levels are elevated in estrogen-treated patients and during pregnancy, as well as aft er treatment with various drugs ( Table 19–2 ). Th ey are depressed by glucocorticoids, androgens, the weak androgen danazol, and the cancer chemotherapeutic agent L-asparaginase. A number of other drugs, including salicylates, the anti-convulsant phenytoin, and the cancer chemotherapeutic agents mitotane (o, p′-DDD) and 5-fl uorouracil inhibit binding of T 4 and T 3 to TBG and consequently produce changes similar to those produced by a decrease in TBG concentration. Changes in total plasma T 4 and T 3 can also be produced by changes in plasma concentrations of albumin and prealbumin. METABOLISM OF THYROID HORMONES T 4 and T 3 are deiodinated in the liver, the kidneys, and many other tissues. Th ese deiodination reactions serve not only to catabolize the hormones, but also to provide a local supply specifi cally of T 3 , which is believed to be the primary mediator of the physiological eff ects of thyroid secretion. One third of the circulating T 4 is normally converted to T 3 in adult humans, and 45% is converted to RT 3 . As shown in Figure 19–7 , only about 13% of the circulating T 3 is secreted by the thyroid while 87% is formed by deiodination of T 4 ; similarly, only 5% of the circulating RT 3 is secreted by the thyroid and 95% is formed by deiodination of T 4 . It should be noted as well that marked diff erences in the ratio of T 3 to T 4 occur in various tissues. Two tissues that have very high T 3 /T 4 ratios are the pituitary and the cerebral cortex, due to the expression of specifi c deiodinases, as discussed below. Th ree diff erent deiodinases act on thyroid hormones: D 1 , D 2 , and D 3 . All are unique in that they contain the rare amino acid selenocysteine, with selenium in place of sulfur, which TABLE 192 Effect of variations in the concentrations of thyroid hormone-binding proteins in the plasma on various parameters of thyroid function after equilibrium has been reached. Condition Concentrations of Binding Proteins Total Plasma T 4 , T 3 , RT 3 Free Plasma T 4 , T 3 , RT 3 Plasma TSH Clinical State Hyperthyroidism Normal High High Low Hyperthyroid Hypothyroidism Normal Low Low High Hypothyroid Estrogens, methadone, heroin, major tranquilizers, clofi brate High High Normal Normal Euthyroid Glucocorticoids, androgens, danazol, asparaginase Low Low Normal Normal Euthyroid CHAPTER 19 The Thyroid Gland 345 Th e functional specifi city of TSH is conferred by the β subunit. Th e structure of TSH varies from species to species, but other mammalian TSHs are biologically active in humans. Th e biologic half-life of human TSH is about 60 min. TSH is degraded for the most part in the kidneys and to a lesser extent in the liver. Secretion is pulsatile, and mean output starts to rise at about 9:00 PM, peaks at midnight, and then declines during the day. Th e normal secretion rate is about 110 μg/d. Th e average plasma level is about 2 μg/mL. Because the α subunit in hCG is the same as that in TSH, large amounts of hCG can activate thyroid receptors (TR) nonspecifi cally. In some patients with benign or malignant tumors of placental origin, plasma hCG levels can rise so high that they produce mild hyperthyroidism. EFFECTS OF TSH ON THE THYROID When the pituitary is removed, thyroid function is depressed and the gland atrophies; when TSH is administered, thyroid function is stimulated. Within a few minutes aft er the injection of TSH, there are increases in iodide binding; synthesis of T 3 , T 4 , and iodotyrosines; secretion of thyroglobulin into the colloid; and endocytosis of colloid. Iodide trapping is increased in a few hours; blood fl ow increases; and, with chronic TSH treatment, the cells hypertrophy and the weight of the gland increases. Whenever TSH stimulation is prolonged, the thyroid becomes detectably enlarged. Enlargement of the thyroid is called a goiter . TSH RECEPTORS Th e TSH receptor is a typical G protein-coupled, seven-transmembrane receptor that activates adenylyl cyclase through G s . It also activates phospholipase C (PLC). Like other glycoprotein hormone receptors, it has an extended, glycosylated extracellular domain. OTHER FACTORS AFFECTING THYROID GROWTH In addition to TSH receptors, thyrocytes express receptors for insulin-like growth factor I (IGF-I), EGF, and other growth factors. IGF-I and EGF promote growth, whereas interferon γ and tumor necrosis factor α inhibit growth. Th e exact physiologic role of these factors in the thyroid has not been established, but the eff ect of the cytokines implies that thyroid function might be inhibited in the setting of chronic infl ammation, which could contribute to cachexia, or weight loss. CONTROL MECHANISMS Th e mechanisms regulating thyroid secretion are summarized in Figure 19–8 . Th e negative feedback eff ect of thyroid hormones on TSH secretion is exerted in part at the hypothalamic level, but it is also due in large part to an action on the pituitary, since T 4 and T 3 block the increase in TSH secretion produced to normal but T 3 remains depressed. At the same time, the basal metabolic rate (BMR) falls and urinary nitrogen excretion, an index of protein breakdown, is decreased. Th us, the decline in T 3 conserves calories and protein. Conversely, overfeeding increases T 3 and reduces RT 3 . REGULATION OF THYROID SECRETION Th yroid function is regulated primarily by variations in the circulating level of pituitary TSH ( Figure 19–8 ). TSH secretion is increased by the hypothalamic hormone TRH (see Chapter 17) and inhibited in a negative feedback fashion by circulating free T 4 and T 3 . Th e eff ect of T 4 is enhanced by production of T 3 in the cytoplasm of the pituitary cells by the 5′-D 2 they contain. TSH secretion is also inhibited by stress, and in experimental animals it is increased by cold and decreased by warmth. CHEMISTRY & METABOLISM OF TSH Human TSH is a glycoprotein that contains 211 amino acid residues. It is made up of two subunits, designated α and β. Th e α subunit is encoded by a gene on chromosome 6 and the β subunit by a gene on chromosome 1. Th e α and β subunits become noncovalently linked in the pituitary thyrotropes. TSH-α is identical to the α subunit of LH, FSH, and hCG-α (see Chapters 18 and 22). Starvation Days 240 200 160 120 80 40 0 −4 −2 0 2 4 6 8 10 +2 +4 12 10 8 6 4 2 0 T4 T3 RT3 ng/dL μg/dL FIGURE 199 Eff ect of starvation on plasma levels of T 4 , T 3 , and RT 3 in humans . The scale for T 3 and RT 3 is on the left and the scale for T 4 is on the right. The most pronounced eff ect is a reduction in T 3 levels with a reciprocal rise in RT 3 . The changes, which conserve calories by reducing tissue metabolism, are reversed promptly by re-feeding. Similar changes occur in wasting diseases. (Reproduced with permission from Burger AG: New aspects of the peripheral action of thyroid hormones. Triangle 1983;22:175. Copyright © 1983 Sandoz Ltd., Basel, Switzerland.) 346 SECTION III Endocrine and Reproductive Physiology the increased secretion of thyroid hormones produced by cold and, presumably, the decrease produced by heat. It is worth noting that although cold produces clear-cut increases in circulating TSH in experimental animals and human infants, the rise produced by cold in adult humans is negligible. Consequently, in adults, increased heat production due to increased thyroid hormone secretion (thyroid hormone thermogenesis) plays little if any role in the response to cold. Stress has an inhibitory eff ect on TRH secretion. Dopamine and somatostatin act at the pituitary level to inhibit TSH secretion, but it is not known whether they play a physiologic role in the regulation of TSH secretion. Glucocorticoids also inhibit TSH secretion. Th e amount of thyroid hormone necessary to maintain normal cellular function in thyroidectomized individuals used to be defi ned as the amount necessary to normalize the BMR, but it is now defi ned as the amount necessary to return plasma TSH to normal. Indeed, with the accuracy and sensitivity of modern assays for TSH and the marked inverse correlation by TRH. Infusion of either T 4 or T 3 reduces the circulating level of TSH, which declines measurably within 1 h. In experimental animals, there is an initial rise in pituitary TSH content before the decline, indicating that thyroid hormones inhibit secretion before they inhibit synthesis. Th e day-to-day maintenance of thyroid secretion depends on the feedback interplay of thyroid hormones with TSH and TRH ( Figure 19–8 ). Th e adjustments that appear to be mediated via TRH include TABLE 193 Causes of congenital hypothyroidism. Maternal iodine defi ciency Fetal thyroid dysgenesis Inborn errors of thyroid hormone synthesis Maternal antithyroid antibodies that cross the placenta Fetal hypopituitary hypothyroidism CLINICAL BOX 19–1 Reduced Thyroid Function The syndrome of adult hypothyroidism is generally called myxedema , although this term is also used to refer specifi cally to the skin changes in the syndrome. Hypothyroidism may be the end result of a number of diseases of the thyroid gland, or it may be secondary to pituitary or hypothalamic failure. In the latter two conditions, the thyroid remains able to respond to TSH. Thyroid function may be reduced by a number of conditions ( Table 19–3 ). For example, when the dietary iodine intake falls below 50 μg/d, thyroid hormone synthesis is inadequate and secretion declines. As a result of increased TSH secretion, the thyroid hypertrophies, producing an iodine defi ciency goiter that may become very large. Such “endemic goiters” have been substantially reduced by the practice of adding iodide to table salt. Drugs may also inhibit thyroid function. Most do so either by interfering with the iodidetrapping mechanism or by blocking the organic binding of iodine. In either case, TSH secretion is stimulated by the decline in circulating thyroid hormones, and a goiter is produced. Paradoxically, another substance that inhibits thyroid function under certain conditions is iodide itself. In normal individuals, large doses of iodide act directly on the thyroid to produce a mild and transient inhibition of organic binding of iodide and hence of hormone synthesis. This inhibition is known as the Wolff –Chaikoff eff ect . In completely athyreotic adults, the BMR falls to about 40%. The hair is coarse and sparse, the skin is dry and yellowish (carotenemia), and cold is poorly tolerated. Mentation is slow, memory is poor, and in some patients there are severe mental symptoms (“myxedema madness”). Plasma cholesterol is elevated. Children who are hypothyroid from birth or before are called cretins . They are dwarfed and mentally retarded. Worldwide, congenital hypothyroidism is one of the most common causes of preventable mental retardation. The main causes are included in Table 19–3 . They include not only maternal iodine defi ciency and various congenital abnormalities of the fetal hypothalamo– pituitary–thyroid axis, but also maternal antithyroid antibodies that cross the placenta and damage the fetal thyroid. T 4 crosses the placenta, and unless the mother is hypothyroid, growth and development are normal until birth. If treatment is started at birth, the prognosis for normal growth and development is good, and mental retardation can generally be avoided; for this reason, screening tests for congenital hypothyroidism are becoming routine. When the mother is hypothyroid as well, as in the case of iodine defi ciency, the mental defi ciency is more severe and less responsive to treatment after birth. It has been estimated that 20 million people in the world now have various degrees of brain damage caused by iodine defi ciency in utero. Uptake of tracer doses of radioactive iodine can be used to assess thyroid function (contrast this with the use of large doses to ablate thyroid tissue in cases of hyperthyroidism (Clinical Box 19–2). THERAPEUTIC HIGHLIGHTS The treatment of hypothyroidism depends on the underlying mechanisms. Iodide defi ciency can be addressed by adding it to the diet, as is done routinely in developed countries with the use of iodized salt. In congenital hypothyroidism, levothyroxine—a synthetic form of the thyroid hormone T 4 —can be given. It is important that this take place as soon as possible after birth, with levels regularly monitored, to minimize long-term adverse eff ects. CHAPTER 19 The Thyroid Gland 347 TABLE 194 Causes of hyperthyroidism. Thyroid overactivity Graves disease Solitary toxic adenoma Toxic multinodular goiter Early stages of Hashimoto thyroiditis a TSH-secreting pituitary tumor Mutations causing constitutive activation of TSH receptor Other rare causes Extrathyroidal Administration of T 3 or T 4 (factitious or iatrogenic hyperthyroidism) Ectopic thyroid tissue a Note that ultimately the thyroid will be destroyed in Hashimoto disease, resulting in hypothyroidism. Many patients only present after they become hypothyroid, and do not recall a transient phase of hyperthyroidism. between plasma free thyroid hormone levels and plasma TSH, measurement of TSH is now widely regarded as one of the best tests of thyroid function. Th e amount of T 4 that normalizes plasma TSH in athyreotic individuals averages 112 μg of T 4 by mouth per day in adults. About 80% of this dose is absorbed from the gastrointestinal tract. It produces a slightly greater than normal FT 4 I but a normal FT 3 I, indicating that in CLINICAL BOX 19–2 Hyperthyroidism The symptoms of an overactive thyroid gland follow logically from the actions of thyroid hormone discussed in this chapter. Thus, hyperthyroidism is characterized by nervousness; weight loss; hyperphagia; heat intolerance; increased pulse pressure; a fi ne tremor of the outstretched fi ngers; warm, soft skin; sweating; and a BMR from +10 to as high as +100. It has various causes ( Table 19–4 ); however, the most common cause is Graves disease (Graves hyperthyroidism), which accounts for 60–80% of the cases. This is an autoimmune disease, more common in women, in which antibodies to the TSH receptor stimulate the receptor. This produces marked T 4 and T 3 secretion and enlargement of the thyroid gland (goiter). However, due to the feedback eff ects of T 4 and T 3 , plasma TSH is low, not high. Another hallmark of Graves disease is the occurrence of swelling of tissues in the orbits, producing protrusion of the eyeballs (exophthalmos). This occurs in 50% of patients and often precedes the development of obvious hyperthyroidism. Other antithyroid antibodies are present in Graves disease, including antibodies to thyroglobulin and thyroid peroxidase. In Hashimoto thyroiditis, autoimmune antibodies and infi ltrating cytotoxic T cells ultimately destroy the thyroid, but during the early stage the infl ammation of the gland causes excess thyroid hormone secretion and thyrotoxicosis similar to that seen in Graves disease. THERAPEUTIC HIGHLIGHTS Some of the symptoms of hyperthyroidism can be controlled by the thioureylenes . These are a group of compounds related to thiourea, which inhibit the iodination of monoiodotyrosine and block the coupling reaction. The two used clinically are propylthiouracil and methimazole. Iodination of tyrosine is inhibited because propylthiouracil and methimazole compete with tyrosine residues for iodine and become iodinated. In addition, propylthiouracil but not methimazole inhibits D 2 deiodinase, reducing the conversion of T 4 to T 3 in many extrathyroidal tissues. In severe cases, hyperthyroidism can also be treated by the infusion of radioactive iodine, which accumulates in the gland and then partially destroys it. Surgery is also considered if the thyroid becomes so large that it aff ects swallowing and/or breathing. humans, unlike some experimental animals, it is circulating T 3 rather than T 4 that is the principal feedback regulator of TSH secretion (see Clinical Boxes 19–1 and 19–2). EFFECTS OF THYROID HORMONES Some of the widespread eff ects of thyroid hormones in the body are secondary to stimulation of O 2 consumption (calorigenic action) , although the hormones also aff ect growth and development in mammals, help regulate lipid metabolism, and increase the absorption of carbohydrates from the intestine ( Table 19–5 ). Th ey also increase the dissociation of oxygen from hemoglobin by increasing red cell 2,3-diphosphoglycerate (DPG) (see Chapter 35). MECHANISM OF ACTION Th yroid hormones enter cells and T 3 binds to TR in the nuclei. T 4 can also bind, but not as avidly. Th e hormone–receptor complex then binds to DNA via zinc fi ngers and increases (or in some cases, decreases) the expression of a variety of diff erent genes that code for proteins that regulate cell function (see Chapters 1 and 16). Th us, the nuclear receptors for thyroid hormones are members of the superfamily of hormone- sensitive nuclear transcription factors. Th ere are two human TR genes: an α receptor gene on chromosome 17 and a β receptor gene on chromosome 3. By 348 SECTION III Endocrine and Reproductive Physiology alternative splicing, each forms at least two diff erent mRNAs and therefore two diff erent receptor proteins. TRβ2 is found only in the brain, but TRα1, TRα2, and TRβ1 are widely distributed. TRα2 diff ers from the other three in that it does not bind T3 and its function is not yet fully established. TRs bind to DNA as monomers, homodimers, and heterodimers with other nuclear receptors, particularly the retinoid X receptor (RXR) . Th e TR/RXR heterodimer does not bind to 9-cis retinoic acid, the usual ligand for RXR, but TR binding to DNA is greatly enhanced in response to thyroid hormones when the receptor is in the form of this heterodimer. Th ere are also coactivator and corepressor proteins that aff ect the actions of TRs. Presumably, this complexity underlies the ability of thyroid hormones to produce many diff erent eff ects in the body. In most of its actions, T 3 acts more rapidly and is three to fi ve times more potent than T 4 ( Figure 19–10 ). Th is is because T 3 is less tightly bound to plasma proteins than is T 4 , but binds TABLE 195 Physiologic effects of thyroid hormones. Target Tissue Effect Mechanism Heart Chronotropic and Inotropic Increased number of β-adrenergic receptors Enhanced responses to circulating catecholamines Increased proportion of α-myosin heavy chain (with higher ATPase activity) Adipose tissue Catabolic Stimulated lipolysis Muscle Catabolic Increased protein breakdown Bone Developmental Promote normal growth and skeletal development Nervous system Developmental Promote normal brain development Gut Metabolic Increased rate of carbohydrate absorption Lipoprotein Metabolic Formation of LDL receptors Other Calorigenic Stimulated oxygen consumption by metabolically active tissues (exceptions: testes, uterus, lymph nodes, spleen, anterior pituitary) Increased metabolic rate Modifi ed and reproduced with permission from McPhee SJ, Lingarra VR, Ganong WF (editors): Pathophysiology of Disease , 6th ed. McGraw-Hill, 2010. 80 60 40 20 20 40 60 Increased metabolism (mL O2/100 g/h) 80 100 Dose (μg/kg/d) T3 T4 FIGURE 1910 Calorigenic responses of thyroidectomized rats to subcutaneous injections of T 4 and T 3 . Note the substantially greater potency of T 3 . (Redrawn and reproduced with permission from Barker SB: Peripheral actions of thyroid hormones. Fed Proc 1962;21:635.) more avidly to thyroid hormone receptors. As previously noted, RT 3 is inert (see Clinical Box 19–3). CALORIGENIC ACTION T 4 and T 3 increase the O 2 consumption of almost all metabolically active tissues. Th e exceptions are the adult brain, testes, uterus, lymph nodes, spleen, and anterior pituitary. T 4 actually depresses the O 2 consumption of the anterior pituitary, presumably because it inhibits TSH secretion. Th e increase in metabolic rate produced by a single dose of T 4 becomes measurable aft er a latent period of several hours and lasts 6 days or more. Some of the calorigenic eff ect of thyroid hormones is due to metabolism of the fatty acids they mobilize. In addition, thyroid hormones increase the activity of the membrane-bound Na, K ATPase in many tissues. Eff ects Secondary to Calorigenesis When the metabolic rate is increased by T 4 and T 3 in adults, nitrogen excretion is increased; if food intake is not increased, endogenous protein and fat stores are catabolized and weight is lost. In hypothyroid children, small doses of thyroid hormones cause a positive nitrogen balance because they stimulate growth, but large doses cause protein catabolism similar to that produced in the adult. Th e potassium liberated during protein catabolism appears in the urine, and there is also an increase in urinary hexosamine and uric acid excretion. When the metabolic rate is increased, the need for all vitamins is increased and vitamin defi ciency syndromes may be precipitated. Th yroid hormones are necessary for hepatic conversion of carotene to vitamin A, and the accumulation of carotene in the bloodstream (carotenemia) in hypothyroidism is responsible for the yellowish tint of the skin. Carotenemia CHAPTER 19 The Thyroid Gland 349 EFFECTS ON THE CARDIOVASCULAR SYSTEM Large doses of thyroid hormones cause enough extra heat production to lead to a slight rise in body temperatures (Chapter 17), which in turn activates heat-dissipating mechanisms. Peripheral resistance decreases because of cutaneous vasodilation, and this increases levels of renal Na + and water absorption, expanding blood volume. Cardiac output is increased by the direct action of thyroid hormones, as well as that of catecholamines, on the heart, so that pulse pressure and cardiac rate are increased and circulation time is shortened. T 3 is not formed from T 4 in cardiac myocytes to any degree, but circulatory T 3 enters the myocytes, combines with its receptors, and enters the nucleus, where it promotes the expression of some genes and inhibits the expression of others. Th ose that are enhanced include the genes for α-myosin heavy chain, sarcoplasmic reticulum Ca 2+ ATPase, β-adrenergic receptors, G proteins, Na, K ATPase, and certain K + channels. Th ose that are inhibited include the genes for β-myosin heavy chain, phospholamban, two types of adenylyl cyclase, T 3 nuclear receptors, and NCX, the Na + –Ca 2+ exchanger. Th e net result is increased heart rate and force of contraction. Th e two myosin heavy chain (MHC) isoforms, α-MHC and β-MHC, produced by the heart are encoded by two highly homologous genes located on the short arm of chromosome 17. Each myosin molecule consists of two heavy chains and two pairs of light chains (see Chapter 5). Th e myosin containing β-MHC has less ATPase activity than the myosin containing α-MHC. α-MHC predominates in the atria in adults, and its level is increased by treatment with thyroid hormone. Th is increases the speed of cardiac contraction. Conversely, expression of the α-MHC gene is depressed and that of the β-MHC gene is enhanced in