U The Adrenal Medulla

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The adrenal medulla is part of the sympathetic division of the autonomic nervous system, and, as such, it functions in unison with the other sympathetic structures. The main secretions of the adrenal medulla are E, NE, and, to a lesser extent, dopamine (DA) (Fig. 3). These chemicals are derived from the amino acid tyrosine and are chemically classified as catecholamines. NE also acts as a neurotransmitter in the central nervous system (CNS).

The adrenal medulla is interrelated anatomically and functionally with the adrenal cortex by a rich vascular network in which blood flowing from the cortex to the medulla provides high concentrations of glucocorticoids which induce in the medulla some of the enzymes for catecholamine synthesis [e.g., the enzyme phenylethanolamine-N-methyltransferase (PNMT)]. NE is formed by hydroxylation and decarboxylation of thyrosine, and E is formed by methylation of NE by the enzyme PNMT. In addition, glucocorticoids have some metabolic interaction with medullary hormones (e.g., mobilization of free fatty acids in emergency situations). Major actions of the catecholamines are summarized in Figure 9, and mechanisms of cellular stimulation are summarized in Figure 10. The catechol-amines, like other transmitters, are released at the synaptic cleft where their actions are terminated by three mechanisms: (i) they bind to the postsynaptic receptors to stimulate the target cell; (ii) they bind to presynaptic receptors for reuptake into the presynaptic cell; and (iii) they are metabolized by the enzymes monoamine oxidase and catechol-O-methyltransferase (Chapter 6, Fig. 6.11). Thus, the efficiency of neurotransmission depends on both the release and the removal of the chemical transmitter at the synapse.

The autonomic nervous system is comprised of sympathetic and parasympathetic divisions, and its dysfunction is a well recognized, although poorly understood, consequence of old age. One of the anatomical characteristics of the autonomic sympathetic division is its organization into a paravertebral sympathetic ganglion chain that, under emergency conditions of stress, can discharge as a unit, as in "rage and fright," when sympathetically innervated structures are stimulated simultaneously over the entire body (Fig. 11). This emergency response causes heart rate to accelerate, blood pressure to increase, bronchioles and pupils to dilate, and many other changes (Table 3). The contribution of the adrenal medulla to "the emergency function" of the sympatho-adrenal system involves the perception of stress and functional responses to it. Although the adrenal medulla is not essential for life under nonstress conditions, as its absence may be relatively well compensated for by activation of other sympathetic neurons, it is indispensable under stress conditions.

U Variability of Changes with Aging

The structure and function of autonomic neurons appear to be altered with aging. Major structural changes include swelling of axonal neurons with neurofilament aggregates, accumulation of

FIGURE 9 Major actions of adrenal catecholamines, E and NE. Both E and NE act on a and p receptors, with NE having a greater affinity for a-adrenergic receptors and E- for p-adrenergic receptors. Abbreviations: E, epinephrine; NE, norepinephrine.

lipofuscin, and decreased catecholamine fluorescence. These structural changes are associated with dysfunction of body temperature, bowel motility, cardiovascular maintenance (also partly regulated by parasympathetic inputs), blood pressure, water and electrolyte distribution, and energy metabolism. Several studies indicate that basal sympathetic activity increases in some elderly individuals, and the increase may be associated with dysregulation of the ability of the sympathetic nervous system to respond to a variety of challenges (49,50). Under basal conditions, in humans, plasma levels and urinary excretion of E and NE are highly variable. With aging, these hormones may do the following:

U Remain unchanged

U Show a reduction in absolute and average circadian amplitude

U Show an increase, with the increase being greater after standing and physical exercise

Elevation of plasma and urinary catecholamines, reported after a variety of stimuli, has been interpreted as a compensatory reaction to the apparently increasing refractoriness with

Hurricane Quadrants
FIGURE 10 Schematic diagram of the action of catecholamines, E and NE, in a target cell. Abbreviations: E, epinephrine; NE, norepinephrine; ATP! adenosine triphosphate; cAMP cyclic adenosine monophosphate; GTP guanosine triphosphate; PO4.

aging (perhaps due to receptor downregulation) of target tissues to catecholamines (33,49-52). However, the apparent increase in NE plasma levels does not occur with all stimuli, and, additionally, the time it takes to return to baseline levels is prolonged in the elderly. Also, NE and E often show differential responses. For example, in an elderly subject during a mental stress test, plasma NE might be elevated, whereas plasma E might stay stable. Given the wide distribution of NE throughout the sympathetic nervous system and CNS, in contrast to the circumscribed localization of E in the medulla, the differential response of NE and E suggests hyperactivity of the sympathetic system in general, rather than that of the adrenal medulla in particular.

