The Adrenals and Pituitary Stress Adaptation and Longevity

Paola S. Timiras

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, U.S.A.

Omer Gersten

Department of Demography, University of California, Berkeley, Berkeley, California, U.S.A

■ INTRODUCTION

The endocrine system, like the nervous system, coordinates physiologic responses to environmental signals to enhance individual survival and reproduction. Since aging often brings about a decline in physiologic function, it is not surprising that, in regard to the endocrine system, old age engenders

■ a diminished capacity to adapt to internal and external demands, especially under stress conditions and

■ a deterioration of reproductive function in men and a cessation of reproduction in women.

Both in early and late stages of the life span, development and aging are associated with changes in endocrine function, and endocrine function is known to affect hormonal levels. It is clear that cellular and molecular changes occur with senescence, but it is not certain that these changes are responsible for senescence and ultimately death. Nevertheless, it is strongly suspected that hormonal changes influence functional decrements, disabilities, diseases of old age, and the length of the life span (1-4).

In recent years, various tools have been added to the classical, clinical, physiological, and biochemical measurements of endocrine function. New techniques, adopted from the fields of genetic engineering and molecular and structural biology, have provided new advances in the study of mutations in humans and in the use of genetic disruption in transgenic or knockout animals (5,6). These new tools and techniques can fruitfully be applied to the study of physiologic systems, such as the hypothalamo-pituitary-adrenal (HPA) axis discussed in this chapter. The HPA axis includes the cortical and medullary components of the Adrenal Gland: HPA may refer specifically to the HPA Adrenal cortical component and its steroid hormones, and/or to the HPA Adrenal Medullary and its catecholamine neurotransmitter, part of the sympathetic nervous system. The HPA axis is primarily regulated by feed back mechanisms. Also, new technologies for detection of hormonal signaling are being used in the study of growth, development, and reproduction. Thus, mimicking human endocrine pathology through animal gene mutations is providing new insights into endocrine aging.

The section following this introduction discusses the assessment and measurement of endocrine function. The subsequent sections discuss the structure and functions of the adrenal cortex, the adrenal medulla, and the pituitary gland. The last section, entitled Stress and Adaptation, discusses the stress response and its consequences, highlighting the key role of the HPA axis and the mechanisms that regulate adaptation and contribute to survival and reproduction.

■ ENDOCRINE GLANDS, HORMONES, AND CHEMICAL MESSENGERS

The wide distribution, multiplicity, and diversity of hormones acting as chemical mediators in the body partly testifies to the critical role of endocrine regulation of bodily functions (Box 1). This important role certainly applies to the hormones of the HPA axis, which is discussed in this chapter. HPA hormones are responsible for communication among cells within the same organism and between the organism and its surrounding environment. The hypothalamus, situated in the midbrain, plays key roles in the regulation of several complex behaviors, such as endocrine, autonomic, and metabolic functions, and circadian rhythms. The pituitary (or hypophysis) secretes several hormones that stimulate peripheral targets, either other endocrine glands or specific tissues and organs. The location of the pituitary—in the close vicinity of the hypothalamus with which it articulates through a vascular net, the portal system, and through direct neuronal connections—makes it an intermediary between the nervous and endocrine systems. Among the endocrine glands, the adrenals regulate certain aspects of metabolism, behavior, and nervous and immune functions and, thus, play a key role in homeostasis. As with all endocrine glands, the adrenals and pituitary do not act in isolation. They are dependent for their function on neuroendocrine signals, usually initiated in or relayed through the hypothalamus (7-9). The endocrine glands are also dependent on the functional status of the target cells. With aging, changes in endocrine function may depend on changes in the following:

■ A single endocrine gland

■ Several endocrine glands simultaneously

■ Other bodily systems (e.g., nervous, immune, cardio-vascular)

■ Body metabolism and composition

■ Cellular and molecular responses of target cells and tissues

In many cases, the assessment of a biological construct, such as aging, is sensitive to different experimental designs. These experimental designs may be modified in different ways to suit research needs. Thus, manipulation in experimental animals and diseases in humans, must be carefully considered by the researcher as they may challenge the validity of the results. Among the variables the most frequently included are:

■ The influence of stress, disease, medications, and drugs

■ The influence of heredity and environment

■ The influence of diet and exercise

■ Assessment of Endocrine Function

It is difficult to evaluate endocrine function, and the reasons for this include the following:

BOX 1 Intercellular Communication by Chemical Mediators

Endocrine communication is mediated through hormones secreted by endocrine glands. Secreted hormones are released into the blood circulation and act on distant target cells. Well-recognized endocrine glands include the pituitary, adrenals, thyroid, parathyroids, pancreas, testes, and ovaries.