hypothyroidism. EFFECTS ON THE NERVOUS SYSTEM In hypothyroidism, mentation is slow and the cerebrospinal fl uid (CSF) protein level is elevated. Th yroid hormones reverse these changes, and large doses cause rapid mentation, irritability, and restlessness. Overall, cerebral blood fl ow and glucose and O 2 consumption by the brain are normal in adult hypoand hyperthyroidism. However, thyroid hormones enter the brain in adults and are found in gray matter in numerous different locations. In addition, astrocytes in the brain convert T 4 to T 3 , and there is a sharp increase in brain D 2 activity aft er thyroidectomy that is reversed within 4 h by a single intravenous dose of T 3 . Some of the eff ects of thyroid hormones on the brain are probably secondary to increased responsiveness to catecholamines, with consequent increased activation of the reticular activating system (see Chapter 14). In addition, thyroid hormones have marked eff ects on brain development. Th e parts of the central nervous system (CNS) most aff ected are the cerebral cortex and the basal ganglia. In addition, the can be distinguished from jaundice because in the former condition the sclera are not yellow. Th e skin normally contains a variety of proteins combined with polysaccharides, hyaluronic acid, and chondroitin sulfuric acid. In hypothyroidism, these complexes accumulate, promoting water retention and the characteristic puffi ness of the skin (myxedema). When thyroid hormones are administered, the proteins are metabolized, and diuresis continues until the myxedema is cleared. Milk secretion is decreased in hypothyroidism and stimulated by thyroid hormones, a fact sometimes put to practical use in the dairy industry. Th yroid hormones do not stimulate the metabolism of the uterus but are essential for normal menstrual cycles and fertility. CLINICAL BOX 19–3 Thyroid Hormone Resistance Some mutations in the gene that codes for TRβ are associated with resistance to the eff ects of T 3 and T 4 . Most commonly, there is resistance to thyroid hormones in the peripheral tissues and the anterior pituitary gland. Patients with this abnormality are usually not clinically hypothyroid, because they maintain plasma levels of T 3 and T 4 that are high enough to overcome the resistance, and hTRα is unaffected. However, plasma TSH is inappropriately high relative to the high circulating T 3 and T 4 levels and is diffi cult to suppress with exogenous thyroid hormone. Some patients have thyroid hormone resistance only in the pituitary. They have hypermetabolism and elevated plasma T 3 and T 4 levels with normal, nonsuppressible levels of TSH. A few patients apparently have peripheral resistance with normal pituitary sensitivity. They have hypometabolism despite normal plasma levels of T 3 , T 4 , and TSH An interesting fi nding is that attention defi cit hyperactivity disorder , a condition frequently diagnosed in children who are overactive and impulsive, is much more common in individuals with thyroid hormone resistance than in the general population. This suggests that hTRβ may play a special role in brain development. THERAPEUTIC HIGHLIGHTS Most patients remain euthyroid in this condition, even in the face of a goiter. It is important to consider thyroid hormone resistance in the diff erential diagnosis of Graves disease to avoid the inappropriate use of antithyroid medications or even thyroid ablation. Isolated peripheral resistance to thyroid hormones can be treated by supplying large doses of synthetic T 4 exogenously. These are suffi cient to overcome the resistance and increase the metabolic rate. 350 SECTION III Endocrine and Reproductive Physiology EFFECTS ON CARBOHYDRATE METABOLISM Th yroid hormones increase the rate of absorption of carbohydrates from the gastrointestinal tract, an action that is probably independent of their calorigenic action. In hyperthyroidism, therefore, the plasma glucose level rises rapidly aft er a carbohydrate meal, sometimes exceeding the renal threshold. However, it falls again at a rapid rate. EFFECTS ON CHOLESTEROL METABOLISM Th yroid hormones lower circulating cholesterol levels. Th e plasma cholesterol level drops before the metabolic rate rises, which indicates that this action is independent of the stimulation of O 2 consumption. Th e decrease in plasma cholesterol concentration is due to increased formation of low-density lipoprotein (LDL) receptors in the liver, resulting in increased hepatic removal of cholesterol from the circulation. Despite considerable eff ort, however, it has not been possible to produce a clinically useful thyroid hormone analog that lowers plasma cholesterol without increasing metabolism. EFFECTS ON GROWTH Th yroid hormones are essential for normal growth and skeletal maturation (see Chapter 21). In hypothyroid children, bone growth is slowed and epiphysial closure delayed. In the absence of thyroid hormones, growth hormone secretion is also depressed. Th is further impairs growth and development, since thyroid hormones normally potentiate the eff ect of growth hormone on tissues. CHAPTER SUMMARY Th e thyroid g ■ land transports and fi xes iodide to amino acids present in thyroglobulin to generate the thyroid hormones thyroxine (T 4 ) and triiodothyronine (T 3 ). ■ Synthesis and secretion of thyroid hormones is stimulated by thyroid-stimulating hormone (TSH) from the pituitary, which in turn is released in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. Th ese releasing factors are controlled by changes in whole body status (eg, exposure to cold or stress). ■ Th yroid hormones circulate in the plasma predominantly in protein-bound forms. Only the free hormones are biologically active, and both feed back to reduce secretion of TSH. ■ Th yroid hormones exert their eff ects by entering cells and binding to thyroid receptors. Th e liganded forms of thyroid receptors are nuclear transcription factors that alter gene expression. ■ Th yroid hormones stimulate metabolic rate, calorigenesis, cardiac function, and normal mentation, and interact synergistically with catecholamines. Th yroid hormones cochlea is also aff ected. Consequently, thyroid hormone defi - ciency during development causes mental retardation, motor rigidity, and deaf–mutism. Defi ciencies in thyroid hormone synthesis secondary to a failure of thyrocytes to transport iodide presumably also contribute to deafness in Pendred syndrome, discussed above. Th yroid hormones also exert eff ects on refl exes. Th e reaction time of stretch refl exes (see Chapter 12) is shortened in hyperthyroidism and prolonged in hypothyroidism. Measurement of the reaction time of the ankle jerk (Achilles refl ex) has attracted attention as a clinical test for evaluating thyroid function, but this reaction time is also aff ected by other diseases and thus is not a specifi c assessment of thyroid activity. RELATION TO CATECHOLAMINES Th e actions of thyroid hormones and the catecholamines norepinephrine and epinephrine are intimately interrelated. Epinephrine increases the metabolic rate, stimulates the nervous system, and produces cardiovascular eff ects similar to those of thyroid hormones, although the duration of these actions is brief. Norepinephrine has generally similar actions. Th e toxicity of the catecholamines is markedly increased in rats treated with T 4 . Although plasma catecholamine levels are normal in hyperthyroidism, the cardiovascular eff ects, tremulousness, and sweating that are seen in the setting of excess thyroid hormones can be reduced or abolished by sympathectomy. Th ey can also be reduced by drugs such as propranolol that block β-adrenergic receptors. Indeed, propranolol and other β blockers are used extensively in the treatment of thyrotoxicosis and in the treatment of the severe exacerbations of hyperthyroidism called thyroid storms . However, even though β blockers are weak inhibitors of extrathyroidal conversion of T 4 to T 3 , and consequently may produce a small fall in plasma T 3 , they have little eff ect on the other actions of thyroid hormones. Presumably, the functional synergism observed between catecholamines and thyroid hormones, particularly in pathological settings, arises from their overlapping biological functions as well as the ability of thyroid hormones to increase expression of catecholamine receptors and the signaling eff ectors to which they are linked. EFFECTS ON SKELETAL MUSCLE Muscle weakness occurs in most patients with hyperthyroidism (thyrotoxic myopathy) , and when the hyperthyroidism is severe and prolonged, the myopathy may be severe. Th e muscle weakness may be due in part to increased protein catabolism. Th yroid hormones aff ect the expression of the MHC genes in skeletal as well as cardiac muscle (see Chapter 5). However, the eff ects produced are complex and their relation to the myopathy is not established. Hypothyroidism is also associated with muscle weakness, cramps, and stiff ness. CHAPTER 19 The Thyroid Gland 351 Hyperthyroidism due to D. diff use hyperplasia of thyrotropes of the anterior pituitary E. Iodine defi ciency 6. Hypothyroidism due to disease of the thyroid gland is associated with increased plasma levels of A. Cholesterol B. Albumin C. RT 3 D. Iodide E. TBG 7. A young woman has puff y skin and a hoarse voice. Her plasma TSH concentration is low but increases markedly when she is given TRH. She probably has A. hyperthyroidism due to a thyroid tumor. B. hypothyroidism due to a primary abnormality in the thyroid gland. C. hypothyroidism due to a primary abnormality in the pituitary gland. D. hypothyroidism due to a primary abnormality in the hypothalamus. E. hyperthyroidism due to a primary abnormality in the hypothalamus. 8. Th e enzyme primarily responsible for the conversion of T 4 to T 3 in the periphery is A. D 1 thyroid deiodinase B. D 2 thyroid deiodinase C. D 3 thyroid deiodinase D. Th yroid peroxidase E. None of the above 9. Which of the following would be least aff ected by injections of TSH? A. Th yroidal uptake of iodine B. Synthesis of thyroglobulin C. Cyclic adenosine monophosphate (AMP) in thyroid cells D. Cyclic guanosine monophosphate (GMP) in thyroid cells E. Size of the thyroid 10. Th yroid hormone receptors bind to DNA in which of the following forms? A. A heterodimer with the prolactin receptor B. A heterodimer with the growth hormone receptor C. A heterodimer with the retinoid X receptor D. A heterodimer with the insulin receptor E. A heterodimer with the progesterone receptor CHAPTER RESOURCES Brent GA: Graves’ disease. N Engl J Med 2008;358:2594. Dohan O, Carrasco N: Advances in Na + /I – symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol 2003;213:59. Glaser B: Pendred syndrome. Pediatr Endocrinol Rev 2003;1(Suppl 2):199. Peeters RP, van der Deure WM, Visser TJ: Genetic variation in thyroid hormone pathway genes: Polymorphisms in the TSH receptor and the iodothyronine deiodinases. Eur J Endocrinol 2006;155:655. also play critical roles in development, particularly of the nervous system, and growth. ■ Disease results with both under- and overactivity of the thyroid gland. Hypothyroidism is accompanied by mental and physical slowing in adults, and by mental retardation and dwarfi sm if it occurs in neonatal life. Overactivity of the thyroid gland, which most commonly is caused by autoantibodies that trigger secretion (Graves disease) results in body wasting, nervousness, and tachycardia. MULTIPLECHOICE QUESTIONS For all questions, select the single best answer unless otherwise directed . 1. A 40-year-old woman comes to her primary care physician complaining of nervousness and an unexplained weight loss of 20 pounds over the past 3 months despite her impression that she is eating all the time. On physical examination, her eyes are found to be protruding, her skin is moist and warm, and her fi ngers have a slight tremor. Compared to a normal individual, a biopsy of her thyroid gland would most likely reveal which of the following: A. Decreased numbers of reabsorption lacunae B. Decreased evidence of endocytosis C. A decrease in the cross-sectional area occupied by colloid D. Increased levels of NIS in the basolateral membrane of thyrocytes E. Decreased evidence of lysosomal activity 2. Which of the following is not essential for normal biosynthesis of thyroid hormones? A. Iodine B. Ferritin C. Th yroglobulin D. Protein synthesis E. TSH 3. Increasing intracellular I – due to the action of NIS is an example of A. Endocytosis B. Passive diff usion C. Na + and K + cotransport D. Primary active transport E. Secondary active transport 4. Th e metabolic rate is least aff ected by an increase in the plasma level of A. TSH B. TRH C. TBG D. Free T 4 E. Free T 3 5. In which of the following conditions is it most likely that the TSH response to TRH will be reduced? A. Hypothyroidism due to tissue resistance to thyroid hormone B. Hypothyroidism due to disease destroying the thyroid gland C. Hyperthyroidism due to circulating antithyroid antibodies with TSH activity This page intentionally left blank 353 O B J E C T I V E S After reading this chapter, you should be able to: ■ Name the three catecholamines secreted by the adrenal medulla and summarize their biosynthesis, metabolism, and function. ■ List the stimuli that increase adrenal medullary secretion. ■ Diff erentiate between C 18 , C 19 , and C 21 steroids and give examples of each. ■ Outline the steps involved in steroid biosynthesis in the adrenal cortex. ■ Name the plasma proteins that bind adrenocortical steroids and discuss their physiologic role. ■ Name the major site of adrenocortical hormone metabolism and the principal metabolites produced from glucocorticoids, adrenal androgens, and aldosterone. ■ Describe the mechanisms by which glucocorticoids and aldosterone produce changes in cellular function. ■ List and briefl y describe the physiologic and pharmacologic eff ects of glucocorticoids. ■ Contrast the physiologic and pathologic eff ects of adrenal androgens. ■ Describe the mechanisms that regulate secretion of glucocorticoids and adrenal sex hormones. ■ List the actions of aldosterone and describe the mechanisms that regulate aldosterone secretion. ■ Describe the main features of the diseases caused by excess or defi ciency of each of the hormones of the adrenal gland. C H A P T E R The Adrenal Medulla & Adrenal Cortex 20 INTRODUCTION Th ere are two endocrine organs in the adrenal gland, one surrounding the other. Th e main secretions of the inner adrenal medulla ( Figure 20–1 ) are the catecholamines epinephrine, norepinephrine, and dopamine; the outer adrenal cortex secretes steroid hormones. Th e adrenal medulla is in eff ect a sympathetic ganglion in which the postganglionic neurons have lost their axons and become secretory cells. Th e cells secrete when stimulated by the preganglionic nerve fi bers that reach the gland via the splanchnic nerves. Adrenal medullary hormones work mostly to prepare the body for emergencies, the so-called “fi ght-orfl ight” responses. Th e adrenal cortex secretes glucocorticoids, steroids with widespread eff ects on the metabolism of carbohydrate and protein; and a mineralocorticoid essential to the maintenance of Na + balance and extracellular fl uid (ECF) volume. It is also a secondary site of androgen synthesis, secreting sex hormones such as testosterone, which can exert eff ects on reproductive function. Mineralocorticoids and the glucocorticoids are necessary for survival. Adrenocortical Ganong_Ch20_353-376.indd 353 1/5/12 7:26:48 354 SECTION III Endocrine and Reproductive Physiology ADRENAL MORPHOLOGY Th e adrenal medulla, which constitutes 28% of the mass of the adrenal gland, is made up of interlacing cords of densely innervated granule-containing cells that abut on venous sinuses. Two cell types can be distinguished morphologically: an epinephrine- secreting type that has larger, less dense granules; and a norepinephrine-secreting type in which smaller, very dense granules fail to fi ll the vesicles in which they are contained. In humans, 90% of the cells are the epinephrine-secreting type and 10% are the norepinephrine-secreting type. Th e type of cell that secretes dopamine is unknown. Paraganglia, small groups of cells resembling those in the adrenal medulla, are found near the thoracic and abdominal sympathetic ganglia ( Figure 20–1 ). In adult mammals, the adrenal cortex is divided into three zones ( Figure 20–2 ). Th e outer zona glomerulosa is made up of whorls of cells that are continuous with the columns of cells that form the zona fasciculata. Th ese columns are separated by venous sinuses. Th e inner portion of the zona fasciculata merges into the zona reticularis, where the cell columns become interlaced in a network. Th e zona glomerulosa makes up 15% of the mass of the adrenal gland; the zona fasciculata, 50%; and the FIGURE 201 Human adrenal glands. Adrenocortical tissue is yellow; adrenal medullary tissue is orange. Note the location of the adrenals at the superior pole of each kidney. Also shown are extra-adrenal sites (gray) at which cortical and medullary tissue is sometimes found. (Reproduced with permission from Williams RH: Textbook of Endocrinology, 4th ed. Williams RH [editor]: Saunders, 1968.) zona reticularis, 7%. Th e adrenocortical cells contain abundant lipid, especially in the outer portion of the zona fasciculata. All three cortical zones secrete corticosterone, but the active enzymatic mechanism for aldosterone biosynthesis is limited to the zona glomerulosa, whereas the enzymatic mechanisms for forming cortisol and sex hormones are found in the two inner zones. Furthermore, subspecialization occurs within the inner two zones, with the zona fasciculata secreting mostly glucocorticoids and the zona reticularis secreting mainly sex hormones. Arterial blood reaches the adrenal from many small branches of the phrenic and renal arteries and the aorta. From a plexus in the capsule, blood fl ows through the cortex to the sinusoids of the medulla. Th e medulla is also supplied by a few arterioles that pass directly to it from the capsule. In most species, including humans, blood from the medulla fl ows into a central adrenal vein. Th e blood fl ow through the adrenal is large, as it is in most endocrine glands. During fetal life, the human adrenal is large and under pituitary control, but the three zones of the permanent cortex represent only 20% of the gland. Th e remaining 80% is the large fetal adrenal cortex, which undergoes rapid degeneration at the time of birth. A major function of this fetal adrenal is synthesis and secretion of sulfate conjugates of androgens that are converted in the placenta to estrogens (see Chapter 22 ). No structure is comparable to the human fetal adrenal in laboratory animals. An important function of the zona glomerulosa, in addition to aldosterone synthesis, is the formation of new cortical cells. Th e adrenal medulla does not regenerate, but when the inner two zones of the cortex are removed, a new zona fasciculata and zona reticularis regenerate from glomerular cells attached to the capsule. Small capsular remnants regrow large pieces of adreno-cortical tissue. Immediately aft er hypophysectomy, the zona fasciculata and zona reticularis begin to atrophy, whereas the zona glomerulosa is unchanged because of the action of angiotensin II on this zone. Th e ability to secrete aldosterone and conserve Na + is normal for some time aft er hypophysectomy, but in long-standing hypopituitarism, aldosterone defi ciency may develop, apparently because of the absence of a pituitary factor that maintains the responsiveness of the zona glomerulosa. Injections of ACTH and stimuli that cause endogenous ACTH secretion produce hypertrophy of the zona fasciculata and zona reticularis but actually decrease, rather than increase, the size of the zona glomerulosa. Th e cells of the adrenal cortex contain large amounts of smooth endoplasmic reticulum, which is involved in the steroid-forming process. Other steps in steroid biosynthesis occur in the mitochondria. Th e structure of steroid-secreting cells is very similar throughout the body. Th e typical features of such cells are shown in Figure 20–3 . secretion is controlled primarily by adrenocorticotropic hormone (ACTH) from the anterior pituitary, but mineralocorticoid secretion is also subject to independent control by circulating factors, of which the most important is angiotensin II, a peptide formed in the bloodstream by the action of renin. CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 355 ADRENAL MEDULLA: STRUCTURE & FUNCTION OF MEDULLARY HORMONES CATECHOLAMINES Norepinephrine, epinephrine, and small amounts of dopamine are synthesized by the adrenal medulla. Cats and some other species secrete mainly norepinephrine, but in dogs and humans, most of the catecholamine output in the adrenal vein is epinephrine. Norepinephrine also enters the circulation from noradrenergic nerve endings. Th e structures of norepinephrine, epinephrine, and dopamine and the pathways for their biosynthesis and metabolism are discussed in Chapter 7 . Norepinephrine is formed by hydroxylation and decarboxylation of tyrosine, and epinephrine by methylation of norepinephrine. Phenylethanolamine-Nmethyltransferase (PNMT), the enzyme that catalyzes the formation of epinephrine from norepinephrine, is found in appreciable quantities only in the brain and the adrenal medulla. Adrenal medullary PNMT is induced by glucocorticoids. Although relatively large amounts are required, the glucocorticoid concentration is high in the blood draining from the cortex to the medulla. Aft er hypophysectomy, the glucocorticoid concentration of this blood falls and epinephrine synthesis is decreased. In addition, glucocorticoids are apparently necessary for the normal development of the adrenal medulla; in 21β-hydroxylase defi ciency, glucocorticoid secretion is reduced during fetal life and the adrenal medulla is dysplastic. In untreated 21β-hydroxylase defi ciency, circulating catecholamines are low aft er birth. In plasma, about 95% of the dopamine and 70% of the norepinephrine and epinephrine are conjugated to sulfate. Sulfate conjugates are inactive and their function is unsettled. In recumbent humans, the normal plasma level of free norepinephrine is about 300 pg/mL (1.8 nmol/L). On standing, the level increases 50–100% ( Figure 20–4 ). Th e plasma norepinephrine level is generally unchanged aft er adrenalectomy, but the free epinephrine level, which is normally about 30 pg/mL (0.16 nmol/L), falls to essentially zero. Th e epinephrine found in tissues other than the adrenal medulla and the brain is for the most part absorbed from the bloodstream rather than synthesized in situ. Interestingly, low levels of epinephrine reappear in the blood some time aft er bilateral adrenalectomy, and these levels are regulated like those secreted by the adrenal medulla. Th ey may come from cells such as the intrinsic cardiac adrenergic (ICA) cells (see Chapter 13 ), but their exact source is unknown. Zona glomerulosa Zona fasciculata Medulla Cortex Zona reticularis Aldosterone Cortisol and androgens Epinephrine and norepinephrine Cortex Medulla FIGURE 202 Section through an adrenal gland showing both the medulla and the zones of the cortex, as well as the hormones they secrete. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2008.) 356 SECTION III Endocrine and Reproductive Physiology Plasma dopamine levels are normally very low, about 0.13 nmol/L. Most plasma dopamine is thought to be derived from sympathetic noradrenergic ganglia. Th e catecholamines have a half-life of about 2 min in the circulation. For the most part, they are methoxylated and then oxidized to 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid [VMA]; see Chapter 7 ). About 50% of the secreted catecholamines appear in the urine as free or conjugated metanephrine and normetanephrine, and 35% as VMA. Only small amounts of free norepinephrine and epinephrine are excreted. In normal humans, about 30 μg of norepinephrine, 6 μg of epinephrine, and 700 μg of VMA are excreted per day. 7 6 5 4 3 1 Receptor 2 Smooth endoplasmic reticulum Mitochondrion Shuttling of intermediates P450 enzymes located on inner membrane Free cholesterol Lipid droplet (from LDL) Phosphoproteins (cholesterol esterase) Proteins PKA active cAMP PKA inactive G-protein Adenylyl cyclase Nucleus ATP H Diffusion of steroid hormone into blood FIGURE 203 Schematic overview of the structures of steroid-secreting cells and the intracellular pathway of steroid synthesis. LDL, low-density lipoprotein; PKA, protein kinase A. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2008.) Pheochromocytoma (16) Cigarette smoking (10) To < 40 mg/dL (6) 95 → 60 mg/dL (10) Mild (8) Moderate (8) Heavy (8) During (11) After (11) Ketoacidosis (10) Myocardial infarction (11) Quiet standing (40) Resting supine (60) Hypoglycemia Exercise Surgery 0 500 1000 1500 2000 2500 0 500 1000 1500 2000 2500 (5310) Plasma norepinephrine (pg/mL) 0 0 100 Plasma epinephrine (pg/mL) 200 300 400 500 1000 5000 100 200 300 400 500 1000 5000 FIGURE 204 Norepinephrine and epinephrine levels in human venous blood in various physiologic and pathologic states. Note that the horizontal scales are diff erent. The numbers to the left in parentheses are the numbers of subjects tested. In each case, the vertical dashed line identifi es the threshold plasma concentration at which detectable physiologic changes are observed. (Modifi ed and reproduced with permission from Cryer PE: Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980;303:436.) CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 357 OTHER SUBSTANCES SECRETED BY THE ADRENAL MEDULLA In the medulla, norepinephrine and epinephrine are stored in granules with ATP. Th e granules also contain chromogranin A (see Chapter 7 ). Secretion is initiated by acetylcholine released from the preganglionic neurons that innervate the secretory cells. Acetylcholine activates cation channels allowing Ca 2+ to enter the cells from the ECF and trigger the exocytosis of the granules. In this fashion, catecholamines, ATP, and proteins from the granules are all released into the blood together. Epinephrine-containing cells of the medulla also contain and secrete opioid peptides (see Chapter 7 ). Th e precursor molecule is preproenkephalin. Most of the circulating metenkephalin comes from the adrenal medulla. Th e circulating opioid peptides do not cross the blood–brain barrier. Adrenomedullin, a vasodepressor polypeptide found in the adrenal medulla, is discussed in Chapter 32 . EFFECTS OF EPINEPHRINE & NOREPINEPHRINE In addition to mimicking the eff ects of noradrenergic nervous discharge, norepinephrine and epinephrine exert metabolic eff ects that include glycogenolysis in liver and skeletal muscle, mobilization of free fatty acids (FFA), increased plasma lactate, and stimulation of the metabolic rate. Th e eff ects of norepinephrine and epinephrine are brought about by actions on two classes of receptors: α- and β-adrenergic receptors. α receptors are subdivided into two groups, α 1 and α 2 receptors, and β receptors into β 1 , β 2 , and β 3 receptors, as outlined in Chapter 7 . Th ere are three subtypes of α 1 receptors and three subtypes of α 2 receptors (see Table 7–2 ). Norepinephrine and epinephrine both increase the force and rate of contraction of the isolated heart. Th ese responses are mediated by β 1 receptors. Th e catecholamines also increase myocardial excitability, causing extrasystoles and, occasionally, more serious cardiac arrhythmias. Norepinephrine produces vasoconstriction in most if not all organs via α 1 receptors, but epinephrine dilates the blood vessels in skeletal muscle and the liver via β 2 receptors. Th is usually overbalances the vasoconstriction produced by epinephrine elsewhere, and the total peripheral resistance drops. When norepinephrine is infused slowly in normal animals or humans, the systolic and diastolic blood pressures rise. Th e hypertension stimulates the carotid and aortic baroreceptors, producing refl ex bradycardia that overrides the direct cardioacceleratory eff ect of norepinephrine. Consequently, cardiac output per minute falls. Epinephrine causes a widening of the pulse pressure, but because baroreceptor stimulation is insuffi cient to obscure the direct eff ect of the hormone on the heart, cardiac rate, and output increase. Th ese changes are summarized in Figure 20–5 . Catecholamines increase alertness (see Chapter 14 ). Epinephrine and norepinephrine are equally potent in this regard, although in humans epinephrine usually evokes more anxiety and fear. 150 100 50 30 20 10 15 20 35 40 Epi Nor 4 6 8 50 100 Time (min) Epi = Epinephrine Nor = Norepinephrine Cardiac output Heart rate (L/min) Total peripheral resistance Arterial BP (mm Hg) FIGURE 205 Circulatory changes produced in humans by the slow intravenous infusion of epinephrine and norepinephrine. Th e catecholamines have several diff erent actions that aff ect blood glucose. Epinephrine and norepinephrine both cause glycogenolysis. Th ey produce this eff ect via β-adrenergic receptors that increase cyclic adenosine monophosphate (cAMP), with activation of phosphorylase, and via α-adrenergic receptors that increase intracellular Ca 2+ (see Chapter 7 ). In addition, the catecholamines increase the secretion of insulin and glucagon via β-adrenergic mechanisms and inhibit the secretion of these hormones via α-adrenergic mechanisms. Norepinephrine and epinephrine also produce a prompt rise in the metabolic rate that is independent of the liver and a smaller, delayed rise that is abolished by hepatectomy and coincides with the rise in blood lactate concentration. Th e initial rise in metabolic rate may be due to cutaneous vasoconstriction, which decreases heat loss and leads to a rise in body temperature, or to increased muscular activity, or both. Th e second rise is probably due to oxidation of lactate in the liver. Mice unable to make norepinephrine or epinephrine because their dopamine β-hydroxylase gene is knocked out are intolerant of cold, but surprisingly, their basal metabolic rate is elevated. Th e cause of this elevation is unknown. When injected, epinephrine and norepinephrine cause an initial rise in plasma K + because of release of K + from the liver and then a prolonged fall in plasma K + because of an increased entry of K + into skeletal muscle that is mediated by β 2 -adrenergic receptors. Some evidence suggests that activation of α receptors opposes this eff ect. Th e increases in plasma norepinephrine and epinephrine that are needed to produce the various eff ects listed above have been determined by infusion of catecholamines in resting humans. In general, the threshold for the cardiovascular and the 358 SECTION III Endocrine and Reproductive Physiology metabolic eff ects of norepinephrine is about 1500 pg/mL, that is, about fi ve times the resting value ( Figure 20–4 ). Epinephrine, on the other hand, produces tachycardia when the plasma level is about 50 pg/mL, that is, about twice the resting value. Th e threshold for increased systolic blood pressure and lipolysis is about 75 pg/mL; the threshold for hyperglycemia, increased plasma lactate, and decreased diastolic blood pressure is about 150 pg/mL; and the threshold for the α-mediated decrease in insulin secretion is about 400 pg/mL. Plasma epinephrine oft en exceeds these thresholds. On the other hand, plasma norepinephrine rarely exceeds the threshold for its cardiovascular and metabolic eff ects, and most of its eff ects are due to its local release from postganglionic sympathetic neurons. Most adrenal medullary tumors (pheochromocytomas) secrete norepinephrine, or epinephrine, or both, and produce sustained hypertension. However, 15% of epinephrine-secreting tumors secrete this catecholamine episodically, producing intermittent bouts of palpitations, headache, glycosuria, and extreme systolic hypertension. Th ese same symptoms are produced by intravenous injection of a large dose of epinephrine. EFFECTS OF DOPAMINE Th e physiologic function of the dopamine in the circulation is unknown. However, injected dopamine produces renal vasodilation, probably by acting on a specifi c dopaminergic receptor. It also produces vasodilation in the mesentery. Elsewhere, it produces vasoconstriction, probably by releasing norepinephrine, and it has a positive inotropic eff ect on the heart by an action on β 1 -adrenergic receptors. Th e net eff ect of moderate doses of dopamine is an increase in systolic pressure and no change in diastolic pressure. Because of these actions, dopamine is useful in the treatment of traumatic and cardiogenic shock (see Chapter 32 ). Dopamine is made in the renal cortex. It causes natriuresis and may exert this eff ect by inhibiting renal Na , K , ATPase. REGULATION OF ADRENAL MEDULLARY SECRETION NEURAL CONTROL Certain drugs act directly on the adrenal medulla, but physiologic stimuli aff ect medullary secretion through the nervous system. Catecholamine secretion is low in basal states, but the secretion of epinephrine and, to a lesser extent, that of norepinephrine is reduced even further during sleep. Increased adrenal medullary secretion is part of the diffuse sympathetic discharge provoked in emergency situations, which Cannon called the “emergency function of the sympathoadrenal system.” Th e ways in which this discharge prepares the individual for fl ight or fi ght are described in Chapter 13 , and the increases in plasma catecholamines under various conditions are shown in Figure 20–4 . Th e metabolic eff ects of circulating catecholamines are probably important, especially in certain situations. Th e calorigenic action of catecholamines in animals exposed to cold is HO 3 4 5 6 1A 2 19 10 14 15 18 13 17 D 12 16 9 8 7 B C 11 20 22 23 24 26 25 27 21 Cyclopentanoperhydrophenanthrene nucleus CH3 C O Progesterone Corticoids Androgens Estrogens Cholesterol (27 carbons) Pregnane derivatives (21 carbons) Androstane derivatives (19 carbons) Estrane derivatives (18 carbons) FIGURE 206 Basic structure of adrenocortical and gonadal steroids. The letters in the formula for cholesterol identify the four basic rings, and the numbers identify the positions in the molecule. As shown here, the angular methyl groups (positions 18 and 19) are usually indicated simply by straight lines. an example, and so is the glycogenolytic eff ect (see Chapter 24 ) in combating hypoglycemia. SELECTIVE SECRETION When adrenal medullary secretion is increased, the ratio of norepinephrine to epinephrine in the adrenal effl uent is generally unchanged. However, norepinephrine secretion tends to be selectively increased by emotional stresses with which the individual is familiar, whereas epinephrine secretion rises selectively in situations in which the individual does not know what to expect. ADRENAL CORTEX: STRUCTURE & BIOSYNTHESIS OF ADRENOCORTICAL HORMONES CLASSIFICATION & STRUCTURE Th e hormones of the adrenal cortex are derivatives of cholesterol. Like cholesterol, bile acids, vitamin D, and ovarian and testicular steroids, they contain the cyclopentanoperhydrophenanthrene nucleus ( Figure 20–6 ). Gonadal and adrenocortical steroids are of three types: C 21 steroids, which have a two-carbon side chain at position 17; C 19 steroids, which CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 359 have a keto or hydroxyl group at position 17; and C 18 steroids, which, in addition to a 17-keto or hydroxyl group, have no angular methyl group attached to position 10. Th e adrenal cortex secretes primarily C 21 and C 19 steroids. Most of the C 19 steroids have a keto group at position 17 and are therefore called 17-ketosteroids. Th e C 21 steroids that have a hydroxyl group at the 17 position in addition to the side chain are oft en called 17-hydroxycorticoids or 17-hydroxycorticosteroids. Th e C 19 steroids have androgenic activity. Th e C 21 steroids are classifi ed, using Selye’s terminology, as mineralocorticoids or glucocorticoids. All secreted C 21 steroids have both mineralocorticoid and glucocorticoid activity; mineralocorticoids are those in which eff ects on Na + and K + excretion predominate and glucocorticoids are those in which eff ects on glucose and protein metabolism predominate. Th e details of steroid nomenclature and isomerism can be found elsewhere. However, it is pertinent to mention that the Greek letter Δ indicates a double bond and that the groups that lie above the plane of each of the steroid rings are indicated by the Greek letter β and a solid line (—OH), whereas those that lie below the plane are indicated by α and a dashed line (- - -OH). Th us, the C 21 steroids secreted by the adrenal have a Δ 4 -3-keto confi guration in the A ring. In most naturally occurring adrenal steroids, 17-hydroxy groups are in the α confi guration, whereas 3-, 11-, and 21-hydroxy groups are in the β confi guration. Th e 18-aldehyde confi guration of naturally occurring aldosterone is the D form. l -aldosterone is physiologically inactive. C O O CH2OH C O HO O CH2OH Corticosterone 11-Deoxycorticosterone C O O CH3 Progesterone C O HO CH3 Pregnenolone ACTH C O O CH2OH C O HO O CH2OH C O O CH3 C O OH HO CH3 17-Hydroxypregnenolone 17-Hydroxyprogesterone 11-Deoxycortisol Cortisol Cholesterol Cholesterol desmolase 3β-Hydroxysteroid dehydrogenase 17α-Hydroxylase 17,20-Lyase 21β-Hydroxylase 11β-Hydroxylase OH O O HO O Dehydroepiandrosterone Androstenedione Testosterone Estradiol OH OH Sulfokinase DHEA sulfate FIGURE 207 Outline of hormone biosynthesis in the zona fasciculata and zona reticularis of the adrenal cortex. The major secretory products are underlined. The enzymes for the reactions are shown on the left and at the top of the chart. When a particular enzyme is defi cient, hormone production is blocked at the points indicated by the shaded bars. SECRETED STEROIDS Innumerable steroids have been isolated from adrenal tissue, but the only steroids normally secreted in physiologically signifi cant amounts are the mineralocorticoid aldosterone, the glucocorticoids cortisol and corticosterone, and the androgens dehydroepiandrosterone (DHEA) and androstenedione. Th e structures of these steroids are shown in Figure 20–7 and Figure 20–8. Deoxycorticosterone is a mineralocorticoid that is normally secreted in about the same amount as aldosterone ( Table 20–1 ) but has only 3% of the mineralocorticoid activity of aldosterone. Its eff ect on mineral metabolism is usually negligible, but in diseases in which its secretion is increased, its eff ect can be appreciable. Most of the estrogens that are not formed in the ovaries are produced in the circulation from adrenal androstenedione. Almost all the dehydroepiandrosterone is secreted conjugated with sulfate, although most if not all of the other steroids are secreted in the free, unconjugated form (Clinical Box 20–1). SPECIES DIFFERENCES In all species from amphibia to humans, the major C 21 steroid hormones secreted by adrenocortical tissue appear to be aldosterone, cortisol, and corticosterone, although the ratio of cortisol to corticosterone varies. Birds, mice, and rats secrete corticosterone almost exclusively; dogs secrete approximately equal amounts of the two glucocorticoids; and cats, 360 SECTION III Endocrine and Reproductive Physiology tion. LDL receptors are especially abundant in adrenocortical cells. Th e cholesterol is esterifi ed and stored in lipid droplets. Cholesterol ester hydrolase catalyzes the formation of free cholesterol in the lipid droplets ( Figure 20–9 ). Th e cholesterol is transported to mitochondria by a sterol carrier protein. In the mitochondria, it is converted to pregnenolone in a reaction catalyzed by an enzyme known as cholesterol desmolase or side-chain cleavage enzyme. Th is enzyme, like most of the enzymes involved in steroid biosynthesis, is a member of the cytochrome P450 superfamily and is also known as P450scc or CYP11A1. For convenience, the various names of the enzymes involved in adrenocortical steroid biosynthesis are summarized in Table 20–3 . Pregnenolone moves to the smooth endoplasmic reticulum, where some of it is dehydrogenated to form progesterone in a reaction catalyzed by 3β-hydroxysteroid dehydrogenase. Th is enzyme has a molecular weight of 46,000 and is not a cytochrome P450. It also catalyzes the conversion of 17α-hydroxypregnenolone to 17α-hydroxyprogesterone, and dehydroepiandrosterone to androstenedione ( Figure 22–7 ) in the smooth endoplasmic reticulum. Th e 17α- hydroxypregnenolone and the 17α-hydroxyprogesterone are formed from pregnenolone and progesterone, respectively ( Figure 20–7 ) by the action of 17α-hydroxylase. Th is is another mitochondrial P450, and it is also known as P450c17 C O HO HO O CH2OH CH2 C O O HO HC O CH2OH Cortisol and sex steroids Cholesterol Pregnenolone Progesterone Deoxycorticosterone Corticosterone 18-Hydroxycorticosterone Aldosterone Aldosterone synthase Aldosterone synthase ANG II Aldosterone synthase ACTH ANG II FIGURE 208 Hormone synthesis in the zona glomerulosa. The zona glomerulosa lacks 17α-hydroxylase activity, and only the zona glomerulosa can convert corticosterone to aldosterone because it is the only zone that normally contains aldosterone synthase. ANG II, angiotensin II. CLINICAL BOX 20–1 Synthetic Steroids As with many other naturally occurring substances, the activity of adrenocortical steroids can be increased by altering their structure. A number of synthetic steroids are available that have many times the activity of cortisol. The relative glucocorticoid and mineralocorticoid potencies of the natural steroids are compared with those of the synthetic steroids 9α-fl uorocortisol, prednisolone, and dexamethasone in Table 20–2 . The potency of dexamethasone is due to its high affi nity for glucocorticoid receptors and its long halflife. Prednisolone also has a long half-life. TABLE 201 Principal adrenocortical hormones in adult humans. a Name Synonyms Average Plasma Concentration (Free and Bound) a μg/dL) Average Amount Secreted (mg/24 h) Cortisol Compound F, hydrocortisone 13.9 10 Corticosterone Compound B 0.4 3 Aldosterone 0.0006 0.15 Deoxycorticosterone DOC 0.0006 0.20 Dehydroepiandrosterone sulfate DHEAS 175.0 20 a All plasma concentration values except DHEAS are fasting morning values after overnight recumbency. sheep, monkeys, and humans secrete predominantly cortisol. In humans, the ratio of secreted cortisol to corticosterone is approximately 7:1. STEROID BIOSYNTHESIS Th e major paths by which the naturally occurring adrenocortical hormones are synthesized in the body are summarized in Figures 20–7 and 20–8 . Th e precursor of all steroids is cholesterol. Some of the cholesterol is synthesized from acetate, but most of it is taken up from LDL in the circula- CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 361 or CYP17. Located in another part of the same enzyme is 17,20-lyase activity that breaks the 17,20 bond, converting 17α-pregnenolone and 17α-progesterone to the C 19 steroids dehydroepiandrosterone and androstenedione. Hydroxylation of progesterone to 11-deoxycorticosterone and of 17α-hydroxyprogesterone to 11-deoxycortisol occurs in the smooth endoplasmic reticulum. Th ese reactions are catalyzed by 21β-hydroxylase, a cytochrome P450 that is also known as P450c21 or CYP21A2. 11-deoxycorticosterone and the 11-deoxycortisol move back to the mitochondria, where they are 11-hydroxylated to form corticosterone and cortisol. Th ese reactions occur in the zona fasciculata and zona reticularis and are catalyzed by 11β-hydroxylase, a cytochrome P450 also known as P450c11 or CYP11B1. In the zona glomerulosa there is no 11β-hydroxylase but a closely related enzyme called aldosterone synthase is present. Th is cytochrome P450 is 95% identical to 11β-hydroxylase and is also known as P450c11AS or CYP11B2. Th e genes that code CYP11B1 and CYP11B2 are both located on chromosome 8. However, aldosterone synthase is normally found only in the zona glomerulosa. Th e zona glomerulosa also lacks 17α-hydroxylase. Th is is why the zona glomerulosa makes aldosterone but fails to make cortisol or sex hormones. Furthermore, subspecialization occurs within the inner two zones. Th e zona fasciculata has more 3β-hydroxysteroid dehydrogenase activity than the zona reticularis, and the zona reticularis has more of the cofactors required for the 17,20-lyase activity of 17α-hydroxylase. Th erefore, the zona fasciculata makes more cortisol and corticosterone, and the zona reticularis makes more androgens. Most of the dehydroepiandrosterone that is formed is converted to dehydroepiandrosterone sulfate (DHEAS) by adrenal sulfokinase, and this enzyme is localized in the zona reticularis as well. ACTION OF ACTH ACTH binds to high-affi nity receptors on the plasma membrane of adrenocortical cells. Th is activates adenylyl cyclase via G s . Th e resulting reactions ( Figure 20–9 ) lead to a prompt increase in the formation of pregnenolone and its derivatives, with secretion of the latter. Over longer periods, ACTH also increases the synthesis of the P450s involved in the synthesis of glucocorticoids. ACTIONS OF ANGIOTENSIN II Angiotensin II binds to AT 1 receptors (see Chapter 38 ) in the zona glomerulosa that act via a G protein to activate phospholipase C. Th e resulting increase in protein kinase C fosters the conversion of cholesterol to pregnenolone ( Figure 20–8 ) and facilitates the action of aldosterone synthase, resulting in increased secretion of aldosterone. ENZYME DEFICIENCIES Th e consequences of inhibiting any of the enzyme systems involved in steroid biosynthesis can be predicted from Figures 20–7 and 20–8 . Congenital defects in the enzymes lead to defi cient cortisol secretion and the syndrome of congenital adrenal hyperplasia. Th e hyperplasia is due to increased ACTH secretion. Cholesterol desmolase defi ciency is fatal in utero because it prevents the placenta from making the progesterone necessary for pregnancy to continue. A cause of severe congenital adrenal hyperplasia in newborns is a loss of function mutation TABLE 202 Relative potencies of corticosteroids compared with cortisol.a Steroid Glucocorticoid Activity Mineralocorticoid Activity Cortisol 1.0 1.0 Corticosterone 0.3 15 Aldosterone 0.3 3000 Deoxycorticosterone 0.2 100 Costisone 0.7 0.8 Prednisolone 4 0.8 9α-Fluorocortisol 10 125 Dexamethasone 25 –0 a Values are approximations based on liver glycogen deposition or antiinfl ammatory assays for glucocorticoid activity, and eff ect on urinary Na + /K + or maintenance of adrenalectomized animals for mineralocorticoid activity. The last three steroids listed are synthetic compounds that do not occur naturally. LDL Cholesteryl esters Cholesterol Cortisol Preg 11-Deoxycortisol 17-OH preg cAMP Protein kinase A ATP CEH SER Lipid droplet Mitochondrion ACTH R GS AC FIGURE 209 Mechanism of action of ACTH on cortisolsecreting cells in the inner two zones of the adrenal cortex. When ACTH binds to its receptor (R), adenylyl cyclase (AC) is activated via Gs. The resulting increase in cAMP activates protein kinase A, and the kinase phosphorylates cholesteryl ester hydrolase (CEH), increasing its activity. Consequently, more free cholesterol is formed and converted to pregnenolone. Note that in the subsequent steps in steroid biosynthesis, products are shuttled between the mitochondria and the smooth endoplasmic reticulum (SER). Corticosterone is also synthesized and secreted. 