Other cells or groups of cells act by paracrine communication. These cells, interspersed among other cells, secrete, in the extracellular fluid, hormones that affect neighboring cells. Examples of paracrine hormone-producing cells are those of the pancreas (with both endocrine and paracrine secretions), the intestinal mucosa, and those producing prostaglandins. Secretory cells may also act by autocrine communication, that is, they secrete chemical messengers that bind to receptors on the very same cell that secreted the messenger. Yet, other cells act by juxtacrine communication in which the cells act directly on the neighboring cells.

Some neurotransmitters, such as epinephrine and norepinephrine, are also considered chemical messengers (Chapter 6). Other important messengers such as cytokines, thymic hormones, membrane receptors, and growth or apoptotic factors regulate immune and hematopoietic functions (Chapters 14 and 17). Chemical messengers are for the most part amines, amino acids, steroids, polypeptides, proteins, and, in a few instances, other substances. In different parts of the body, the same chemical messenger can function as a neurotransmitter, a paracrine mediator, and a neurohormone.

■ Hormonal actions simultaneously affect several bodily functions

■ Hormones regulate responses generated by internal (genes) and external (environmental) signals to promote reproduction and to maintain homeostasis

■ The repertory and efficiency of integrative hormonal responses, which are optimally available during adulthood, diminish with advancing age and, thus, compromise strategies for adaptation and survival

The evaluation of endocrine function in humans often relies on relatively noninvasive measurements of blood, urine, and saliva, under basal conditions (resting or steady state) and under stress. Such an assessment often leads to incomplete and erroneous conclusions, since an adequate endocrine evaluation must assess several levels of endocrine action as well as assess the relationship between endocrine and other bodily systems (primarily the nervous and immune systems), hormone-receptor interactions at the target cell, and molecular events inside the cell, as listed in Table 1. Although none of these aging-related changes alone may be sufficient to irrevocably damage physiologic competence, a number of minor changes may desynchronize the appropriate signal at the target cell/ molecule and alter hormonal actions. Factors involved in the design of the experimental protocol (e.g., sample size, health, and sex of subjects) to assess endocrine function may also influence the evaluation of changes that occur with old age.

An ideal "global" approach (as outlined above) to the study of endocrine aging is currently very difficult to achieve in humans. This global approach may be implemented more easily in experimental animals and in cultured tissues or cells. Such in vivo and in vitro models represent an important corollary to human studies. As illustrated in Figure 1, changes with aging may occur at all levels of the endocrine system:

■ At the endocrine gland level, weight loss with atrophy, fibrosis, and vascular changes occur in most glands, with or without the concomitant occurrence of glandular tumors (adenomas).

■ Under basal conditions, blood plasma hormones (free, biologically active hormones or hormones bound to plasma proteins) in humans and in animals are generally not altered in healthy old age, although some hormones (such as sex hormones) decrease significantly.

■ Hormone release depends on nervous and environmental stimuli as well as positive and negative feedback from circulating hormones.

■ Some hormones act exclusively on one type of target cells, while other hormones act on many cell types (targets) and by several mechanisms. Thus, the same hormone may have different actions in different tissues.

■ With aging, one of the many hormonal actions or one of the many targets may be selectively affected while other actions and targets are preserved.

TABLE 1 Factors that Influence an Evaluation of Endocrine Function

Biologic factors

Physiologic factors Metabolic state Body composition Dietary regimen Physical exercise

Exposure to stress (environmental and psychosocial) Relationship to other endocrines and bodily systems The rate of secretion of secretory cells Transport of the hormones to target cells Metabolism of the secreted hormones Metabolites may be more or less biologically active than the secreted hormones (e.g., conversion of T to the more active DHT (Chapter 11) and conversion of T4 to the more active T3 (Chapter 12)) Number and affinity of hormone receptors Intracellular postreceptor molecular events Occurrence of disease and use of medications Experimental design factors Sample size

Health status of subjects Conceptualization of age categories Comorbidity of subjects Sex of subjects

Subjects under steady state or under stress

Quality, intensity, timing, and duration of stress Outcome of study Parameters measured

Duration of parameters measured (long- vs. short-term experiments)

Abbreviations: DHT, dihydrotestosterone; T testosterone; T4, thyroxine; T3, 3, 5, 3', -triiodothyronine;.