362 SECTION III Endocrine and Reproductive Physiology of the gene for the steroidogenic acute regulatory (StAR) protein. Th is protein is essential in the adrenals and gonads but not in the placenta for the normal movement of cholesterol into the mitochondria to reach cholesterol desmolase, which is located on the matrix space side of the internal mitochondrial membrane (see Chapter 16 ). In its absence, only small amounts of steroids are formed. Th e degree of ACTH stimulation is marked, resulting eventually in accumulation of large numbers of lipoid droplets in the adrenal. For this reason, the condition is called congenital lipoid adrenal hyperplasia. Because androgens are not formed, female genitalia develop regardless of genetic sex (see Chapter 22 ). In 3β hydroxysteroid dehydrogenase defi - ciency, another rare condition, DHEA secretion is increased. Th is steroid is a weak androgen that can cause some masculinization in females with the disease, but it is not adequate to produce full masculinization of the genitalia in genetic males. Consequently, hypospadias, a condition where the opening of the urethra is on the underside of the penis rather than its tip, is common. In fully developed 17α-hydroxylase defi ciency, a third rare condition due to a mutated gene for CYP17, no sex hormones are produced, so female external genitalia are present. However, the pathway leading to corticosterone and aldosterone is intact, and elevated levels of 11-deoxycorticosterone and other mineralocorticoids produce hypertension and hypokalemia. Cortisol is defi cient, but this is partially compensated by the glucocorticoid activity of corticosterone. Unlike the defects discussed in the preceding paragraph, 21β-hydroxylase defi ciency is common, accounting for 90% or more of the enzyme defi ciency cases. Th e 21β-hydroxylase gene, which is in the human leukocyte antigen (HLA) complex of genes on the short arm of chromosome 6 (see Chapter 3 ) is one of the most polymorphic in the human genome. Mutations occur at many diff erent sites in the gene, and the abnormalities that are produced therefore range from mild to severe. Production of cortisol and aldosterone are generally reduced, so ACTH secretion and consequently production of precursor steroids are increased. Th ese steroids are converted to androgens, producing virilization. Th e characteristic pattern that develops in females in the absence of treatment is the adrenogenital syndrome. Masculization may not be marked until later in life and mild cases can be detected only by laboratory tests. In 75% of the cases, aldosterone defi ciency causes appreciable loss of Na + ( salt-losing form of adrenal hyperplasia). Th e resulting hypovolemia can be severe. In 11β-hydroxylase defi ciency, virilization plus excess secretion of 11-deoxycortisol and 11-deoxycorticosterone take place. Because the former is an active mineralocorticoid, patients with this condition also have salt and water retention and, in two-thirds of the cases, hypertension ( hypertensive form of congenital adrenal hyperplasia). Glucocorticoid treatment is indicated in all of the virilizing forms of congenital adrenal hyperplasia because it repairs the glucocorticoid defi cit and inhibits ACTH secretion, reducing the abnormal secretion of androgens and other steroids. Expression of the cytochrome P450 enzymes responsible for steroid hormone biosynthesis depends on steroid factor-1 (SF-1), an orphan nuclear receptor. If Ft2-F1, the gene for SF-1, is knocked out, the gonads as well as adrenals fail to develop and additional abnormalities are present at the pituitary and hypothalamic level. TRANSPORT, METABOLISM, & EXCRETION OF ADRENOCORTICAL HORMONES GLUCOCORTICOID BINDING Cortisol is bound in the circulation to an α globulin called transcortin or corticosteroid-binding globulin (CBG). A minor degree of binding to albumin also takes place. Corticosterone is similarly bound, but to a lesser degree. Th e halflife of cortisol in the circulation is therefore longer (about 60–90 min) than that of corticosterone (50 min). Bound steroids are physiologically inactive (see Chapter 16 ). In addition, relatively little free cortisol and corticosterone are found in the urine because of protein binding. Th e equilibrium between cortisol and its binding protein and the implications of binding in terms of tissue supplies and ACTH secretion are summarized in Figure 20–10 . Th e bound cortisol functions as a circulating reservoir of hormone that keeps a supply of free cortisol available to the tissues. TABLE 203 Nomenclature for adrenal steroidogenic enzymes and their location in adrenal cells. Trivial Name P450 CYP Location Cholesterol desmolase; side-chain cleavage enzyme P450SCC CYP11A1 Mitochondria 3β-Hydroxysteroid dehydrogenase . . . . . . SER 17α-Hydroxylase, 17,20-lyase P450 C 17 CYP17 Mitochondria 21β-Hydroxylase P450 C 21 CYP21A2 SER 11β-Hydroxylase P450 C 11 CYP11B1 Mitochondria Aldosterone synthase P450 C 11AS CYP11B2 Mitochondria SER, smooth endoplasmic reticulum. CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 363 Th e relationship is similar to that of T 4 and its binding protein (see Chapter 19 ). At normal levels of total plasma cortisol (13.5 μg/dL or 375 nmol/L), very little free cortisol is present in the plasma, but the binding sites on CBG become saturated when the total plasma cortisol exceeds 20 μg/dL. At higher plasma levels, binding to albumin increases, but the main increase is in the unbound fraction. CBG is synthesized in the liver and its production is increased by estrogen. CBG levels are elevated during pregnancy and depressed in cirrhosis, nephrosis, and multiple ACTH Anterior pituitary Tissue cortisol Protein-bound cortisol in plasma (13 μg/dL) Adrenal cortex Free cortisol in plasma (~0.5 μg/dL) FIGURE 2010 The interrelationships of free and bound cortisol. The dashed arrow indicates that cortisol inhibits ACTH secretion. The value for free cortisol is an approximation; in most studies, it is calculated by subtracting the protein-bound cortisol from the total plasma cortisol. O HO C O OH Δ4-Hydrogenase; NADPH Cortisol Cortisone Tetrahydrocortisol glucuronide Dihydrocortisol Tetrahydrocortisol 17-Ketosteroids Tetrahydrocortisone glucuronide 17-Ketosteroids 11β-Hydroxysteroid dehydrogenase Glucuronyl transferase; uridine-diphosphoglucuronic acid 3α-Hydroxysteroid dehydrogenase; NADPH or NADH CH2OH C O OH CH2OH C O OH CH2OH C O OH CH2OH C O OH CH2OH O O O HO H HO H HO HC O H HO HCOH HOCH HCOH HC O COO– FIGURE 2011 Outline of hepatic metabolism of cortisol. myeloma. When the CBG level rises, more cortisol is bound, and initially the free cortisol level drops. Th is stimulates ACTH secretion, and more cortisol is secreted until a new equilibrium is reached at which the bound cortisol is elevated but the free cortisol is normal. Changes in the opposite direction occur when the CBG level falls. Th is explains why pregnant women have high total plasma cortisol levels without symptoms of glucocorticoid excess and, conversely, why some patients with nephrosis have low total plasma cortisol without symptoms of glucocorticoid defi ciency. METABOLISM & EXCRETION OF GLUCOCORTICOIDS Cortisol is metabolized in the liver, which is the principal site of glucocorticoid catabolism. Most of the cortisol is reduced to dihydrocortisol and then to tetrahydrocortisol, which is conjugated to glucuronic acid ( Figure 20–11 ). Th e glucuronyl transferase system responsible for this conversion also catalyzes the formation of the glucuronides of bilirubin (see Chapter 28 ) and a number of hormones and drugs. Competitive inhibition takes place between these substrates for the enzyme system. Th e liver and other tissues contain the enzyme 11β hydroxysteroid dehydrogenase. Th ere are at least two forms of this enzyme. Type 1 catalyzes the conversion of cortisol to cortisone and the reverse reaction, though it functions primarily as a reductase, forming cortisol from corticosterone. Type 2 catalyzes almost exclusively the one-way conversion of cortisol to cortisone. Cortisone is an active glucocorticoid because it is 364 SECTION III Endocrine and Reproductive Physiology converted to cortisol, and it is well known because of its extensive use in medicine. It is not secreted in appreciable quantities by the adrenal glands. Little, if any, of the cortisone formed in the liver enters the circulation, because it is promptly reduced and conjugated to form tetrahydrocortisone glucuronide. Th e tetrahydroglucuronide derivatives (“conjugates”) of cortisol and corticosterone are freely soluble. Th ey enter the circulation, where they do not become bound to protein. Th ey are rapidly excreted in the urine. About 10% of the secreted cortisol is converted in the liver to the 17-ketosteroid derivatives of cortisol and cortisone. Th e ketosteroids are conjugated for the most part to sulfate and then excreted in the urine. Other metabolites, including 20-hydroxy derivatives, are formed. Th ere is an enterohepatic circulation of glucocorticoids and about 15% of the secreted cortisol is excreted in the stool. Th e metabolism of corticosterone is similar to that of cortisol, except that it does not form a 17-ketosteroid derivative (see Clinical Box 20–2). ALDOSTERONE Aldosterone is bound to protein to only a slight extent, and its half-life is short (about 20 min). Th e amount secreted is small ( Table 20–1 ), and the total plasma aldosterone level in humans is normally about 0.006 μg/dL (0.17 nmol/L), compared with a cortisol level (bound and free) of about 13.5 μg/dL (375 nmol/L). Much of the aldosterone is converted in the liver to the tetrahydroglucuronide derivative, but some is changed in the liver and in the kidneys to an 18-glucuronide. Th is glucuronide, which is unlike the breakdown products of other steroids, is converted to free aldosterone by hydrolysis at pH 1.0, and it is therefore oft en referred to as the “acid-labile conjugate.” Less than 1% of the secreted aldosterone appears in the urine in the free form. Another 5% is in the form of the acid-labile conjugate, and up to 40% is in the form of the tetrahydroglucuronide. 17KETOSTEROIDS Th e major adrenal androgen is the 17-ketosteroid dehydroepiandrosterone, although androstenedione is also secreted. Th e 11-hydroxy derivative of androstenedione and the 17-ketosteroids formed from cortisol and cortisone by side chain cleavage in the liver are the only 17-ketosteroids that have an =O or an —OH group in the 11 position (“11-oxy- CLINICAL BOX 20–2 Variations in the Rate of Hepatic Metabolism The rate of hepatic inactivation of glucocorticoids is depressed in liver disease and, interestingly, during surgery and other stresses. Thus, in stressed humans, the plasmafree cortisol level rises higher than it does with maximal ACTH stimulation in the absence of stress. 17-ketosteroids”). Testosterone is also converted to a 17-ketosteroid. Because the daily 17-ketosteroid excretion in normal adults is 15 mg in men and 10 mg in women, about two thirds of the urinary ketosteroids in men are secreted by the adrenal or formed from cortisol in the liver and about one third are of testicular origin. Etiocholanolone, one of the metabolites of the adrenal androgens and testosterone, can cause fever when it is unconjugated (see Chapter 17 ). Certain individuals have episodic bouts of fever due to periodic accumulation in the blood of unconjugated etiocholanolone (“etiocholanolone fever”). EFFECTS OF ADRENAL ANDROGENS & ESTROGENS ANDROGENS Androgens are the hormones that exert masculinizing eff ects and they promote protein anabolism and growth (see Chapter 23 ). Testosterone from the testes is the most active androgen and the adrenal androgens have less than 20% of its activity. Secretion of the adrenal androgens is controlled acutely by ACTH and not by gonadotropins. However, the concentration of DHEAS increases until it peaks at about 225 mg/dL in the early 20s, and then falls to very low values in old age ( Figure 20–12 ). Th ese long-term changes are not due to changes in ACTH secretion and appear to be due instead to a rise and then a gradual fall in the lyase activity of 17α-hydroxylase. All but about 0.3% of the circulating DHEA is conjugated to sulfate (DHEAS). Th e secretion of adrenal androgens is nearly as great in castrated males and females as it is in normal males, so it is clear that these hormones exert very little masculinizing eff ect when secreted in normal amounts. However, they can produce appreciable masculinization when secreted 600 500 400 300 200 100 0 0 10 20 30 40 50 60 70 80 Age (years) DHEAS (μg/dL) Males Females FIGURE 2012 Change in serum dehydroepiandrosterone sulfate (DHEAS) with age. The middle line is the mean, and the dashed lines identify ±1.96 standard deviations. (Reproduced, with permission, from Smith MR, et al: A radioimmunoassay for the estimation of serum dehydroepiandrosterone sulfate in normal and pathological sera. Clin Chim Acta 1975;65:5.) CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 365 in excessive amounts. In adult males, excess adrenal androgens merely accentuate existing characteristics, but in prepubertal boys they can cause precocious development of the secondary sex characteristics without testicular growth (precocious pseudopuberty). In females they cause female pseudo-hermaphroditism and the adrenogenital syndrome. Some health practitioners recommend injections of dehydroepiandrosterone to combat the eff ects of aging (see Chapter 1 ), but results to date are controversial at best. ESTROGENS Th e adrenal androgen androstenedione is converted to testosterone and to estrogens (aromatized) in fat and other peripheral tissues. Th is is an important source of estrogens in men and postmenopausal women (see Chapters 22 and 23 ). PHYSIOLOGIC EFFECTS OF GLUCOCORTICOIDS ADRENAL INSUFFICIENCY In untreated adrenal insuffi ciency, Na + loss and shock occurs due to the lack of mineralocorticoid activity, as well as abnormalities of water, carbohydrate, protein, and fat metabolism due to the lack of glucocorticoids. Th ese metabolic abnormalities are eventually fatal despite mineralocorticoid treatment. Small amounts of glucocorticoids correct the metabolic abnormalities, in part directly and in part by permitting other reactions to occur. It is important to separate these physiologic actions of glucocorticoids from the quite diff erent eff ects produced by large amounts of the hormones. MECHANISM OF ACTION Th e multiple eff ects of glucocorticoids are triggered by binding to glucocorticoid receptors, and the steroid–receptor complexes act as transcription factors that promote the transcription of certain segments of DNA (see Chapter 1 ). Th is, in turn, leads via the appropriate mRNAs to synthesis of enzymes that alter cell function. In addition, it seems likely that glucocorticoids have nongenomic actions. EFFECTS ON INTERMEDIARY METABOLISM Th e actions of glucocorticoids on the intermediary metabolism of carbohydrate, protein, and fat are discussed in Chapter 24. Th ey include increased protein catabolism and increased hepatic glycogenesis and gluconeogenesis. Glucose 6-phosphatase activity is increased, and the plasma glucose level rises. Glucocorticoids exert an anti-insulin action in peripheral tissues and make diabetes worse. However, the brain and the heart are spared, so the increase in plasma glucose provides extra glucose to these vital organs. In diabetics, glucocorticoids raise plasma lipid levels and increase ketone body formation, but in normal individuals, the increase in insulin secretion provoked by the rise in plasma glucose obscures these actions. In adrenal insuffi ciency, the plasma glucose level is normal as long as an adequate caloric intake is maintained, but fasting causes hypoglycemia that can be fatal. Th e adrenal cortex is not essential for the ketogenic response to fasting. PERMISSIVE ACTION Small amounts of glucocorticoids must be present for a number of metabolic reactions to occur, although the glucocorticoids do not produce the reactions by themselves. Th is eff ect is called their permissive action. Permissive eff ects include the requirement for glucocorticoids to be present for glucagon and catecholamines to exert their calorigenic eff ects (see above and Chapter 24 ), for catecholamines to exert their lipolytic eff ects, and for catecholamines to produce pressor responses and bronchodilation. EFFECTS ON ACTH SECRETION Glucocorticoids inhibit ACTH secretion, which represents a negative feedback response on the pituitary. ACTH secretion is increased in adrenalectomized animals. Th e consequences of the negative feedback action of cortisol on ACTH secretion are discussed below in the section on regulation of glucocorticoid secretion. VASCULAR REACTIVITY In adrenally insuffi cient animals, vascular smooth muscle becomes unresponsive to norepinephrine and epinephrine. Th e capillaries dilate and, terminally, become permeable to colloidal dyes. Failure to respond to the norepinephrine liberated at noradrenergic nerve endings probably impairs vascular compensation for the hypovolemia of adrenal insuffi ciency and promotes vascular collapse. Glucocorticoids restore vascular reactivity. EFFECTS ON THE NERVOUS SYSTEM Changes in the nervous system in adrenal insuffi ciency that are reversed only by glucocorticoids include the appearance of electroencephalographic waves slower than the normal β rhythm, and personality changes. Th e latter, which are mild, include irritability, apprehension, and inability to concentrate. EFFECTS ON WATER METABOLISM Adrenal insuffi ciency is characterized by an inability to excrete a water load, causing the possibility of water intoxication. Only glucocorticoids repair this defi cit. In patients with adrenal 366 SECTION III Endocrine and Reproductive Physiology insuffi ciency who have not received glucocorticoids, glucose infusion may cause high fever (“glucose fever”) followed by collapse and death. Presumably, the glucose is metabolized, the water dilutes the plasma, and the resultant osmotic gradient between the plasma and the cells causes the cells of the thermoregulatory centers in the hypothalamus to swell to such an extent that their function is disrupted. Th e cause of defective water excretion in adrenal insuffi ciency is unsettled. Plasma vasopressin levels are elevated in adrenal insuffi ciency and reduced by glucocorticoid treatment. Th e glomerular fi ltration rate is low, and this probably contributes to the reduction in water excretion. Th e selective eff ect of glucocorticoids on the abnormal water excretion is consistent with this possibility, because even though the mineralocorticoids improve fi ltration by restoring plasma volume, the glucocorticoids raise the glomerular fi ltration rate to a much greater degree. EFFECTS ON THE BLOOD CELLS & LYMPHATIC ORGANS Glucocorticoids decrease the number of circulating eosinophils by increasing their sequestration in the spleen and lungs. Glucocorticoids also lower the number of basophils in the circulation and increase the number of neutrophils, platelets, and red blood cells ( Table 20–4 ). Glucocorticoids decrease the circulating lymphocyte count and the size of the lymph nodes and thymus by inhibiting lymphocyte mitotic activity. Th ey reduce secretion of cytokines by inhibiting the eff ect of NF-κB on the nucleus. Th e reduced secretion of the cytokine IL-2 leads to reduced proliferation of lymphocytes (see Chapter 3 ), and these cells undergo apoptosis. RESISTANCE TO STRESS Th e term stress as used in biology has been defi ned as any change in the environment that changes or threatens to change an existing optimal steady state. Most, if not all, of these stresses activate TABLE 204 Typical effects of cortisol on the white and red blood cell counts in humans (cells/ μL). Cell Normal Cortisol-Treated White blood cells Total 9000 10,000 PMNs 5760 8330 Lymphocytes 2370 1080 Eosinophils 270 20 Basophils 60 30 Monocytes 450 540 Red blood cells 5 million 5.2 million processes at the molecular, cellular, or systemic level that tend to restore the previous state, that is, they are homeostatic reactions. Some, but not all, of the stresses stimulate ACTH secretion. Th e increase in ACTH secretion is essential for survival when the stress is severe. If animals are then hypophysectomized, or adrenalectomized but treated with maintenance doses of glucocorticoids, they die when exposed to the same stress. Th e reason an elevated circulating ACTH, and hence glucocorticoid level, is essential for resisting stress remains for the most part unknown. Most of the stressful stimuli that increase ACTH secretion also activate the sympathetic nervous system, and part of the function of circulating glucocorticoids may be maintenance of vascular reactivity to catecholamines. Glucocorticoids are also necessary for the catecholamines to exert their full FFA-mobilizing action, and the FFAs are an important emergency energy supply. However, sympathectomized animals tolerate a variety of stresses with relative impunity. Another theory holds that glucocorticoids prevent other stress-induced changes from becoming excessive. At present, all that can be said is that stress causes increases in plasma glucocorticoids to high “pharmacologic” levels that in the short run are life-saving. It should also be noted that the increase in ACTH, which is benefi cial in the short term, becomes harmful and disruptive in the long term, causing among other things, the abnormalities of Cushing syndrome. PHARMACOLOGIC & PATHOLOGIC EFFECTS OF GLUCOCORTICOIDS CUSHING SYNDROME Th e clinical picture produced by prolonged increases in plasma glucocorticoids was described by Harvey Cushing and is called Cushing syndrome ( Figure 20–13 ). It may be ACTH-independent or ACTH-dependent. Th e causes of ACTH-independent Cushing syndrome include glucocorticoid-secreting adrenal tumors, adrenal hyperplasia, and prolonged administration of exogenous glucocorticoids for diseases such as rheumatoid arthritis. Rare but interesting ACTH-independent cases have been reported in which adrenocortical cells abnormally express receptors for gastric inhibitory polypeptide (GIP) (see Chapter 25 ), vasopressin (see Chapter 38 ), β-adrenergic agonists, IL-1, or gonadotropin-releasing hormone (GnRH; see Chapter 22 ), causing these peptides to increase glucocorticoid secretion. Th e causes of ACTH-dependent Cushing syndrome include ACTH-secreting tumors of the anterior pituitary gland and tumors of other organs, usually the lungs, that secrete ACTH (ectopic ACTH syndrome) or corticotropin releasing hormone (CRH). Cushing syndrome due to anterior pituitary tumors is oft en called Cushing disease because these tumors were the cause of the cases described by Cushing. However, it is confusing to speak of Cushing disease as a subtype of CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 367 Cushing syndrome, and the distinction seems to be of little more than historical value. Patients with Cushing syndrome are protein-depleted as a result of excess protein catabolism. Th e skin and subcutaneous tissues are therefore thin and the muscles are poorly developed. Wounds heal poorly, and minor injuries cause bruises and ecchymoses. Th e hair is thin and scraggly. Many patients with the disease have some increase in facial hair and acne, but this is caused by the increased secretion of adrenal androgens and oft en accompanies the increase in glucocorticoid secretion. Body fat is redistributed in a characteristic way. Th e extremities are thin, but fat collects in the abdominal wall, face, and upper back, where it produces a “buff alo hump.” As the thin skin of the abdomen is stretched by the increased subcutaneous fat depots, the subdermal tissues rupture to form prominent reddish purple striae. Th ese scars are seen normally whenever a rapid stretching of skin occurs, but in normal individuals the striae are usually inconspicuous and lack the intense purplish color. Many of the amino acids liberated from catabolized proteins are converted into glucose in the liver and the resultant hyperglycemia and decreased peripheral utilization of glucose may be suffi cient to precipitate insulin-resistant diabetes mellitus, especially in patients genetically predisposed to diabetes. Hyperlipidemia and ketosis are associated with the diabetes, but acidosis is usually not severe. Th e glucocorticoids are present in such large amounts in Cushing syndrome that they may exert a signifi cant mineralocorticoid action. Deoxycorticosterone secretion is also elevated in cases due to ACTH hypersecretion. Th e salt and water retention plus the facial obesity cause the characteristic plethoric, rounded “moon-faced” appearance, and there may be signifi cant K + depletion and weakness. About 85% Moon face Red cheeks Bruisability with ecchymoses Thin skin Poor muscle development Poor wound healing Striae Pendulous abdomen Fat pads FIGURE 2013 Typical fi ndings in Cushing syndrome. (Reproduced with permission from Forsham PH, Di Raimondo VC: Traumatic Medicine and Surgery for the Attorney. Butterworth, 1960.) of patients with Cushing syndrome are hypertensive. Th e hypertension may be due to increased deoxycorticosterone secretion, increased angiotensinogen secretion, or a direct glucocorticoid eff ect on blood vessels (see Chapter 32 ). Glucocorticoid excess leads to bone dissolution by decreasing bone formation and increasing bone resorption. Th is leads to osteoporosis, a loss of bone mass that leads eventually to collapse of vertebral bodies and other fractures. Th e mechanisms by which glucocorticoids produce their eff ects on bone are discussed in Chapter 21 . Glucocorticoids in excess accelerate the basic electroencephalographic rhythms and produce mental aberrations ranging from increased appetite, insomnia, and euphoria to frank toxic psychoses. As noted above, glucocorticoid defi ciency is also associated with mental symptoms, but the symptoms produced by glucocorticoid excess are more severe. ANTIINFLAMMATORY & ANTIALLERGIC EFFECTS OF GLUCOCORTICOIDS Glucocorticoids inhibit the infl ammatory response to tissue injury. Th e glucocorticoids also suppress manifestations of allergic disease that are due to the release of histamine frommast cells and basophils. Both of these eff ects require high levels of circulating glucocorticoids and cannot be produced by administering steroids without producing the other manifestations of glucocorticoid excess. Furthermore, large doses of exogenous glucocorticoids inhibit ACTH secretion to the point that severe adrenal insuffi ciency can be a dangerous problem when therapy is stopped. However, local administration of glucocorticoids, for example, by injection into an infl amed joint or near an irritated nerve, produces a high local concentration of the steroid, oft en without enough systemic absorption to cause serious side eff ects. Th e actions of glucocorticoids in patients with bacterial infections are dramatic but dangerous. For example, in pneumococcal pneumonia or active tuberculosis, the febrile reaction, the toxicity, and the lung symptoms disappear, but unless antibiotics are given at the same time, the bacteria spread throughout the body. It is important to remember that the symptoms are the warning that disease is present; when these symptoms are masked by treatment with glucocorticoids, there may be serious and even fatal delays in diagnosis and the institution of treatment with antimicrobial drugs. Th e role of NF-κB in the anti-infl ammatory and antiallergic eff ects of glucocorticoids has been mentioned above and is discussed in Chapter 3 . An additional action that combats local infl ammation is inhibition of phospholipase A 2 . Th is reduces the release of arachidonic acid from tissue phospholipids and consequently reduces the formation of leukotrienes, thromboxanes, prostaglandins, and prostacyclin (see Chapter 32 ). 368 SECTION III Endocrine and Reproductive Physiology OTHER EFFECTS Large doses of glucocorticoids inhibit growth, decrease growth hormone secretion (see Chapter 18 ), induce PNMT, and decrease thyroid-stimulating hormone (TSH) secretion. During fetal life, glucocorticoids accelerate the maturation of surfactant in the lungs (see Chapter 34 ). REGULATION OF GLUCOCORTICOID SECRETION ROLE OF ACTH Both basal secretion of glucocorticoids and the increased secretion provoked by stress are dependent upon ACTH from the anterior pituitary. Angiotensin II also stimulates the adrenal cortex, but its eff ect is mainly on aldosterone secretion. Large doses of a number of other naturally occurring substances, including vasopressin, serotonin, and vasoactive intestinal polypeptide (VIP), are capable of stimulating the adrenal directly, but there is no evidence that these agents play any role in the physiologic regulation of glucocorticoid secretion. CHEMISTRY & METABOLISM OF ACTH ACTH is a single-chain polypeptide containing 39 amino acids. Its origin from proopiomelanocortin (POMC) in the pituitary is discussed in Chapter 18 . Th e fi rst 23 amino acids in the chain generally constitute the active “core” of the molecule. Amino acids 24–39 constitute a “tail” that stabilizes the molecule and varies slightly in composition from species to species Th e ACTHs that have been isolated are generally active in all species but antigenic in heterologous species. ACTH is inactivated in blood in vitro more slowly than in vivo; its half-life in the circulation in humans is about 10 min. A large part of an injected dose of ACTH is found in the kidneys, but neither nephrectomy nor evisceration appreciably enhances its in vivo activity, and the site of its inactivation is not known. EFFECT OF ACTH ON THE ADRENAL Aft er hypophysectomy, glucocorticoid synthesis and output decline within 1 h to very low levels, although some hormone is still secreted. Within a short time aft er an injection of ACTH (in dogs, less than 2 min), glucocorticoid output is increased. With low doses of ACTH, the relationship between the log of the dose and the increase in glucocorticoid secretion is linear. However, the maximal rate at which glucocorticoids can be secreted is rapidly reached, and this “ceiling on output” also exists in humans. Th e eff ects of ACTH on adrenal morphology and the mechanism by which it increases steroid secretion have been discussed above. 4 8 24 Time (h) 0 2 10 20 30 40 50 ACTH IV N DX CST HI Plasma cortisol (μg/dL) FIGURE 2014 Loss of ACTH responsiveness when ACTH secretion is decreased in humans. The 1- to 24-amino-acid sequence of ACTH was infused intravenously (IV) in a dose of 250 μg over 8 h. CST, long-term corticosteroid therapy; DX, dexamethasone 0.75 mg every 8 h for 3 days; HI, anterior pituitary insuffi ciency; N, normal subjects. (Reproduced with permission from Kolanowski J, et al: Adrenocortical response upon repeated stimulation with corticotropin in patients lacking endogenous corticotropin secretion. Acta Endocrinol [Kbh] 1977;85:595.) ADRENAL RESPONSIVENESS ACTH not only produces prompt increases in glucocorticoid secretion but also increases the sensitivity of the adrenal to subsequent doses of ACTH. Conversely, single doses of ACTH do not increase glucocorticoid secretion in chronically hypophysectomized animals and patients with hypopituitarism, and repeated injections or prolonged infusions of ACTH are necessary to restore normal adrenal responses to ACTH. Decreased responsiveness is also produced by doses of glucocorticoids that inhibit ACTH secretion. Th e decreased adrenal responsiveness to ACTH is detectable within 24 h aft er hypophysectomy and increases progressively with time ( Figure 20–14 ). It is marked when the adrenal is atrophic but develops before visible changes occur in adrenal size or morphology. CIRCADIAN RHYTHM ACTH is secreted in irregular bursts throughout the day and plasma cortisol tends to rise and fall in response to these bursts ( Figure 20–15 ). In humans, the bursts are most frequent in the early morning, and about 75% of the daily production of cortisol occurs between 4:00 am and 10:00 am. Th e bursts are least frequent in the evening. Th is diurnal (circadian) rhythm in ACTH secretion is present in patients with adrenal insuffi ciency receiving constant doses of glucocorticoids. It is not due to the stress of getting up in the morning, traumatic as that may be, because the increased ACTH secretion occurs before waking up. If the “day” is lengthened experimentally to more than 24 h, that is, if the individual is isolated and the day’s activities are spread over more than 24 h, the adrenal cycle also lengthens, but the increase in ACTH secretion still occurs during the period of sleep. Th e CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 369 biologic clock responsible for the diurnal ACTH rhythm is located in the suprachiasmatic nuclei of the hypothalamus (see Chapter 14 ). THE RESPONSE TO STRESS Th e morning plasma ACTH concentration in a healthy resting human is about 25 pg/mL (5.5 pmol/L). ACTH and cortisol values in various abnormal conditions are summarized in Figure 20–16 . During severe stress, the amount of ACTH secreted exceeds the amount necessary to produce maximal glucocorticoid output. However, prolonged exposure to ACTH in conditions such as the ectopic ACTH syndrome increases the adrenal maximum. Increases in ACTH secretion to meet emergency situations are mediated almost exclusively through the 200 180 160 140 120 100 80 60 40 20 0 25 20 15 10 5 0 Noon 4 PM 8 PM Mid- Noon night 4 AM 8 AM Lunch Dinner Snack Sleep B'kfast Snack Plasma ACTH (pg/mL) Plasma 11-OHCS (μg/dL) FIGURE 2015 Fluctuations in plasma ACTH and glucocorticoids throughout the day in a normal girl (age 16). The ACTH was measured by immunoassay and the glucocorticoids as 11-oxysteroids (11-OHCS). Note the greater ACTH and glucocorticoid rises in the morning, before awakening. (Reproduced, with permission, from Krieger DT, et al: Characterization of the normal temporal pattern of plasma corticosteroid levels. J Clin Endocrinol Metab 1971;32:266.) hypothalamus via release of CRH. Th is polypeptide is produced by neurons in the paraventricular nuclei. It is secreted in the median eminence and transported in the portal-hypophysial vessels to the anterior pituitary, where it stimulates ACTH secretion (see Chapter 18 ). If the median eminence is destroyed, increased secretion in response to many diff erent stresses is blocked. Aff erent nerve pathways from many parts of the brain converge on the paraventricular nuclei. Fibers from the amygdaloid nuclei mediate responses to emotional stresses, and fear, anxiety, and apprehension cause marked increases in ACTH secretion. Input from the suprachiasmatic nuclei provides the drive for the diurnal rhythm. Impulses ascending to the hypothalamus via the nociceptive pathways and the reticular formation trigger increased ACTH secretion in response to injury ( Figure 20–16 ). Th e baroreceptors exert an inhibitory input via the nucleus of the tractus solitarius. GLUCOCORTICOID FEEDBACK Free glucocorticoids inhibit ACTH secretion, and the degree of pituitary inhibition is proportional to the circulating glucocorticoid level. Th e inhibitory eff ect is exerted at both the pituitary and the hypothalamic levels. Th e inhibition is due primarily to an action on DNA, and maximal inhibition takes several hours to develop, although more rapid “fast feedback” also occurs. Th e ACTH-inhibiting activity of the various steroids parallels their glucocorticoid potency. A drop in resting corticoid levels stimulates ACTH secretion, and in chronic adrenal insuffi ciency the rate of ACTH synthesis and secretion is markedly increased. Th us, the rate of ACTH secretion is determined by two opposing forces: the sum of the neural and possibly other stimuli converging through the hypothalamus to increase ACTH secretion, and the magnitude of the braking action of glucocorticoids on ACTH secretion, which is proportional to their level in the circulating blood ( Figure 20–17 ). Normal, morning Normal, evening Normal, dexamethasone Normal, metyrapone Normal, stress Addison disease Hypopituitarism Congenital adrenal hyperplasia Cushing, hyperplasia Cushing, dexamethasone Cushing, postadrenalectomy Cushing, ectopic ACTH syndrome Cushing, adrenal tumor 0 5 50 500 5000 5 50 500 5000 0 0 0 12 25 50 100 12 25 50 100 Condition Plasma ACTH (pg/mL) Plasma cortisol (μg/dL) FIGURE 2016 Plasma concentrations of ACTH and cortisol in various clinical states. (Reproduced with permission from Williams RH [editor]: Textbook of Endocrinology, 5th ed. Saunders, 1974.) 370 SECTION III Endocrine and Reproductive Physiology Th e dangers involved when prolonged treatment with anti-infl ammatory doses of glucocorticoids is stopped deserve emphasis. Not only is the adrenal atrophic and unresponsive aft er such treatment, but even if its responsiveness is restored by injecting ACTH, the pituitary may be unable to secrete normal amounts of ACTH for as long as a month. Th e cause of the defi ciency is presumably diminished ACTH synthesis. Th ereaft er, ACTH secretion slowly increases to supranormal levels. Th ese in turn stimulate the adrenal, and glucocorticoid output rises, with feedback inhibition gradually reducing the elevated ACTH levels to normal ( Figure 20–18 ). Th e complications of sudden cessation of steroid therapy can usually be avoided by slowly decreasing the steroid dose over a long period of time. CRH Trauma via nociceptive pathways Systemic effects Cortisol Afferents from NTS Emotion via limbic system Drive for circadian rhythm ACTH Hypothalamus Anterior pituitary Adrenal cortex FIGURE 2017 Feedback control of the secretion of cortisol and other glucocorticoids via the hypothalamic-pituitary-adrenal axis. The dashed arrows indicate inhibitory eff ects and the solid arrows indicate stimulating eff ects. NTS, nucleus tractus solitarius. 0 2 4 6 8 10 12 ACTH Cortisol Months after stopping glucocorticoid treatment High Normal Low Plasma concentration FIGURE 20 18 Pattern of plasma ACTH and cortisol values in patients recovering from prior long-term daily treatment with large doses of glucocorticoids. (Courtesy of R Ney.) 45 40 35 98 96 94 92 90 80 70 400 300 200 60 40 20 0 0 30 60 80 110 140 170 200 230 260 Time (min) Aldosterone Creatinine clearance K+ excretion Percent filtered K+ reabsorbed Percent filtered Na+ reabsorbed Na+ excretion Percent mL/min μeq/min FIGURE 2019 Eff ect of aldosterone (5 μg as a single dose injected into the aorta) on electrolyte excretion in an adrenalectomized dog. The scale for creatinine clearance is on the right. EFFECTS OF MINERALOCORTICOIDS ACTIONS Aldosterone and other steroids with mineralocorticoid activity increase the reabsorption of Na + from the urine, sweat, saliva, and the contents of the colon. Th us, mineralocorticoids cause retention of Na + in the ECF. Th is expands ECF volume. In the kidneys, they act primarily on the principal cells (P cells) of the collecting ducts (see Chapter 37 ). Under the infl uence of aldosterone, increased amounts of Na + are in eff ect exchanged for K + and H + in the renal tubules, producing a K + diuresis ( Figure 20–19 ) and an increase in urine acidity. MECHANISM OF ACTION Like many other steroids, aldosterone binds to a cytoplasmic receptor, and the receptor–hormone complex moves to the nucleus where it alters the transcription of mRNAs. Th is in turn increases the production of proteins that alter cell function. Th e aldosterone-stimulated proteins have two eff ects—a rapid eff ect, to increase the activity of epithelial sodium channels (ENaCs) by increasing the insertion of these channels into the cell membrane from a cytoplasmic pool; and a slower eff ect to increase the synthesis of ENaCs. Among the genes activated by aldosterone is the gene for serum- and glucocorticoid regulated kinase (sgk), a serine-threonine protein kinase. Th e gene for sgk is an early response gene, and sgk increases ENaC activity. Aldosterone also increases the mRNAs for the three subunits CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 371 that make up ENaCs. Th e fact that sgk is activated by glucocorticoids as well as aldosterone is not a problem because glucocorticoids are inactivated at mineralocorticoid receptor sites. However, aldosterone activates the genes for other proteins in addition to sgk and ENaCs and inhibits others. Th erefore, the exact mechanism by which aldosterone-induced proteins increase Na + reabsorption is still unsettled. Evidence is accumulating that aldosterone also binds to the cell membrane and by a rapid, nongenomic action increases the activity of membrane Na + –K + exchangers. Th is produces an increase in intracellular Na + , and the second messenger involved is probably IP 3 . In any case, the principal eff ect of aldosterone on Na + transport takes 10–30 min to develop and peaks even later ( Figure 20–19 ), indicating that it depends on the synthesis of new proteins by a genomic mechanism. RELATION OF MINERALOCORTICOID TO GLUCOCORTICOID RECEPTORS It is intriguing that in vitro, the mineralocorticoid receptor has an appreciably higher affi nity for glucocorticoids than the glucocorticoid receptor does, and glucocorticoids are present in large amounts in vivo. Th is raises the question of why glucocorticoids do not bind to the mineralocorticoid receptors in the kidneys and other locations and produce mineralocorticoid eff ects. At least in part, the answer is that the kidneys and other mineralocorticoid-sensitive tissues also contain the enzyme 11β-hydroxysteroid dehydrogenase type 2. Th is enzyme leaves aldosterone untouched, but it converts cortisol to cortisone ( Figure 20–11 ) and corticosterone to its 11-oxy derivative. Th ese 11-oxy derivatives do not bind to the receptor (Clinical Box 20–3). OTHER STEROIDS THAT AFFECT NA + EXCRETION Aldosterone is the principal mineralocorticoid secreted by the adrenal, although corticosterone is secreted in suffi cient amounts to exert a minor mineralocorticoid eff ect ( Tables 20–1 and 20–2 ). Deoxycorticosterone, which is secreted in appreciable amounts only in abnormal situations, has about 3% of the activity of aldosterone. Large amounts of progesterone and some other steroids cause natriuresis, but there is little evidence that they play any normal role in the control of Na + excretion. EFFECT OF ADRENALECTOMY In adrenal insuffi ciency, Na + is lost in the urine; K + is retained, and the plasma K + rises. When adrenal insuffi ciency develops rapidly, the amount of Na + lost from the ECF exceeds the amount excreted in the urine, indicating that Na + also must be entering cells. When the posterior pituitary is intact, salt loss exceeds water loss, and the plasma Na + falls ( Table 20–5 ). However, the plasma volume is also reduced, resulting in hypotension, circulatory insuffi ciency, and, CLINICAL BOX 20–3 Apparent Mineralocorticoid Excess If 11β-hydroxysteroid dehydrogenase type 2 is inhibited or absent, cortisol has marked mineralocorticoid eff ects. The resulting syndrome is called apparent mineralocorticoid excess (AME). Patients with this condition have the clinical picture of hyperaldosteronism because cortisol is acting on their mineralocorticoid receptors, and their plasma aldosterone level as well as their plasma renin activity is low. The condition can be due to congenital absence of the enzyme. THERAPEUTIC HIGHLIGHTS Prolonged ingestion of licorice can also cause an increase in blood pressure. Outside of the United States, licorice contains glycyrrhetinic acid, which inhibits 11β-hydroxysteroid dehydrogenase type 2. Individuals who eat large amounts of licorice have an increase in MR-activated sodium absorption via the epithelial sodium channel ENaC in the renal collecting duct, and blood pressure can rise. eventually, fatal shock. Th ese changes can be prevented to a degree by increasing dietary NaCl intake. Rats survive indefinitely on extra salt alone, but in dogs and most humans, the amount of supplementary salt needed is so large that it is almost impossible to prevent eventual collapse and death unless mineralocorticoid treatment is also instituted (see Clinical Box 20–4). REGULATION OF ALDOSTERONE SECRETION STIMULI Th e principal conditions that increase aldosterone secretion are summarized in Table 20–6 . Some of them also increase glucocorticoid secretion; others selectively aff ect the output TABLE 205 Typical plasma electrolyte levels in normal humans and patients with adrenocortical diseases. State Plasma Electolytes (mEq/L) Na + K + Cl – HCO 3 – Normal 142 4.5 105 25 Adrenal insuffi ciency 120 6.7 85 25 Primary hyperaldosteronism 145 2.4 96 41 372 SECTION III Endocrine and Reproductive Physiology CLINICAL BOX 20–4 Secondary Eff ects of Excess Mineralocorticoids A prominent feature of prolonged mineralocorticoid excess ( Table 20–5 ) is K + depletion due to prolonged K + diuresis. H + is also lost in the urine. Na + is retained initially, but the plasma Na + is elevated only slightly if at all, because water is retained with the osmotically active sodium ions. Consequently, ECF volume is expanded and the blood pressure rises. When the ECF expansion passes a certain point, Na + excretion is usually increased in spite of the continued action of mineralocorticoids on the renal tubules. This escape phenomenon ( Figure 20–20 ) is probably due to increased secretion of ANP (see Chapter 38 ). Because of increased excretion of Na + when the ECF volume is expanded, mineralocorticoids do not produce edema in normal individuals and patients with hyperaldosteronism. However, escape may not occur in certain disease states, and in these situations, continued expansion of ECF volume leads to edema (see Chapters 37 and 38 ). of aldosterone. Th e primary regulatory factors involved are ACTH from the pituitary, renin from the kidney via angiotensin II, and a direct stimulatory eff ect on the adrenal cortex of a rise in plasma K + concentration. EFFECT OF ACTH When fi rst administered, ACTH stimulates the output of aldosterone as well as that of glucocorticoids and sex hormones. Although the amount of ACTH required to increase aldosterone output is somewhat greater than the amount that stimulates maximal glucocorticoid secretion ( Figure 20–21 ), TABLE 206 Conditions that increase aldosterone secretion. Glucocorticoid secretion also increased Surgery Anxiety Physical trauma Hemorrhage Glucocorticoid secretion unaff ected High potassium intake Low sodium intake Constriction of inferior vena cava in thorax Standing Secondary hyperaldosteronism (in some cases of congestive heart failure, cirrhosis, and nephrosis) it is well within the range of endogenous ACTH secretion. Th e eff ect is transient, and even if ACTH secretion remains elevated, aldosterone output declines in 1 or 2 days. On the other hand, the output of the mineralocorticoid deoxycorticosterone remains elevated. Th e decline in aldosterone output is partly due to decreased renin secretion secondary to hypervolemia, but it is possible that some other factor also decreases the conversion of corticosterone to aldosterone. Aft er hypophysectomy, the basal rate of aldosterone secretion is normal. Th e increase normally produced by surgical and other stresses is absent, but the increase produced by dietary salt restriction is unaff ected for some time. Later on, atrophy of the zona glomerulosa complicates the picture in long-standing hypopituitarism, and this may lead to salt loss and hypoaldosteronism. Normally, glucocorticoid treatment does not suppress aldosterone secretion. However, an interesting recently described syndrome is glucocorticoid-remediable aldosteronism (GRA). Th is is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient. Th e hypersecretion of aldosterone and the accompanying hypertension are remedied when ACTH secretion is suppressed by administering glucocorticoids. Th e genes encoding aldosterone synthase and 11β-hydroxylase are 95% identical and are close together on chromosome 8. In individuals with GRA, there is unequal crossing over so that the 5΄- regulatory region of the 11βhydroxylase gene is fused to the coding region of the aldosterone synthase gene. Th e product of this hybrid gene is an ACTH-sensitive aldosterone synthase. EFFECTS OF ANGIOTENSIN II & RENIN Th e octapeptide angiotensin II is formed in the body from angiotensin I, which is liberated by the action of renin on circulating angiotensinogen (see Chapter 38 ). Injections of angiotensin II stimulate adrenocortical secretion and, in small doses, aff ect primarily the secretion of aldosterone ( Figure 20–22 ). Th e sites of action of angiotensin II are both early and late in the steroid biosynthetic pathway. Th e early action is on the conversion of cholesterol to pregnenolone, and the late action is on the conversion of corticosterone to aldosterone ( Figure 20–8 ). Angiotensin II does not increase the secretion of deoxycorticosterone, which is controlled by ACTH. Renin is secreted from the juxtaglomerular cells that surround the renal aff erent arterioles as they enter the glomeruli (see Chapter 38 ). Aldosterone secretion is regulated via the renin–angiotensin system in a feedback fashion ( Figure 20–23 ). A drop in ECF volume or intra-arterial vascular volume leads to a refl ex increase in renal nerve discharge and decreases renal arterial pressure. Both changes increase renin secretion, and the angiotensin II formed by the action of renin increases the rate of secretion of aldosterone. Th e aldosterone causes Na + and, secondarily, water retention, expanding ECF volume, and shutting off the stimulus that initiated increased renin secretion. Hemorrhage stimulates ACTH and renin secretion. Like hemorrhage, standing and constriction of the thoracic inferior CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 373 vena cava decrease intrarenal arterial pressure. Dietary sodium restriction also increases aldosterone secretion via the renin– angiotensin system ( Figure 20–24 ). Such restriction reduces ECF volume, but aldosterone and renin secretion are increased before any consistent decrease in blood pressure takes place. Consequently, the initial increase in renin secretion produced by dietary sodium restriction is probably due to a refl ex increase in the activity of the renal nerves. Th e increase in circulating angiotensin II produced by salt depletion upregulates the angiotensin II receptors in the adrenal cortex and hence 150 100 50 0 6 Serum K+ (meq/L) Serum Na+ (meq/L) 4 DOCA 10 mg IM every 12 h 300 200 100 0 150 130 Intake Intake 60 58 56 Days 1 Body weight (kg) 3 5 7 9 11 13 15 17 11.40 L 4.26 L 1.14 L 3.12 L 9.14 L 3.55 L 1.48 L 2.07 L ECF TBV RCV PV Urinary Na+ (meq/24 h) Urinary K+ (meq/24 h) Male, age 29 Bilateral adrenalectomy Dexamethasone, 0.25 mg/6 h FIGURE 2020 “Escape” from the sodium-retaining eff ect of desoxycorticosterone acetate (DOCA) in an adrenalectomized patient. ECF, extracellular fl uid volume; PV, plasma volume; RCV, red cell volume; TBV, total blood volume. (Courtesy of EG Biglieri.) 12 40 10 Change in 8 17-hydroxycorticoid output (μg/min) Change in aldosterone output (ng/min) 6 4 2 0 30 25 20 15 10 5 0 2 5 10 100 1000 Dose of ACTH (mU) No. of dogs (4) (8) (6) (3) (10) FIGURE 2021 Changes in adrenal venous output of steroids produced by ACTH in nephrectomized hypophysectomized dogs. increases the response to angiotensin II, whereas it downregulates the angiotensin II receptors in the blood vessels. ELECTROLYTES & OTHER FACTORS An acute decline in plasma Na + of about 20 mEq/L stimulates aldosterone secretion, but changes of this magnitude are rare. However, the plasma K + level need increase only 1 mEq/L to stimulate aldosterone secretion, and transient increases of this 8 Change in 17-hydroxycorticoid (μg/min) Change in aldosterone output (ng/min) 6 4 2 0 25 20 15 10 5 0 0.042 0.083 0.167 0.42 1.67 Dose of angiotensin II (μg/min) No. of dogs (5)* (2) (8) (7) (7) *Aldosterone values in 3 dogs FIGURE 2022 Changes in adrenal venous output of steroids produced by angiotensin II in nephrectomized hypophysectomized dogs. 374 SECTION III Endocrine and Reproductive Physiology magnitude may occur aft er a meal, particularly if it is rich in K + . Like angiotensin II, K + stimulates the conversion of cholesterol to pregnenolone and the conversion of deoxycorticosterone to aldosterone. It appears to act by depolarizing the cell, which opens voltage-gated Ca 2+ channels, increasing intracellular Ca 2+ . Th e sensitivity of the zona glomerulosa to angiotensin II and consequently to a low-sodium diet is decreased by a lowpotassium diet. In normal individuals, plasma aldosterone concentrations increase during the portion of the day that the individual is carrying on activities in the upright position. Th is increase is due to a decrease in the rate of removal of aldosterone from the circulation by the liver and an increase in aldosterone secretion due to a postural increase in renin secretion. Individuals who are confi ned to bed show a circadian rhythm of aldosterone and renin secretion, with the highest values in the early morning before awakening. Atrial natriuretic peptide (ANP) inhibits renin secretion and decreases the responsiveness of the zona glomerulosa to angiotensin II (see Chapter 38 ). Th e mechanisms by which ACTH, angiotensin II, and K + stimulate aldosterone secretion are summarized in Table 20–7 . ROLE OF MINERALOCORTICOIDS IN THE REGULATION OF SALT BALANCE Variations in aldosterone secretion is only one of many factors aff ecting Na + excretion. Other major factors include the glomerular fi ltration rate, ANP, the presence or absence of osmotic diuresis, and changes in tubular reabsorption of Na + independent of aldosterone. It takes some time for aldosterone to act. When one rises from the supine to the standing position, aldosterone secretion increases and Na + is retained from the urine. However, the decrease in Na + excretion develops too rapidly to be explained solely by increased aldosterone Angiotensinconverting enzyme Angiotensinogen Renin Angiotensin I Angiotensin II Aldosterone Decreased Na+ (and water) excretion Increased extracellular fluid volume Increased renal arterial mean pressure, decreased discharge of renal nerves Juxtaglomerular apparatus Adrenal cortex FIGURE 2023 Feedback mechanism regulating aldosterone secretion. The dashed arrow indicates inhibiition. secretion. Th e primary function of the aldosterone-secreting mechanism is the defense of intravascular volume, but it is only one of the homeostatic mechanisms involved in this regulation. SUMMARY OF THE EFFECTS OF ADRENOCORTICAL HYPER & HYPOFUNCTION IN HUMANS Recapitulating the manifestations of excess and defi ciency of the adrenocortical hormones in humans is a convenient way to summarize the multiple and complex actions of these steroids. A characteristic clinical syndrome is associated with excess secretion of each of the types of hormones. Excess androgen secretion causes masculinization (adrenogenital syndrome) and precocious pseudopuberty or female pseudohermaphroditism. Excess glucocorticoid secretion produces a moon-faced, plethoric appearance, with trunk obesity, purple abdominal striae, hypertension, osteoporosis, protein depletion, mental abnormalities, and, frequently, diabetes mellitus (Cushing syndrome). Excess mineralocorticoid secretion leads to K + depletion and Na + retention, usually without edema but with weakness, hypertension, tetany, polyuria, and hypokalemic alkalosis (hyperaldosteronism). Th is condition may be due to primary adrenal disease (primary hyperaldosteronism; Conn syndrome) such as an adenoma of the zona glomerulosa, unilateral or bilateral adrenal hyperplasia, adrenal carcinoma, or by GRA. In patients with primary hyperaldosteronism, renin secretion is depressed. Secondary hyperaldosteronism with high plasma renin activity is caused by cirrhosis, heart failure, and nephrosis. Increased renin secretion is also found in individuals with the salt-losing form of the adrenogenital syndrome (see above), because their ECF volume is low. In patients with elevated renin secretion due to renal artery constriction, aldosterone secretion is increased; in those in whom renin secretion CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 375 TABLE 207 Second messengers involved in the regulation of aldosterone secretion. Secretagogue Intracellular Mediator ACTH Cyclic AMP, protein kinase A Angiotensin II Diacylglycerol, protein kinase C K + Ca 2+ via voltage-gated Ca 2+ channels 150 140 130 120 15 10 400 300 200 100 2000 0 1500 1000 500 0 15 20 10 5 0 5 0 2.0 2.5 1.5 1.0 0.5 0 Low Normal High Sodium intake Plasma vasopressin (pg/mL) Plasma renin activity (ng AI/mL/h) Plasma Na+ (mmol/L) Plasma aldosterone (pmol/L) Urinary Na+ excretion (mmol/day) Plasma ANP (pg/mL) FIGURE 2024 Eff ect of low-, normal-, and high-sodium diets on sodium metabolism and plasma renin activity, aldosterone, vasopressin, and ANP in normal humans. (Data from Sagnella GA, et al: Plasma atrial natriuretic peptide: Its relationship to changes in sodium in-take, plasma renin activity, and aldosterone in man. Clin Sci 1987;72:25.) is not elevated, aldosterone secretion is normal. Th e relationship of aldosterone to hypertension is discussed in Chapter 32 . Primary adrenal insuffi ciency due to disease processes that destroy the adrenal cortex is called Addison disease. Th e condition used to be a relatively common complication of tuberculosis, but now it is usually due to autoimmune infl ammation of the adrenal. Patients lose weight, are tired, and become chronically hypotensive. Th ey have small hearts, probably because the hypotension decreases the work of the heart. Eventually they develop severe hypotension and shock (addisonian crisis). Th is is due not only to mineralocorticoid defi - ciency but to glucocorticoid defi ciency as well. Fasting causes fatal hypoglycemia, and any stress causes collapse. Water is retained, and there is always the danger of water intoxication. Circulating ACTH levels are elevated. Th e diff use tanning of the skin and the spotty pigmentation characteristic of chronic glucocorticoid defi ciency are due, at least in part, to the melanocyte- stimulating hormone (MSH) activity of the ACTH in the blood. Pigmentation of skin creases on the hands and the gums are common. Minor menstrual abnormalities occur in women, but the defi ciency of adrenal sex hormones usually has little eff ect in the presence of normal testes or ovaries. Secondary adrenal insuffi ciency is caused by pituitary diseases that decrease ACTH secretion, and tertiary adrenal insuffi ciency is caused by hypothalamic disorders disrupting CRH secretion. Both are usually milder than primary adrenal insuffi ciency because electrolyte metabolism is aff ected to a lesser degree. In addition, there is no pigmentation because in both of these conditions, plasma ACTH is low, not high. Cases of isolated aldosterone defi ciency have also been reported in patients with renal disease and a low circulating renin level (hyporeninemic hypoaldosteronism). In addition, pseudohypoaldosteronism is produced when there is resistance to the action of aldosterone. Patients with these syndromes have marked hyperkalemia, salt wasting, and hypotension, and they may develop metabolic acidosis. CHAPTER SUMMARY ■ Th e adrenal gland consists of the adrenal medulla that secretes dopamine and the catecholamines epinephrine and norepinephrine, and the adrenal cortex that secretes steroid hormones. ■ Norepinephrine and epinephrine act on two classes of receptors, α- and β-adrenergic receptors, and exert metabolic eff ects that include glycogenolysis in liver and skeletal muscle, mobilization of FFA, increased plasma lactate, and stimulation of the metabolic rate. ■ Th e hormones of the adrenal cortex are derivatives of cholesterol and include the mineralocorticoid aldosterone, the glucocorticoids cortisol and corticosterone, and the androgens dehydroepiandrosterone (DHEA) and androstenedione. ■ Androgens are the hormones that exert masculinizing eff ects, and they promote protein anabolism and growth. Th e adrenal androgen androstenedione is converted to testosterone and to estrogens (aromatized) in fat and other peripheral 376 SECTION III Endocrine and Reproductive Physiology tissues. Th is is an important source of estrogens in men and postmenopausal women. ■ Th e mineralocorticoid aldosterone has eff ects on Na + and K + excretion and glucocorticoids aff ect glucose and protein metabolism. ■ Glucocorticoid secretion is dependent on ACTH from the anterior pituitary and is increased by stress. Angiotensin II increases the secretion of aldosterone. MULTIPLECHOICE QUESTIONS For all questions, select the single best answer unless otherwise directed. 1. Which of the following is produced only by large amounts of glucocorticoids? A. Normal responsiveness of fat depots to norepinephrine B. Maintenance of normal vascular reactivity C. Increased excretion of a water load D. Inhibition of the infl ammatory response E. Inhibition of ACTH secretion 2. Which of the following are incorrectly paired? A. Gluconeogenesis : Cortisol B. Free fatty acid mobilization : Dehydroepiandrosterone C. Muscle glycogenolysis : Epinephrine D. Kaliuresis : Aldosterone E. Hepatic glycogenesis : Insulin 3. Which of the following hormones has the shortest plasma halflife? A. Corticosterone B. Renin C. Dehydroepiandrosterone D. Aldosterone E. Norepinephrine 4. Mole for mole, which of the following has the greatest eff ect on Na + excretion? A. Progesterone B. Cortisol C. Vasopressin D. Aldosterone E. Dehydroepiandrosterone 5. Mole for mole, which of the following has the greatest eff ect on plasma osmolality? A. Progesterone B. Cortisol C. Vasopressin D. Aldosterone E. Dehydroepiandrosterone 6. Th e secretion of which of the following would be least aff ected by a decrease in extracellular fl uid volume? A. CRH B. Arginine vasopressin C. Dehydroepiandrosterone D. Estrogens E. Aldosterone 7. A young man presents with a blood pressure of 175/110 mm Hg. He is found to have a high circulating aldosterone but a low circulating cortisol. Glucocorticoid treatment lowers his circulating aldosterone and lowers his blood pressure to 140/85 mm Hg. He probably has an abnormal A. 17α-hydroxylase. B. 21β-hydroxylase. C. 3β-hydroxysteroid dehydrogenase. D. aldosterone synthase. E. cholesterol desmolase. 8. A 32-year-old woman presents with a blood pressure of 155/96 mm Hg. In response to questioning, she admits that she loves licorice and eats some at least three times a week. She probably has a low level of A. type 2 11β-hydroxysteroid dehydrogenase activity. B. ACTH. C. 11β-hydroxylase activity. D. glucuronyl transferase. E. norepinephrine. 9. In its action in cells, aldosterone A. increases transport of ENaCs from the cytoplasm to the cell membrane. B. does not act on the cell membrane. C. binds to a receptor excluded from the nucleus. D. may activate a heat shock protein. E. also binds to glucocorticoid receptors. CHAPTER RESOURCES Goldstein JL, Brown MS: Th e cholesterol quartet. Science 2001;292:1510. Goodman HM (editor): Handbook of Physiology, Section 7: Th e Endocrine System. Oxford University Press, 2000. Larsen PR, Kronenberg HM, Melmed S, et al. (editors). Williams Textbook of Endocrinology, 9th ed. Saunders, 2003. Stocco DM: A review of the characteristics of the protein required for the acute regulation of steroid hormone biosynthesis: Th e case for the steroidogenic acute regulatory (StAR) protein. Proc Soc Exp Biol Med 1998;217:123. White PC: Disorders of aldosterone biosynthesis and action. N Engl J Med 1994;331:250. 377 O B J E C T I V E S After studying this chapter, you should be able to: ■ Understand the importance of maintaining homeostasis of body calcium and phosphate concentrations, and how this is accomplished. ■ Describe the body pools of calcium, their rates of turnover, and the organs that play central roles in regulating movement of calcium between stores. ■ Delineate the mechanisms of calcium and phosphate absorption and excretion. ■ Identify the major hormones and other factors that regulate calcium and phosphate homeostasis and their sites of synthesis as well as targets of their action. ■ D efi ne the basic anatomy of bone. ■ Delineate cells and their functions in bone formation and resorption. liver and kidneys. Its primary action is to increase calcium absorption from the intestine. Calcitonin, a calcium-lowering hormone that in mammals is secreted primarily by cells in the thyroid gland, inhibits bone resorption. Although the role of calcitonin seems to be relatively minor, all three hormones probably operate in concert to maintain the constancy of the calcium level in the body fl uids. Phosphate homeostasis is likewise critical to normal body function, particularly given its inclusion in adenosine triphosphate (ATP), its role as a biological buff er, and its role as a modifi er of proteins, thereby altering their functions. Many of the systems that regulate calcium homeostasis also contribute to that of phosphate, albeit sometimes in a reciprocal fashion, and thus will also be discussed in this chapter. Hormonal Control of C H A P T E R Calcium & Phosphate Metabolism & the Physiology of Bone 21 INTRODUCTION Calcium is an essential intracellular signaling molecule and also plays a variety of extracellular functions, thus the control of body calcium concentrations is vitally important. Th e components of the system that maintains calcium homeostasis include cell types that sense changes in extracellular calcium and release calcium-regulating hormones, and the targets of these hormones, including the kidneys, bones, and intestine, that respond with changes in calcium mobilization, excretion, or uptake. Th ree hormones are primarily concerned with the regulation of calcium homeostasis. Parathyroid hormone (PTH) is secreted by the parathyroid glands. Its main action is to mobilize calcium from bone and increase urinary phosphate excretion. 