FIGURE 1 Diagrammatic representation of a typical sequence of hormone action and regulation. Abbreviation: CNS, central nervous system.

FIGURE 2 Diagram of the kidneys and adrenals.

FIGURE 1 Diagrammatic representation of a typical sequence of hormone action and regulation. Abbreviation: CNS, central nervous system.

■ Secretory and clearance rates often decrease, although it is not clear in these cases whether the primary defect involves hormone secretion or hormone clearance. The pertinent question is to what extent the capacity to maintain stable levels of plasma hormones is preserved. To better understand at which levels defects may be occurring, it is important to study hormonal biosynthetic precursors, their enzymes, and intermediary metabolites.

■ Receptors located on target cells mediate specific actions of hormones on particular cells and the number of receptors may increase (upregulation) or decrease (downregulation) depending on the stimulus. Hormone-receptor complexes are usually internalized by endocytosis, bind to the nucleus, and stimulate or repress the transcription of selected RNAs or the activity of specific enzymes. Cellular responses are determined by the genetic programming of the particular cell. With aging, receptor binding and intra-cellular responses vary greatly depending on the hormone and the target cell.

■ THE ADRENAL CORTEX

The adrenals are paired glands that lie above the kidneys (Fig. 2). They have an inner medulla and an outer cortex (Fig. 3). The medulla is considered a sympathetic ganglion and it secretes the catecholamines [epinephrine (E) and norepineph-rine (NE)], which are amines derived from the amino acid tyrosine. The cortex secretes several steroid compounds, characterized chemically by a 17-carbon ring system. The following are derivatives of cholesterol and share the same steroid structure: sterols, bile acids, vitamin D, and hormones from the ovary (e.g., estrogens), the testis (e.g., testosterone), and from the adrenal cortex (corticoids). Corticoids are distinguished into three categories:

FIGURE 2 Diagram of the kidneys and adrenals.

■ Glucocorticoids: In this group, cortisol is the principal glucocorticoid secreted in humans, and corticosterone is the principal glucocorticoid secreted in rats (Fig. 3).

■ Sex hormones: Dehydroepiandrosterone (DHEA) is the principal adrenal androgen in humans. Cortisol and DHEA are secreted by the cells of the zona fasciculata and zona reticularis, and corticosterone is secreted by these and also the zona glomerulosa.

■ Mineralocorticoids: Secreted by the cells of the zona glomerulosa, aldosterone is the principal hormone of this group.

The HPA axis is the most important system to guarantee adaptation and survival of an organism upon exposure to stress (Table 2). Given the complex interrelationships among the hypothalamus, anterior pituitary, and adrenal cortex, it is necessary, in evaluating the function of each component, to consider the entire axis as one entity (Fig. 4). Secretion of the adrenocorticotropin or adrenocorticotropic hormone (ACTH)

FIGURE 3 Diagram of a section of the adrenal grand illustrating the various zones and hormones.

TABLE 2 Some Characteristics of Stress

Stress induces defense mechanisms for maintenance of homeostasis in response to challenges Some types of stress known to stimulate the HPA axis

Physical stress Hypoglycemia Trauma

Exposure to extreme temperatures Infections Heavy exercise Psychological stress Acute anxiety Chronic anxiety

Anticipation of stressful situations Novel situations Consequences of exposure to stress

Specific responses (varying with the type of stimulus) Nonspecific responses (always the same, regardless of the stimulus and mediated through stimulation of neural, endocrine, and immune axes)

Abbreviation: HPA axis, hypothalamo-pituitary-adrenal axis.

from the anterior pituitary is stimulated by the action of the hypothalamic corticotropin-releasing hormone (CRH). In turn, ACTH causes the release of cortisol (with a half-life in plasma of 60 to 90 minutes and a proportion in plasma of approximately 10% free and 90% bound to plasma proteins). The effects of old age on the HPA axis have been studied extensively given its importance in the maintenance of homeostasis.