1,25-Dihydroxycholecalciferol is a steroid hormone formed from vitamin D by successive hydroxylations in the CALCIUM & PHOSPHORUS METABOLISM CALCIUM Th e body of a young adult human contains about 1100 g (27.5 moles) of calcium. Ninety-nine per cent of the calcium is in the skeleton. Plasma calcium, normally at a concentration of around 10 mg/dL (5 mEq/L, 2.5 mmol/L), is partly bound to protein and partly diff usible ( Table 21–1 ). Th e distribution of calcium inside cells and the role of Ca 2+ as a second messenger molecule is discussed in Chapter 2 . It is the free, ionized calcium (Ca 2+ ) in the body fl uids that is a vital second messenger and is necessary for blood coagulation, muscle contraction, and nerve function. A decrease in extracellular Ca 2+ exerts a net excitatory eff ect on nerve Ganong_Ch21_377-390.indd 377 1/4/12 1:08:20 PM 378 SECTION III Endocrine and Reproductive Physiology and muscle cells in vivo (see Chapters 4 and 5). Th e result is hypocalcemic tetany , which is characterized by extensive spasms of skeletal muscle, involving especially the muscles of the extremities and the larynx. Laryngospasm can become so severe that the airway is obstructed and fatal asphyxia is produced. Ca 2+ also plays an important role in blood clotting (see Chapter 31 ), but in vivo, fatal tetany would occur before compromising the clotting reaction. Because the extent of Ca 2+ binding by plasma proteins is proportional to the plasma protein level, it is important to know the plasma protein level when evaluating the total plasma calcium. Other electrolytes and pH also aff ect the free Ca 2+ level. Th us, for example, symptoms of tetany appear at higher total calcium levels if the patient hyperventilates, thereby increasing plasma pH. Plasma proteins are more ionized when the pH is high, providing more protein anions to bind with Ca 2+ . Th e calcium in bone is of two types: a readily exchangeable reservoir and a much larger pool of stable calcium that TABLE 211 Distribution (mg/dL) of calcium in normal human plasma. Total diff usible 5.36 Ionized (Ca 2+ ) 4.72 Complexed to HCO 3 – , citrate, etc 0.64 Total nondiff usible (protein-bound) 4.64 Bound to albumin 3.68 Bound to globulin 0.96 Total plasma calcium 10.00 Diet 25 mmol GI tract Feces 22.5 mmol Absorption 15 mmol Secretion 12.5 mmol Reabsorption 247.5 mmol ECF 35 mmol Glomerular filtrate 250 mmol Urine 2.5 mmol Rapid exchange Accretion 500 mmol 7.5 mmol Reabsorption 7.5 mmol Bone Exchangeable 100 mmol Stable 27,200 mmol FIGURE 211 Calcium metabolism in an adult human. A typical daily dietary intake of 25 mmol Ca 2+ (1000 mg) moves through many body compartments. Note that the majority of body calcium is in bones, in a pool that is only slowly exchangeable with the extracellular fl uid (ECF). is only slowly exchangeable. Two independent but interacting homeostatic systems aff ect the calcium in bone. One is the system that regulates plasma Ca 2+ , providing for the movement of about 500 mmol of Ca 2+ per day into and out of the readily exchangeable pool in the bone ( Figure 21–1 ). Th e other system involves bone remodeling by the constant interplay of bone resorption and deposition (see following text). However, the Ca 2+ interchange between plasma and this stable pool of bone calcium is only about 7.5 mmol/d. Ca 2+ is transported across the brush border of intestinal epithelial cells via channels known as transient receptor potential vanilloid type 6 (TRPV6) and binds to an intracellular protein known as calbindin-D 9k . Calbindin-D 9k sequesters the absorbed calcium so that it does not disturb epithelial signaling processes that involve calcium. Th e absorbed Ca 2+ is thereby delivered to the basolateral membrane of the epithelial cell, from where it can be transported into the bloodstream by either a Na + /Ca 2+ exchanger (NCX1) or a Ca2+-dependent ATPase. Nevertheless, it should be noted that recent studies indicate that some intestinal Ca 2+ uptake persists even in the absence of TRPV6 and calbindin-D 9k , suggesting that additional pathways are likely also involved in this critical process. Th e overall transport process is regulated by 1,25-dihydroxycholecalciferol (see below). As Ca 2+ uptake rises, moreover, 1,25-dihydroxycholecalciferol levels fall in response to increased plasma Ca 2+ . Plasma Ca 2+ is fi ltered in the kidneys, but 98–99% of the fi ltered Ca 2+ is reabsorbed. About 60% of the reabsorption occurs in the proximal tubules and the remainder in the ascending limb of the loop of Henle and the distal tubule. Distal tubular reabsorption depends on the TRPV5 channel, which is related to TRPV6 discussed previously, and whose expression is regulated by PTH. CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 379 PHOSPHORUS Phosphate is found in ATP, cyclic adenosine monophosphate (cAMP), 2,3-diphosphoglycerate, many proteins, and other vital compounds in the body. Phosphorylation and dephosphorylation of proteins are involved in the regulation of cell function (see Chapter 2 ). Th erefore, it is not surprising that, like calcium, phosphate metabolism is closely regulated. Total body phosphorus is 500–800 g (16.1–25.8 moles), 85–90% of which is in the skeleton. Total plasma phosphorus is about 12 mg/dL, with two-thirds of this total in organic compounds and the remaining inorganic phosphorus (P i ) mostly in PO 4 3– , HPO 4 2– , and H 2 PO 4 – . Th e amount of phosphorus normally entering bone is about 3 mg (97 μmol)/kg/d, with an equal amount leaving via reabsorption. P i in the plasma is fi ltered in the glomeruli, and 85–90% of the fi ltered P i is reabsorbed. Active transport in the proximal tubule accounts for most of the reabsorption and involves two related sodium-dependent P i cotransporters, NaPi-IIa and NaPi-IIc. NaPi-IIa is powerfully inhibited by PTH, which causes its internalization and degradation and thus a reduction in renal P i reabsorption (see below). P i is absorbed in the duodenum and small intestine. Uptake occurs by a transporter related to those in the kidney, NaPi-IIb, that takes advantage of the low intracellular Na + concentration established by the Na, K ATPase on the basolateral membrane of intestinal epithelial cells to load P i against its concentration gradient. However, the pathway by which P i exits into the bloodstream is not known. Many stimuli that increase Ca 2+ absorption, including 1,25-dihydroxycholecalciferol, also increase P i absorption via increased NaPi-IIb expression and/ or its insertion into the enterocyte apical membrane. VITAMIN D & THE HYDROXYCHOLECALCIFEROLS CHEMISTRY Th e active transport of Ca 2+ and PO 4 3– from the intestine is increased by a metabolite of vitamin D . Th e term “vitamin D” is used to refer to a group of closely related sterols produced by the action of ultraviolet light on certain provitamins ( Figure 21–2 ). Vitamin D 3 , which is also called cholecalciferol, is produced in the skin of mammals from 7-dehydrocholesterol by the action of sunlight. Th e reaction involves the rapid formation of previtamin D 3 , which is then converted more slowly to vitamin D 3 . Vitamin D 3 and its hydroxylated derivatives are transported in the plasma bound to a globulin vitamin D-binding protein (DBP). Vitamin D 3 is also ingested in the diet. Vitamin D 3 is metabolized by enzymes that are members of the cytochrome P450 (CYP) superfamily (see Chapters 1 and 28). In the liver, vitamin D 3 is converted to 25-hydroxycholecalciferol (calcidiol, 25-OHD 3 ). Th e 25-hydroxycholecalciferol is converted in the cells of the proximal tubules of the kidneys to the more active HO 7-Dehydrocholesterol 7-Dehydrocholesterol 1,25-Dihydroxycholecalciferol 24,25-Dihydroxycholecalciferol 1,25-Dihydroxycholecalciferol 25-Hydroxycholecalciferol 24 25 Vitamin D3 CH2 26 27 HO CH2 HO OH OH KIDNEY Other metabolites LIVER SKIN 25-Hydroxylase 24-Hydroxylase 1α-Hydroxylase Vitamin D3 (cholecalciferol) Previtamin D3 Sunlight FIGURE 212 Formation and hydroxylation of vitamin D 3 . 25-Hydroxylation takes place in the liver, and the other hydroxylations occur primarily in the kidneys. The structures of 7-dehydrocholesterol, vitamin D 3 , and 1,25-dihydroxycholecalciferol are also shown in the boxed area. 380 SECTION III Endocrine and Reproductive Physiology metabolite 1,25-dihydroxycholecalciferol , which is also called calcitriol or 1,25-(OH) 2 D 3 . 1,25-Dihydroxycholecalciferol is also made in the placenta, in keratinocytes in the skin, and in macrophages. Th e normal plasma level of 25-hydroxycholecalciferol is about 30 ng/mL, and that of 1,25-dihydroxycholecalciferol is about 0.03 ng/mL (approximately 100 pmol/L). Th e less active metabolite 24,25-dihydroxycholecalciferol is also formed in the kidneys ( Figure 21–2 ). MECHANISM OF ACTION 1,25 Dihydroxycholecalciferol stimulates the expression of a number of gene products involved in Ca 2+ transport and handling via its receptor, which acts as a transcriptional regulator in its ligand-bound form. One group is the family of calbindin-D proteins. Th ese are members of the troponin C superfamily of Ca 2+ -binding proteins that also includes calmodulin (see Chapter 2 ). Calbindin-Ds are found in human intestine, brain, and kidneys. In the intestinal epithelium and many other tissues, two calbindins are induced: calbindinD 9K and calbindin- D 28K , with molecular weights of 9000 and 28,000, respectively. 1,25-Dihydroxycholecalciferol also increases the number of Ca 2+ –ATPase and TRPV6 molecules in the intestinal cells, and thus, the overall capacity for absorption of dietary calcium. In addition to increasing Ca 2+ absorption from the intestine, 1,25-dihydroxycholecalciferol facilitates Ca 2+ reabsorption in the kidneys via increased TRPV5 expression in the proximal tubules, increases the synthetic activity of osteoblasts, and is necessary for normal calcifi cation of matrix (see Clinical Box 21–1). Th e stimulation of osteoblasts brings about a secondary increase in the activity of osteoclasts (see below). REGULATION OF SYNTHESIS Th e formation of 25-hydroxycholecalciferol does not appear to be stringently regulated. However, the formation of 1,25-dihydroxycholecalciferol in the kidneys, which is catalyzed by the renal 1α-hydroxylase, is regulated in a feedback fashion by plasma Ca 2+ and PO 4 3+ ( Figure 21–3 ). When the plasma Ca 2+ level is high, little 1,25-dihydroxycholecalciferol is produced, and the kidneys produce the relatively inactive metabolite 24,25-dihydroxycholecalciferol instead. Th is eff ect of Ca 2+ on production of 1,25-dihydroxycholecalciferol is the mechanism that brings about adaptation of Ca 2+ absorption from the intestine (see previous text). Conversely, expression of 1α-hydroxylase is stimulated by PTH, and when the plasma Ca 2+ level is low, PTH secretion is increased. Th e production of 1,25-dihydroxycholecalciferol is also increased by low and inhibited by high plasma PO 4 3– levels, by a direct inhibitory eff ect of PO 4 3– on the 1α-hydroxylase. Additional control of 1,25-dihydroxycholecalciferol formation results from a direct negative feedback eff ect of the metabolite on 1α-hydroxylase, a positive feedback action on the formation of 24,25-dihydroxycholecalciferol, and a direct action on the parathyroid gland to inhibit PTH expression. An “anti-aging” protein called α-Klotho (named aft er Klotho, a daughter of Zeus in Greek mythology who spins the thread of life) has also recently been discovered to play important roles in calcium and phosphate homeostasis, in part by reciprocal eff ects on 1,25-dihydroxycholecalciferol levels. Mice defi cient in α-Klotho displayed accelerated aging, decreased bone mineral density, calcifi cations, and hypercalcemia and hyperphosphatemia. α-Klotho plays an important role in stabilizing the membrane localization of proteins important in calcium and phosphate (re)absorption, CLINICAL BOX 21–1 Rickets & Osteomalacia Vitamin D defi ciency causes defective calcifi cation of bone matrix and the disease called rickets in children and osteomalacia in adults. Even though 1,25-dihydroxycholecalciferol is necessary for normal mineralization of bone matrix, the main defect in this condition is failure to deliver adequate amounts of Ca 2+ and PO 4 3– to the sites of mineralization. The full-blown condition in children is characterized by weakness and bowing of weight-bearing bones, dental defects, and hypocalcemia. In adults, the condition is less obvious. It used to be most commonly due to inadequate exposure to the sun in smoggy cities, but now it is more commonly due to inadequate intake of the provitamins on which the sun acts in the skin. These cases respond to administration of vitamin D. The condition can also be caused by inactivating mutations of the gene for renal 1α-hydroxylase, or in severe renal or liver diseases, in which case there is no response to vitamin D but a normal response to 1,25-dihydroxycholecalciferol (type I vitamin D-resistant rickets). In rare instances, it can be due to inactivating mutations of the gene for the 1,25-dihydroxycholecalciferol receptor (type II vitamin Dresistant rickets) , in which case there is a defi cient response to both vitamin D and 1,25-dihydroxycholecalciferol. THERAPEUTIC HIGHLIGHTS Treatment of these conditions depends on the underlying biochemical basis, as indicated above. Routine supplementation of milk with vitamin D has greatly reduced the occurrence of rickets in Western countries, but the condition remains among the most common childhood diseases in developing countries. Orthopedic surgery may be necessary in severely aff ected children. CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 381 such as TRPV5 and Na, K ATPase. Likewise, it enhances the activity of another factor, fi broblast growth factor 23 (FGF23), at its receptor. FGF23 thereby decreases renal NaPi-IIa and NaPi-IIc expression and inhibits the production of 1α-hydroxylase, reducing levels of 1,25-dihydroxycholecalciferol (Clinical Box 21–1). THE PARATHYROID GLANDS ANATOMY Humans usually have four parathyroid glands: two embedded in the superior poles of the thyroid and two in its inferior poles ( Figure 21–4 ). Each parathyroid gland is a richly vascularized disk, about 3 × 6 × 2 mm, containing two distinct types of cells ( Figure 21–5 ). Th e abundant chief cells , which contain a prominent Golgi apparatus plus endoplasmic reticulum and secretory granules, synthesize and secrete PTH . Th e less abundant and larger oxyphil cells contain oxyphil granules and Release of calcium into plasma Bone Resorption Intestine Calcium absorption Urinary excretion of calcium Plasma 1,25–(OH)2D3 Kidneys Calcium reabsorption 1,25–(OH)2D3 formation Plasma parathyroid hormone Parathyroid glands Parathyroid hormone secretion Plasma calcium Restoration of plasma calcium toward normal FIGURE 213 Eff ects of PTH and 1,25-dihydroxycholecalciferol on whole body calcium homeostasis. A reduction in plasma calcium stimulates parathyroid hormone secretion. PTH in turn causes calcium conservation and production of 1,25-dihydroxycholecalciferol in the kidneys, the latter of which increases calcium uptake in the intestine. PTH also releases calcium from the readily exchangeable pool in the bone. All of these actions act to restore normal plasma calcium. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology , 10th ed. McGraw-Hill, 2006.) Common carotid artery Right parathyroids Pharynx Recurrent laryngeal nerve Inferior thyroid artery FIGURE 214 The human parathyroid glands, viewed from behind. The glands are small structures adherent to the posterior surface of the thyroid gland. FIGURE 215 Section of human parathyroid ( Reduced 50% from × 960). Small cells are chief cells; large stippled cells (especially prominent in the lower left of picture) are oxyphil cells. (Reproduced with permission from Fawcett DW: Bloom and Fawcett , A Textbook of Histology , 11th ed. Saunders, 1986.) large numbers of mitochondria in their cytoplasm. In humans, few oxyphil cells are seen before puberty, and thereaft er they increase in number with age. Th eir function is unknown. Consequences of loss of the parathyroid glands are discussed in Clinical Box 21–2. SYNTHESIS & METABOLISM OF PTH Human PTH is a linear polypeptide with a molecular weight of 9500 that contains 84 amino acid residues ( Figure 21–6 ). It is synthesized as part of a larger molecule containing 115 amino acid residues ( preproPTH ). On entry of preproPTH 382 SECTION III Endocrine and Reproductive Physiology into the endoplasmic reticulum, a leader sequence is removed from the amino terminal to form the 90-amino-acid polypeptide proPTH. Six additional amino acid residues are removed from the amino terminal of proPTH in the Golgi apparatus, and the 84-amino-acid polypeptide PTH is packaged in secretory granules and released as the main secretory product of the chief cells. S V S E I Q A M H N L G K H L N V D L K K R L W E V R F V A L G A P L A P R D H Q N S S I V H L S M E L F S S I Y E L S E H S A D K A D V D V L G K Q A Q T K A I I K S Q P P A G G G S Q E V L V N D R P R K K E S 5 10 15 20 30 25 35 45 65 60 70 55 75 80 Human Bovine Porcine 50 FIGURE 216 Parathyroid hormone. The symbols above and below the human structure show where amino acid residues are diff erent in bovine and porcine PTH. (Reproduced with permission from Keutmann HT, et al: Complete amino acid sequence of human parathyroid hormone. Biochemistry 1978;17:5723. Copyright © 1978 by the American Chemical Society.) CLINICAL BOX 21–2 Eff ects of Parathyroidectomy Occasionally, inadvertent parathyroidectomy occurs in humans during thyroid surgery. This can have serious consequences as PTH is essential for life. After parathyroidectomy, there is a steady decline in the plasma Ca 2+ level. Signs of neuromuscular hyperexcitability appear, followed by full-blown hypocalcemic tetany (see text). Plasma phosphate levels usually rise as the plasma Ca 2+ level falls. Symptoms usually develop 2–3 days postoperatively but may not appear for several weeks or more. The signs of tetany in humans include Chvostek’s sign , a quick contraction of the ipsilateral facial muscles elicited by tapping over the facial nerve at the angle of the jaw, and Trousseau’s sign , a spasm of the muscles of the upper extremity that causes fl exion of the wrist and thumb with extension of the fi ngers. In individuals with mild tetany in whom spasm is not yet evident, Trousseau’s sign can sometimes be produced by occluding the circulation for a few minutes with a blood pressure cuff . THERAPEUTIC HIGHLIGHTS Treatment centers around replacing the PTH that would normally be produced by the missing glands. Injections of PTH can be given to correct the chemical abnormalities, and the symptoms then disappear. Injections of Ca 2+ salts can also give temporary relief. Th e normal plasma level of intact PTH is 10–55 pg/mL. Th e half-life of PTH is approximately 10 min, and the secreted polypeptide is rapidly cleaved by the Kupff er cells in the liver into fragments that are probably biologically inactive. PTH and these fragments are then cleared by the kidneys. Currently used immunoassays for PTH are designed only to measure mature PTH (ie, 84 amino acids) and not these fragments to obtain an accurate measure of “active” PTH. ACTIONS PTH acts directly on bone to increase bone resorption and mobilize Ca 2+ . In addition to increasing plasma Ca 2+ , PTH increases phosphate excretion in the urine and thereby depresses plasma phosphate levels. Th is phosphaturic action is due to a decrease in reabsorption of phosphate via eff ects on NaPi-IIa in the proximal tubules, as discussed previously. PTH also increases reabsorption of Ca 2+ in the distal tubules, although Ca 2+ excretion in the urine is oft en increased in hyperparathyroidism because the increase in the load of fi ltered calcium overwhelms the eff ect on reabsorption (Clinical Box 21–3). PTH also increases the formation of 1,25-dihydroxycholecalciferol, and this increases Ca 2+ absorption from the intestine. On a longer time scale, PTH stimulates both osteoblasts and osteoclasts. MECHANISM OF ACTION It now appears that there are at least three diff erent PTH receptors. One also binds parathyroid hormone-related protein (PTHrP; see below) and is known as the hPTH/PTHrP receptor. A second receptor, PTH2 (hPTH2-R), does not bind PTHrP and is found in the brain, placenta, and pancreas. In addition, there is evidence for a third receptor, CPTH, which reacts with the carboxyl terminal rather than the amino CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 383 terminal of PTH. Th e fi rst two receptors are coupled to G s , and via this heterotrimeric G protein they activate adenylyl cyclase, increasing intracellular cAMP. Th e hPTH/PTHrP receptor also activates PLC via G q , increasing intracellular Ca 2+ concentrations and activating protein kinase C ( Figure 21–7 ). However, the way these second messengers aff ect Ca 2+ in bone is unsettled. In the disease called pseudohypoparathyroidism, the signs and symptoms of hypoparathyroidism develop but the circulating level of PTH is normal or even elevated. Because tissues fail to respond to the hormone, this is a receptor disease. Th ere are two forms. In the more common form, a congenital 50% reduction of the activity of G s occurs and PTH fails to produce a normal increase in cAMP concentration. In a diff erent, less common form, the cAMP response is normal but the phosphaturic action of the hormone is defective. REGULATION OF SECRETION Circulating Ca 2+ acts directly on the parathyroid glands in a negative feedback fashion to regulate the secretion of PTH. Th e key to this regulation is a cell membrane Ca 2+ receptor, CaR. Activation of this G-protein coupled receptor leads to phosphoinositide turnover in many tissues. In the parathyroid, its activation inhibits PTH secretion. In this way, when the plasma Ca 2+ level is high, PTH secretion is inhibited and Ca 2+ is deposited in the bones. When it is low, secretion is increased and Ca 2+ is mobilized from the bones. 1,25-Dihydroxycholecalciferol acts directly on the parathyroid glands to decrease preproPTH mRNA. Increased CLINICAL BOX 21–3 Diseases of Parathyroid Excess Hyperparathyroidism due to hypersecretion from a functioning parathyroid tumor in humans is characterized by hypercalcemia and hypophosphatemia. Humans with PTH-secreting adenomas are usually asymptomatic, with the condition detected when plasma Ca 2+ is measured in conjunction with a routine physical examination. However, there may be minor changes in personality, and calcium-containing kidney stones occasionally form. In conditions such as chronic renal disease and rickets, in which the plasma Ca 2+ level is chronically low, stimulation of the parathyroid glands causes compensatory parathyroid hypertrophy and secondary hyperparathyroidism. The plasma Ca 2+ level is low in chronic renal disease primarily because the diseased kidneys lose the ability to form 1,25-dihydroxycholecalciferol. Finally, mutations in the Ca 2+ receptor (CaR) gene cause predictable long-term changes in plasma Ca 2+ . Individuals heterozygous for inactivating mutations have familial benign hypocalciuric hypercalcemia, a condition in which there is a chronic moderate elevation in plasma Ca 2+ because the feedback inhibition of PTH secretion by Ca 2+ is reduced. Plasma PTH levels are normal or even elevated. However, children who are homozygous for inactivating mutations develop neonatal severe primary hyperparathyroidism. Conversely, individuals with gain-of-function mutations of the CaR gene develop familial hypercalciuric hypocalcemia due to increased sensitivity of the parathyroid glands to plasma Ca 2+ . THERAPEUTIC HIGHLIGHTS Subtotal parathyroidectomy is sometimes necessary in patients who develop parathyroid adenoma or hyperplasia with associated hypercalcemia and resulting symptoms. However, because parathyroid disease is often benign or only slowly progressing, surgery remains controversial in most patients and is typically reserved for those who have experienced life-threatening complications of hypercalcemia. Gs Gq AC PLC PTHrP PTH ATP cAMP PIP2 PTH-R Diacylglycerol Protein kinase C activation Intracellular Ca2+ mobilization 1,4,5-InsP3 FIGURE 217 Signal transduction pathways activated by PTH or PTHrP binding to the hPTH/hPTHrP receptor. Intracellular cAMP is increased via G s and adenylyl cyclase (AC). Diacylglycerol and IP 3 (1,4,5-InsP 3 ) are increased via G q and phospholipase C (PLC). (Modifi ed and reproduced with permission from McPhee SJ, Lingappa VR, Ganong WF [editors]: Pathophysiology of Disease , 6th ed. McGraw-Hill, 2010.) plasma phosphate stimulates PTH secretion by lowering plasma levels of free Ca 2+ and inhibiting the formation of 1,25-dihydroxycholecalciferol. Magnesium is required to maintain normal parathyroid secretory responses. Impaired PTH release along with diminished target organ responses to PTH account for the hypocalcemia that occasionally occurs in magnesium defi ciency (Clinical Box 21–2 and Clinical Box 21–3). 