■ Changes with Aging in Adrenocortical

Hormones Under Basal and Stress Conditions

With aging, the adrenal cortex undergoes some structural changes. For instance, its weight is decreased in humans, and

FIGURE 4 Diagrammatic representation of the HPA axis. Abbreviations: ACTH, adrenocorticotropic hormone; CNS, central nervous system; CRH, corticotropin-releasing hormone; HPA, hypothalamo-pituitary-adrenocortical axis.

in the various animal species that have been examined, nodules (i.e., localized hyperplastic changes, perhaps reactive to a reduced blood supply or consequence of multifocal adenomas) occur frequently. The adrenocortical cells, which are typical secretory cells rich in mitochondria and endoplas-mic reticulum with numerous lipid droplets where the steroid hormones are stored, undergo several changes. Of these, the most widespread is the accumulation of lipofuscin granules (Chapters 3 and 6), ultrastructural changes in mitochondria, and the thickening of the connective support tissue (as shown by the thick capsule and the fibrous infiltrations around blood vessels). Major actions of glucocorticoids are described below and in Figure 5. DHEA, the principal adrenocortical sex hormone, has weak androgenic (masculinizing) and anabolic (protein building) actions, and mineralocorticoids, such as aldosterone, regulate primarily water and electrolyte metabolism through their action on the renal tubule (Chapter 18).

Glucocorticoids

Under basal conditions, the following parameters remain essentially unchanged in men and women well into old age (10-12):

Plasma levels of cortisol and ACTH Circadian rhythm of ACTH release Cortisol release

Responses of ACTH and cortisol to administered CRH

FIGURE 5 Diagram of the major actions of glucocorticoid hormones. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotro-pin-releasing hormone; EEG, electroencephalogram.

FIGURE 4 Diagrammatic representation of the HPA axis. Abbreviations: ACTH, adrenocorticotropic hormone; CNS, central nervous system; CRH, corticotropin-releasing hormone; HPA, hypothalamo-pituitary-adrenocortical axis.

FIGURE 5 Diagram of the major actions of glucocorticoid hormones. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotro-pin-releasing hormone; EEG, electroencephalogram.

■ Number of glucocorticoid receptors in target cells or affinity of these receptors for cortisol

A number of early studies suggested that secretion of cortisol is reduced in old age. However, the reduction of corticoid secretion be compensated for by a decreased clearance (i.e., reduced metabolism and excretion), or increased hormone production may be compensated for by an increased removal (clearance). Such metabolic compensatory mechanisms could remain operative into old age, with the body adapting to decreasing production rates of the hormone by reducing the rate of its removal or vice versa and, thus, maintaining normal circulating levels. However, more recent studies indicate that the production and clearance of cortisol are unchanged if the elderly subjects are in good health (12). Yet other studies have reported that in some species [e.g., rats (13), vervet monkeys (14), tree shrews (15), baboons (16)], glucocorticoid levels are slightly increased with senescence.

Stress stimulates the entire HPA axis, resulting in increased synthesis and secretion of CRH, ACTH, and glucocorticoids. Stress also stimulates the sympathetic nervous system and the adrenal medulla to increase E and NE secretion. In some animal species, under conditions of stress (physical or psychological) or after injection of exogenous glucocorticoids, the levels of glucocorticoids are more highly elevated in the older animals. This is the case for injections of corticosterone, which not only cause corticosterone levels to increase above those of controls of the same age, but also cause the higher levels to persist for longer periods in older rats (of some strains) (Fig. 6). These persistently higher corticosterone levels after stress or after administration of exogenous corticosterone have been interpreted as a loss of resiliency of the HPA axis. That is, it is thought that the HPA axis fails to set into action the negative feedback necessary for

FIGURE 6 Corticosterone levels in young (three to five months) and old (24-28 months) Fisher 344 rats during one hour of immobilization stress followed by four hours of post-stress recovery. Corticosterone levels were higher and persisted higher in the old compared to the young subjects. Indicates the times when levels are no longer significantly elevated above base line (determined by two-tailed paired t-test). In the case of young rats, this was one hour after the recovery period; for aged rats, such recovery did not occur during the monitored time period. Source: From Ref. 17.