384 SECTION III Endocrine and Reproductive Physiology PTHrP Another protein with PTH activity, parathyroid hormonerelated protein (PTHrP) , is produced by many diff erent tissues in the body. It has 140 amino acid residues, compared with 84 in PTH, and is encoded by a gene on human chromosome 12, whereas PTH is encoded by a gene on chromosome 11. PTHrP and PTH have marked homology at their amino terminal ends and they both bind to the hPTH/PTHrP receptor, yet their physiologic eff ects are very diff erent. How is this possible when they bind to the same receptor? For one thing, PTHrP is primarily a paracrine factor, acting close to where it is produced. It may be that circulating PTH cannot reach at least some of these sites. Second, subtle conformational differences may be produced by binding of PTH versus PTHrP to their receptor, despite their structural similarities. Another possibility is action of one or the other hormone on additional, more selective receptors. PTHrP has a marked eff ect on the growth and development of cartilage in utero. Mice in which both alleles of the PTHrP gene are knocked out have severe skeletal deformities and die soon aft er birth. In normal animals, on the other hand, PTHrP-stimulated cartilage cells proliferate and their terminal diff erentiation is inhibited. PTHrP is also expressed in the brain, where evidence indicates that it inhibits excitotoxic damage to developing neurons. In addition, there is evidence that it is involved in Ca 2+ transport in the placenta. PTHrP is also found in keratinocytes in the skin, in smooth muscle, and in the teeth, where it is present in the enamel epithelium that caps each tooth. In the absence of PTHrP, teeth cannot erupt. HYPERCALCEMIA OF MALIGNANCY Hypercalcemia is a common metabolic complication of cancer. About 20% of hypercalcemic patients have bone metastases that produce the hypercalcemia by eroding bone (local osteolytic hypercalcemia). Evidence suggests that this erosion is produced by prostaglandins such as prostaglandin E 2 arising from the tumor. Th e hypercalcemia in the remaining 80% of the patients is due to elevated circulating levels of PTHrP (humoral hypercalcemia of malignancy). Th e tumors responsible for this hypersecretion include cancers of the breast, kidney, ovary, and skin. CALCITONIN ORIGIN In dogs, perfusion of the thyroparathyroid region with solutions containing high concentrations of Ca 2+ leads to a fall in peripheral plasma Ca 2+ , and aft er damage to this region, Ca 2+ infusions cause a greater increase in plasma Ca 2+ than they do in control animals. Th ese and other observations led to the discovery that a Ca 2+ -lowering as well as a Ca 2+ -elevating hormone was secreted by structures in the neck. Th e Ca 2+ - lowering hormone has been named calcitonin. In mammals, calcitonin is produced by the parafollicular cells of the thyroid gland, which are also known as the clear or C cells. SECRETION & METABOLISM Human calcitonin has a molecular weight of 3500 and contains 32 amino acid residues. Its secretion is increased when the thyroid gland is exposed to a plasma calcium level of approximately 9.5 mg/dL. Above this level, plasma calcitonin is directly proportional to plasma calcium. β-Adrenergic agonists, dopamine, and estrogens also stimulate calcitonin secretion. Gastrin, cholecystokinin (CCK), glucagon, and secretin have also been reported to stimulate calcitonin secretion, with gastrin being the most potent stimulus (see Chapter 25 ). Th us, the plasma calcitonin level is elevated in Zollinger–Ellison syndrome and in pernicious anemia (see Chapter 25 ). However, the dose of gastrin needed to stimulate calcitonin secretion is supraphysiological and not seen aft er eating in normal individuals, so dietary calcium in the intestine probably does not induce secretion of a calcium-lowering hormone prior to the calcium being absorbed. In any event, the actions of calcitonin are short-lived because it has a half-life of less than 10 min in humans. ACTIONS Receptors for calcitonin are found in bones and the kidneys. Calcitonin lowers circulating calcium and phosphate levels. It exerts its calcium-lowering eff ect by inhibiting bone resorption. Th is action is direct, and calcitonin inhibits the activity of osteoclasts in vitro. It also increases Ca 2+ excretion in the urine. Th e exact physiologic role of calcitonin is uncertain. Th e calcitonin content of the human thyroid is low, and aft er thyroidectomy, bone density and plasma Ca 2+ level are normal as long as the parathyroid glands are intact. In addition, aft er thyroidectomy, there are only transient abnormalities of Ca 2+ homeostasis when a Ca 2+ load is injected. Th is may be explained in part by secretion of calcitonin from tissues other than the thyroid. However, there is general agreement that the hormone has little long-term eff ect on the plasma Ca 2+ level in adult animals and humans. Further, unlike PTH and 1,25-dihydroxycholecalciferol, calcitonin does not appear to be involved in phosphate homeostasis. Moreover, patients with medullary carcinoma of the thyroid have a very high circulating calcitonin level but no symptoms directly attributable to the hormone, and their bones are essentially normal. No syndrome due to calcitonin defi ciency has been described. More hormone is secreted in young individuals, and it may play a role in skeletal development. In addition, it may protect the bones of the mother from excess calcium loss during pregnancy. Bone formation in the infant and lactation are major drains on Ca 2+ stores, and plasma concentrations of CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 385 1,25-dihydroxycholecalciferol are elevated in pregnancy. Th ey would cause bone loss in the mother if bone resorption were not simultaneously inhibited by an increase in the plasma calcitonin level. SUMMARY OF CALCIUM HOMEOSTATIC MECHANISMS Th e actions of the three principal hormones that regulate the plasma concentration of Ca 2+ can now be summarized. PTH increases plasma Ca 2+ by mobilizing this ion from bone. It increases Ca 2+ reabsorption in the kidney, but this may be off set by the increase in fi ltered Ca 2+ . It also increases the formation of 1,25-dihydroxycholecalciferol. 1,25-Dihydroxycholecalciferol increases Ca 2+ absorption from the intestine and increases Ca 2+ reabsorption in the kidneys. Calcitonin inhibits bone resorption and increases the amount of Ca 2+ in the urine. EFFECTS OF OTHER HORMONES & HUMORAL AGENTS ON CALCIUM METABOLISM Calcium metabolism is aff ected by various hormones in addition to 1,25-dihydroxycholecalciferol, PTH, and calcitonin. Glucocorticoids lower plasma Ca 2+ levels by inhibiting osteoclast formation and activity, but over long periods they cause osteoporosis by decreasing bone formation and increasing bone resorption. Th ey decrease bone formation by inhibiting protein synthesis in osteoblasts. Th ey also decrease the absorption of Ca 2+ and PO 4 3– from the intestine and increase the renal excretion of these ions. Th e decrease in plasma Ca 2+ concentration also increases the secretion of PTH, and bone resorption is facilitated. Growth hormone increases Ca 2+ excretion in the urine, but it also increases intestinal absorption of Ca 2+ , and this eff ect may be greater than the eff ect on excretion, with a resultant positive calcium balance. Insulin-like growth factor I (IGF-I) generated by the action of growth hormone stimulates protein synthesis in bone. As noted previously, thyroid hormones may cause hypercalcemia, hypercalciuria, and, in some instances, osteoporosis. Estrogens prevent osteoporosis by inhibiting the stimulatory eff ects of certain cytokines on osteoclasts. Insulin increases bone formation, and there is signifi cant bone loss in untreated diabetes. BONE PHYSIOLOGY Bone is a special form of connective tissue with a collagen framework impregnated with Ca 2+ and PO 4 3– salts, particularly hydroxyapatites, which have the general formula Ca 10 (PO 4 ) 6 (OH) 2 . Bone is also involved in overall Ca 2+ and PO 4 3– homeostasis. It protects vital organs, and the rigidity it provides permits locomotion and the support of loads against gravity. Old bone is constantly being resorbed and new bone formed, permitting remodeling that allows it to respond to the stresses and strains that are put upon it. It is a living tissue that is well vascularized and has a total blood fl ow of 200–400 mL/ min in adult humans. STRUCTURE Bone in children and adults is of two types: compact or cortical bone , which makes up the outer layer of most bones ( Figure 21–8 ) and accounts for 80% of the bone in the body; and trabecular or spongy bone inside the cortical bone, which makes up the remaining 20% of bone in the body. In compact bone, the surface-to-volume ratio is low, and bone cells lie in lacunae. Th ey receive nutrients by way of canaliculi that ramify throughout the compact bone ( Figure 21–8 ). Trabecular bone is made up of spicules or plates, with a high surface to volume ratio and many cells sitting on the surface of the plates. Nutrients diff use from bone extracellular fl uid (ECF) into the trabeculae, but in compact bone, nutrients are provided via haversian canals ( Figure 21–8 ), which contain blood vessels. Around each Haversian canal, collagen is arranged in concentric layers, forming cylinders called osteons or haversian systems . Th e protein in bone matrix is over 90% type I collagen, which is also the major structural protein in tendons and skin. Th is collagen, which weight for weight is as strong as steel, is made up of a triple helix of three polypeptides bound tightly together. Two of these are identical α1 polypeptides encoded by one gene, and one is an α2 polypeptide encoded by a different gene. Collagens make up a family of structurally related proteins that maintain the integrity of many diff erent organs. Fift een diff erent types of collagens encoded by more than 20 diff erent genes have so far been identifi ed. BONE GROWTH During fetal development, most bones are modeled in cartilage and then transformed into bone by ossifi cation ( enchondral bone formation ). Th e exceptions are the clavicles, the mandibles, and certain bones of the skull in which mesenchymal cells form bone directly ( intramembranous bone formation ). During growth, specialized areas at the ends of each long bone ( epiphyses ) are separated from the shaft of the bone by a plate of actively proliferating cartilage, the epiphysial plate ( Figure 21–9 ). Th e bone increases in length as this plate lays down new bone on the end of the shaft . Th e width of the epiphysial plate is proportional to the rate of growth. Th e width is aff ected by a number of hormones, but most markedly by the pituitary growth hormone and IGF-I (see Chapter 18 ). Linear bone growth can occur as long as the epiphyses are separated from the shaft of the bone, but such growth ceases aft er the epiphyses unite with the shaft (epiphysial closure). Th e cartilage cells stop proliferating, become 386 SECTION III Endocrine and Reproductive Physiology hypertrophic, and secrete vascular endothelial growth factor (VEGF), leading to vascularization and ossifi cation. Th e epiphyses of the various bones close in an orderly temporal sequence, the last epiphyses closing aft er puberty. Th e normal age at which each of the epiphyses closes is known, and the “bone age” of a young individual can be determined by X-raying the skeleton and noting which epiphyses are open and which are closed. Th e periosteum is a dense fi brous, vascular, and innervated membrane that covers the surface of bones. Th is layer consists of an outer layer of collagenous tissue and an inner layer of fi ne elastic fi bers that can include cells that have the potential to contribute to bone growth. Th e periosteum covers all surfaces of the bone except for those capped with cartilage (eg, at the joints) and serves as a site of attachment of ligaments and tendons. As one ages, the periosteum becomes thinner and loses some of its vasculature. Th is renders bones more susceptible to injury and disease. BONE FORMATION & RESORPTION Th e cells responsible for bone formation are osteoblasts and the cells responsible for bone resorption are osteoclasts. Osteoblasts are modifi ed fi broblasts. Th eir early development from the mesenchyme is the same as that of fi broblasts, with extensive growth factor regulation. Later, ossifi cationspecifi c transcription factors, such as Cbfa1/Runx2, contribute to their diff erentiation. Th e importance of this transcription Cortical (compact) bone Lacunae Trabecular (cancellous) bone Osteons Canaliculi Haversian canal Resorption spaces FIGURE 218 Structure of compact and trabecular bone. The compact bone is shown in horizontal section (top) and vertical section (bottom). (Reproduced with permission from Williams PL et al (editors): Gray’s Anatomy , 37th ed. Churchill Livingstone, 1989.) CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 387 Epiphysis Epiphysis Diaphysis Epiphysial plate Marrow cavity Compact bone Periosteum Trabecular bone FIGURE 219 Structure of a typical long bone before (left) and after (right) epiphysial closure. Note the rearrangement of cells and growth of the bone as the epiphysial plate closes (see text for details). Bone-resorbing compartment Ruffled apical membrane Sealing zone Integrins Basolateral membrane Bone matrix n n n mi n FIGURE 2110 Osteoclast resorbing bone. The edges of the cell are tightly sealed to bone, permitting secretion of acid from the ruffl ed apical membrane and consequent erosion of the bone underneath the cell. Note the multiple nuclei (n) and mitochondria (mi). (Courtesy of R Baron.) factor in bone development is underscored in knockout mice defi cient for the Cbfa1/Runx gene. Th ese mice develop to term with their skeletons made exclusively of cartilage; no ossifi - cation occurs. Normal osteoblasts are able to lay down type 1 collagen and form new bone. Osteoclasts, on the other hand, are members of the monocyte family. Stromal cells in the bone marrow, osteoblasts, and T lymphocytes all express receptor activator for nuclear factor kappa beta ligand (RANKL) on their surface. When these cells come in contact with appropriate monocytes expressing RANK (ie, the RANKL receptor) two distinct signaling pathways are initiated: (1) there is a RANKL/RANK interaction between the cell pairs, (2) mononuclear phagocyte colony stimulating factor (M-CSF) is secreted by the nonmonocytic cells and it binds to its corresponding receptor on the monocytes (c-fi n). Th e combination of these two signaling events leads to diff erentiation of the monocytes into osteoclasts. Th e precursor cells also secrete osteoprotegerin (OPG) , which controls for diff erentiation of the monocytes by competing with RANK for binding of RANKL. Osteoclasts erode and absorb previously formed bone. Th ey become attached to bone via integrins in a membrane extension called the sealing zone . Th is creates an isolated area between the bone and a portion of the osteoclast. Proton pumps (ie, H + -dependent ATPases) then move from endosomes into the cell membrane apposed to the isolated area, and they acidify the area to approximately pH 4.0. Similar proton pumps are found in the endosomes and lysosomes of all eukaryotic cells, but in only a few other instances do they move into the cell membrane. Note in this regard that the sealed-off space formed by the osteoclast resembles a large lysosome. Th e acidic pH dissolves hydroxyapatite, and acid proteases secreted by the cell break down collagen, forming a shallow depression in the bone ( Figure 21–10 ). Th e products of digestion are then endocytosed and move across the osteoclast by transcytosis (see Chapter 2 ), with release into the interstitial fl uid. Th e collagen breakdown products have pyridinoline structures, and pyridinolines can be measured in the urine as an index of the rate of bone resorption. Th roughout life, bone is being constantly resorbed and new bone is being formed. Th e calcium in bone turns over at a rate of 100% per year in infants and 18% per year in adults. Bone remodeling is mainly a local process carried out in small areas by populations of cells called bone-remodeling units. First, osteoclasts resorb bone, and then osteoblasts lay down new bone in the same general area. Th is cycle takes about 100 days. Modeling drift s also occur in which the shapes of bones change as bone is resorbed in one location and added in another. Osteoclasts tunnel into cortical bone followed by osteoblasts, whereas trabecular bone remodeling occurs on the surface of the trabeculae. About 5% of the bone mass is being remodeled by about 2 million boneremodeling units in the human skeleton at any one time. Th e renewal rate for bone is about 4% per year for compact bone and 20% per year for trabecular bone. Th e remodeling is related in part to the stresses and strains imposed on the skeleton by gravity. At the cellular level, there is some regulation of osteoclast formation by osteoblasts via the RANKL–RANK and the M-CSF–OPG mechanism; however, specifi c feedback mechanisms of osteoclasts on osteoblasts are not well defi ned. In a broader sense, the bone remodeling process is primarily under endocrine control. PTH accelerates bone resorption, and estrogens slow bone resorption by inhibiting the production of bone-eroding cytokines. An interesting new observation 388 SECTION III Endocrine and Reproductive Physiology FIGURE 2111 Normal trabecular bone (left) compared with trabecular bone from a patient with osteoporosis (right). The loss of mass in osteoporosis leaves bones more susceptible to breakage. 1500 1000 500 0 0 20 40 60 80 100 Age (years) Total body calcium (grams) I I II III III FIGURE 2112 Total body calcium, an index of bone mass, at various ages in men and women. Note the rapid increase to young adult levels (phase I) followed by the steady loss of bone with advancing age in both sexes (phase III) and the superimposed rapid loss in women after menopause (phase II). (Reproduced by permission of Oxford University Press from Riggs BL, Melton LJ III: Involutional osteoporosis. In Evans TG, Williams TF (editors): Oxford Textbook of Geriatric Medicine . Oxford University Press, 1992.) is that intracerebroventricular, but not intravenous, leptin decreases bone formation. Th is fi nding is consistent with the observations that obesity protects against bone loss and that most obese humans are resistant to the eff ects of leptin on appetite. Th us, there may be neuroendocrine regulation of bone mass via leptin. BONE DISEASE Th e diseases produced by selective abnormalities of the cells and processes discussed above illustrate the interplay of factors that maintain normal bone function. In osteopetrosis , a rare and oft en severe disease, the osteoclasts are defective and are unable to resorb bone in their usual fashion so the osteoblasts operate unopposed. Th e result is a steady increase in bone density, neurologic defects due to narrowing and distortion of foramina through which nerves normally pass, and hematologic abnormalities due to crowding out of the marrow cavities. Mice lacking the protein encoded by the immediate-early gene c- fos develop osteopetrosis; osteopetrosis also occurs in mice lacking the PU.1 transcription factor. Th is suggests that all these factors are involved in normal osteoclast development and function. On the other hand, osteoporosis is caused by a relative excess of osteoclastic function. Loss of bone matrix in this condition ( Figure 21–11 ) is marked, and the incidence of fractures is increased. Fractures are particularly common in the distal forearm (Colles fracture), vertebral body, and hip. All of these areas have a high content of trabecular bone, and because trabecular bone is more active metabolically, it is lost more rapidly. Fractures of the vertebrae with compression cause kyphosis, with the production of a typical “widow’s hump” that is common in elderly women with osteoporosis. Fractures of the hip in elderly individuals are associated with a mortality rate of 12–20%, and half of those who survive require prolonged expensive care. Osteoporosis has multiple causes, but by far the most common form is involutional osteoporosis. All normal humans gain bone early in life, during growth. Aft er a plateau, they begin to lose bone as they grow older ( Figure 21–12 ). When this loss is accelerated or exaggerated, it leads to osteoporosis (see Clinical Box 21–4). Increased intake of calcium, particularly from natural sources such as milk, and moderate exercise may help prevent or slow the progress of osteoporosis, although their eff ects are not great. Bisphosphonates such as etidronate, which inhibit osteoclastic activity, increase the mineral content of bone and decrease the rate of new vertebral fractures when administered in a cyclical fashion. Fluoride stimulates osteoblasts, making bone more dense, but it has proven to be of little value in the treatment of the disease. CHAPTER SUMMARY Circulating levels of ■ calcium and phosphate ions are controlled by cells that sense the levels of these electrolytes in the blood and release hormones, and eff ects of these hormones are evident in mobilization of the minerals from the bones, intestinal absorption, and/or renal wasting. ■ Th e majority of the calcium in the body is stored in the bones but it is the free, ionized calcium in the cells and extracellular fl uids that fulfi lls physiological roles in cell signaling, nerve function, muscle contraction, and blood coagulation, among others. ■ Phosphate is likewise predominantly stored in the bones and regulated by many of the same factors that infl uence calcium levels, sometimes reciprocally. ■ Th e two major hormones regulating calcium and phosphate homeostasis are 1,25-dihydroxycholecalciferol (a derivative of vitamin D) and parathyroid hormone; calcitonin is also capable of regulating levels of these ions, but its full physiologic contribution is unclear.

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