FIGURE 6 Corticosterone levels in young (three to five months) and old (24-28 months) Fisher 344 rats during one hour of immobilization stress followed by four hours of post-stress recovery. Corticosterone levels were higher and persisted higher in the old compared to the young subjects. Indicates the times when levels are no longer significantly elevated above base line (determined by two-tailed paired t-test). In the case of young rats, this was one hour after the recovery period; for aged rats, such recovery did not occur during the monitored time period. Source: From Ref. 17.

returning the elevated hormone blood concentrations to basal levels (Box 2) (13-17).

In the rat, high glucocorticoid levels are toxic to neurons, particularly those of the hippocampus in which there is a high concentration of glucocorticoid receptors (18). Hippocampal cells under basal conditions inhibit CRH release. Therefore, when some of these cells are lost due to the toxic action of high corticosterone levels, CRH inhibition is also lost. Consequently, secretion of ACTH and glucocorticoids is increased and the levels of corticosterone in the blood continue to increase, thereby generating the "glucocorticoid cascade hypothesis of aging" (13). Young rats stressed for several weeks or treated with high glucocorticoid doses show hippocampal cell loss and changes in HPA axis function resembling those in old, stressed animals (13,17-20). In healthy humans, the relationship among the three components of the HPA axis do not appear to change significantly after long exposure to stress or with increasing age (21).

In contrast to levels of glucocorticoids that remain steady under basal conditions and rise under stress conditions, levels of the other adrenocortical steroids appear to decline with aging. This is the case for aldosterone in which values are almost undetectable beyond the age of 65 years (22). For DHEA, values for those aged 60 and older are approximately one-third of those for individuals around age 30 (23,24).

Adrenal Sex Steroids and DHEA Replacement Therapy

DHEA, the principal adrenal androgen, is considered a prototype of the adrenal sex hormones. DHEA follows a characteristic life cycle in which levels are

■ rising before puberty,

■ progressively declining to low or negligible levels by the age of 70 years.

DHEA secretion is regulated by ACTH. Under conditions of stress, the secretion of cortisol and DHEA is increased, but the ratio of DHEA to cortisol falls as the enzymatic pathways for the biosynthesis of both hormones use the same intermediates, with preferential formation of cortisol (23,24). The reduced plasma levels together with the lower response of DHEA to ACTH administration have led to the suggestion that DHEA may have some antiaging effects, perhaps attributable to an antiglucocorticoid action. For example, severely atherosclerotic individuals have lower DHEA levels compared to normal individuals (25-27). This and other evidence have led to the claim that DHEA replacement may prevent some of the functional decrements and pathology of old age. It may be recalled that the physiologist C.-E. Brown-Sequard, by early 1889, recognized an association between aging and secretory actions attributed to an organ (the testis), and he extolled the antiaging properties of testicular secretions (androgens)

(28). Testicular transplants and administration of androgens have been used repeatedly as possible rejuvenating measures to delay or reverse aging, but these attempts have met with little success. Indeed, high levels of androgens in aging men may even aggravate the incidence and severity of prostate hypertrophy and cancer (Chapter 18).

Effects of DHEA replacement therapy have been examined in animals. Long-term DHEA administration in old mice has reduced the incidence of mammary cancer, has increased survival, and has delayed the onset of immune dysfunction

(29). DHEA administration also leads, in animals, to decreased

BOX 2 Feedback Mechanisms Applicable to Hypothalamo-Pituitary-Endocrine Axes and the

Portal Pituitary Blood Vessels

Hypothalamo-pituitary-endocrine axes use feedback signals to regulate their secretory activity around a set-point value necessary for homeostasis. The set-point is maintained by negative feedbacks operating in a manner similar to an engineering control system with a set-point, a controlling element, a variable element, an integrator, and a feedback signal.

In almost all physiologic systems, if a discrepancy arises between the set-point and the variable element, an error signal is delivered to the controlling element to produce an adjustment in the direction opposite to the original deviation from the set-point. This type of control system, in which a variable provides a signal for compensatory reduction in the value of the variable, is referred to as a negative feedback mechanism. In the case of the hypothalamo-pituitary-adrenal axis, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoid secretions are inter-regulated by feedbacks operating at each level. Low blood glucocorticoid levels increase CRH secretion and CRH stimulates ACTH release, which, in turn, stimulates adrenal cortex glucocorticoid secretion. High levels of blood glucocorticoid levels inhibit CRH and ACTH secretion and, consequently, decrease adrenal glucocorticoid secretion. In each case, the needed result is the return of glucocorticoid levels to the original "set-point" level.

Signals are relayed from one component of the axis to the other and from the periphery to the axis by short- and long-term loops. The short-term-loop feedback signals are carried through the portal blood vessels from the hypothalamus to the pituitary and vice versa (by retrograde flow). In the long-term loop, feedback signals are relayed from the peripheral endocrine gland and the target tissues to the pituitary and the hypothalamus through the general blood circulation.

Portal pituitary vessels represent a direct vascular link between the hypothalamus and the anterior pituitary. On the ventral surface of the hypothalamus, capillary loops from the carotid arteries and the circle of Willis form a vascular plexus that carries blood down the pituitary stalk to the capillaries of the anterior pituitary. This arrangement constitutes a blood portal system beginning and ending in capillaries without going through the heart and general circulation. Hypothalamic hypophysiotropic hormones are carried without dilution in the peripheral blood, directly to the anterior pituitary where they stimulate synthesis and release of the pituitary hormones.

food intake and body weight loss. This suggests that, despite its minor anabolic activity, DHEA may act in a manner similar to caloric restriction in extending the life span and in retarding tumorigenesis and immunosenescence (30-32) (Chapter 23).

Mineralocorticoids

Secretion, blood levels, and clearance rates of aldosterone decrease in the elderly (22). This decrease has been attributed to a declining adrenergic receptor activity (33); yet, the persistence of normal plasma electrolyte balance despite lower aldosterone levels demonstrates the efficiency of compensatory mechanisms even in old age (22). Impaired conservation of urinary sodium, which may occur in old age (Chapter 18), has been attributed to defects in the renin-angiotensin-aldosterone axis (34). While renin concentrations remain stable or decline with advancing age, plasma aldosterone levels decline. Reduced aldosterone levels have been attributed not only to the decrease in renin (when renin declines do occur) (35), but also to the reduced activity of biosynthetic enzymes for the hormone (as well as to the reduced number of calcium channels) (35,36).

Adrenal Steroid Receptors

The classical view of the mechanism of action of adrenal steroids is that adrenal steroids exert their cellular and molecular actions by binding to cytoplasmic (cytosolic) and nuclear receptors and that the degree of cellular responsiveness is directly proportional to the number of occupied receptors. The hormone-receptor complexes are then translocated to nuclear receptor sites in the nucleus where they modify gene expression (Fig. 7). The ensuing action occurs with a lag time lasting hours or days. It is now recognized that hormone-receptor responses are mediated, in addition to genomic mechanisms, by nongenomic mechanisms. Nongenomic mechanisms are characterized by rapid-onset actions that are mediated through binding of the hormone to membrane receptors, which, in turn, activate second messengers and various signal transduction cascades (37).

Adrenocortical steroid receptors are members of the steroid hormone/nuclear receptor family comprised of the vitamin D receptor, retinoid receptor, and thyroid hormone receptor, as well as a number of so-called "orphan" receptors (because their ligand and function are not well identified) (38-40). All classical steroid receptors (androgen, AR; estrogen, ER; glucocorticoid, GR; mineralocorticoid, MR; and progesterone, PR) are phos-phoproteins that, in the absence of the activating signal, are

associated with heat shock proteins (HSPs) (41). They all act as transcriptional regulatory proteins and are able to interact with select target genes (40-42).

Numerous mechanisms account for this selectivity, such as interaction with DNA-bound transcription factors, the presence of chaperones, phosphorylation, and subnuclear trafficking pathways that facilitate receptor scanning of the genome (37-43). Several steroid receptors can be activated in the absence of the hormone. This is the case of ERs that bind competitively to antagonist or agonist nonsteroidal molecules (i.e., selective estrogen receptor modulators, Chapter 10), but this does not seem to be the case for glucocorticoids (43) despite data on the binding of the antagonist RU486 (44). The finding that some of the receptors may be activated by signal transduction pathways in the absence of the specific hormone, although not immediately applicable to adrenocortical receptors, may be worth pursuing in future studies considering the current progress in our understanding of the role of coactivators and corepressors in modulating action of estrogen and progesterone receptors (44,45).

All molecular events in the hormone-cellular response pathway subsequent to receptor binding are subject to alteration with age, although the nature and magnitude of these age-related changes are variable depending on the hormone, the target cell, and the animal species. Overall, the concentration of corticosteroid receptors decreases either in early adulthood or during senescence (46). For example, in the rat brain, glucocorticoid receptors are detectable on day 17 of gestation, the receptors increase gradually after birth to adult levels by 15 days of postnatal age, but then are significantly reduced in aged animals (24-months-old) (47). The concentration of cytosolic corticosterone receptors in the primary glucocorticoid-concentrating region of the brain, the hippocampus, decreases with aging, with no change in receptor affinity or capacity for nuclear translocation (47). Some of the receptor physicochemical properties (e.g., activation, transformation) seem to be more susceptible to aging than the number of receptors. Such age-related changes have been reported in glucocorticoid receptors in liver, in skeletal muscle, and in the cerebral hemisphere. Aging changes in corticosteroid receptors that alter the responsiveness of target cells and molecules to hormones may contribute to the decline in the effectiveness of adrenocortical responses to stress.

■ Regulation of Adrenocortical Secretion

As illustrated in Figure 8, circulating levels of adrenocortical hormones depend on a hierarchy of regulation, from the hypothalamus to the pituitary, to the adrenal gland (Box 2) and, ultimately, to the target tissues, cells, and molecules. With aging and under conditions of stress, a disruption of this complex regulatory system at one or more levels may result in failure of homeostasis and adaptation.

CRH, a polypeptide released from neurons in the median eminence of the hypothalamus, is transported via the portal system to the corticotropes of the anterior pituitary, where CRH stimulates synthesis and release of the ACTH. ACTH, a protein released from the anterior pituitary, stimulates cells of the two inner zones of the adrenal cortex to synthesize and release the glucocorticoids and sex hormones (Fig. 3). Thus, after ablation of the pituitary, these two zones atrophy, and the circulating levels of the corresponding hormones decrease. Conversely, in tumors of the pituitary in which ACTH levels are increased (as may occur in Cushing's disease), the two adrenocortical zones hypertrophy, and the hormonal levels increase (48).

ACTH is secreted in bursts throughout the 24-hour day, with the pulses being most frequent in the early morning and least frequent in

FIGURE 8 Diagram of the relationships among hypothalamus, pituitary, and target tissues. The neuroendocrine cells of the hypothalamus secrete both (1) hypophysiotropic hormones that are carried by a local portal system directly to the anterior pituitary where they stimulate the synthesis and release of anterior pituitary hormones, and (2) hormones that are carried to the posterior pituitary and released from there into the general circulation. Major hypophysiotropic hormones include GnRH, CRH, GHRH, GHIH or somatostatin, PRH, PIH, and TRH. The hypothalamic hormones that are carried to the posterior pituitary include ADH or vasopressin and oxytocin. The arrows indicate the presence of regulatory feedbacks between the circulating levels of the hormones and their release from the hypothalamic neuroendocrine cells. Abbreviation: CRH, corticotropin-releasing hormone; GHIH, growth hormone-inhibiting hormone; GHRH, growth hormone-releasing hormone; PIH, prolactin-inhibiting hormone; PRH, prolactin-releasing hormone; TRH, thyrotropin-releasing hormone; ADH, antidiuretic hormone; GnRH, gonadotropins releasing hormones.

the evening. The resulting circadian (diurnal) rhythm in cortisol secretion is largely preserved during aging in humans, but there may be a modest flattening and shift of the diurnal rhythm. Regardless, sustained nighttime Cortisol levels (i.e., a reduced nocturnal drop in Cortisol levels compared with daytime values) have been correlated with (i) reduced renal clearance of the hormone (Chapter 18), (ii) reduced muscle mass and generally reduced basal metabolism (Chapter 24), and (iii) alterations in sleep patterns and insomnia (Chapter 7).

In addition to ACTH, the adrenal cortex is stimulated to secrete glucocorticoids by the action of the antidiuretic hormone (ADH), one of the two hormones of the posterior pituitary. The major action of ADH is to stimulate retention of water by the kidney in which urine becomes concentrated and its volume decreases (Chapter 18). Other functions of ADH include elevation of arterial blood pressure (hence the alternative name of vasopressin) and maintenance of blood homeostasis. ADH also has some metabolic actions and causes glycogenolysis in the liver. In relation to the adrenal cortex, ADH increases ACTH secretion by stimulation of the corticotropes (pituitary cells secreting corticosteroids). Lastly, a variety of stimuli increase ADH secretion, such as pain, nausea, stress, some emotions, and some drugs.

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