■ Target Differential Responsiveness

In the elderly, high levels of catecholamines may be due to either a higher release from the adrenal medulla or a reduction in peripheral clearance. One proposed explanation for the overall increase of sympatho-adrenal activity with aging is an increased refractoriness (or decreased sensitivity) of target tissues to catecholamines due to alterations in transport and binding, and, therefore, the need for enhanced NE and E secretion. A decrease in the number of adrenergic receptors with aging has been reported in some organs and cells (e.g., cerebellum, adipocytes) and a decrease in receptor affinity has been reported in others (e.g., lung), but in many cases, changes are not observed. Although current findings do not support the view that the number of receptors decreases with aging, several concomitant factors (e.g., aging-associated decrease in cell membrane fluidity) may mask true declines.

NE and E both act on a and b receptors, but NE has a greater affinity for a adrenergic receptors, whereas E has a greater affinity for b adrenergic receptors. Both a and b receptors are G protein receptors that span the cell membrane; G proteins are nucleotides, regulatory proteins that bind to GTP (guanosine triphosphate protein) (Fig. 10). Clinical and experimental observations have been conducted primarily of b1 receptors and the other b2 and a adrenergic receptors. An important finding is that the responsiveness of the receptors to adrenergic stimulation depends on the type of tissue in which the receptors are located (47,51,52). Decreased responsiveness may be found in the diminished efficiency of hemodynamic and cardiovascular responses to changes in posture (Chapter 7) and the slower dark adaptation of pupil size (Chapter 8). In contrast, increased responsiveness occurs in those organs and tissues regulating blood pressure. It is worthwhile to recall here that the loss of dopaminergic neurons in the cerebral basal ganglia is a major cause of Parkinson's disease (Chapter 6). Other hormones, such as thyroid hormones, that are known to affect catecholamine metabolism, may also increase the effects of catecholamines on blood pressure (Chapter 12).

■ THE PITUITARY GLAND

The pituitary gland (also called the hypophysis) regulates, through the secretion of its tropic hormones, the activity of several peripheral endocrine organs (adrenal cortex, thyroid, gonads) and other target tissues (e.g., bones, muscles). In humans, the pituitary gland is divided into two lobes, anterior and posterior. A third part, between the two, the intermediate lobe, is structurally and functionally rudimentary in humans. Together with cells dispersed in the anterior lobe, the intermediate lobe secretes melanotropin, which is related to skin and hair pigmentation (Chapter 21) and g lipotropin, whose function is still little known.

The pituitary has close functional ties with the hypothalamus and, indirectly, other CNS centers, especially the limbic system. The hypothalamus produces a number of peptides, the hypophysiotropic hormones, that are carried directly to the anterior pituitary by a local portal system (Fig. 8). The hypophysio-tropic hormones stimulate or inhibit the synthesis and release of the anterior pituitary hormones. Hormones of the anterior pituitary and their major functions are listed in Figure 12. The hypothalamic neuroendocrine cells secrete two peptide hormones that are carried by axonal flow to the posterior pituitary where they are stored until they are released into the circulation. Hormones of the posterior pituitary and their major actions are illustrated in Figure 13. The hypothalamus is also involved in the regulation of the autonomic nervous system and of a number of behaviors (e.g., sex, fear, rage) (53,54).

■ Structural Changes

The pituitary gland changes little with aging. Although changes have been described, it is still unclear if these changes involve the gland globally or involve localized parts of the gland.

In the anterior lobe, changes with aging are relatively few and include cellular changes typical of aging cells (e.g., accumulation of lipofuscin). Tumor incidence, primarily pro-lactinomas [tumors secreting prolactin (PRL)], increases with aging in rats and mice, and more so female. In the posterior lobe, studies in old rodents reveal a number of changes, such as decreased size and number of neurosecretory granules, reduced number of hormone receptors, increased autophagic activity, increased perivascular space, decline in cell volume, and

FIGURE 11 Diagram of the efferent pathways of the autonomic nervous system. The two systems, the sympathetic and the parasympathetic, often act antagonistically: for example, sympathetic stimulation usually accelerates the speed of cardiac contraction and increases blood pressure, whereas parasympathetic stimulation decreases both of them. Stimuli from the sympathetic neurons, located in the lateral columns of the spinal cord, are relayed to the paravertebral sympathetic ganglion chain and from the ganglia to the peripheral viscera. In the case of stress, they are activated simultaneously and generate those multiple responses necessary for survival and adaptation. Other sympathetic neurons include the (1) superior, (2) middle, (3) inferior, cervical ganglia (4), celiac ganglion (5), superior mesenteric ganglion (6), inferior mesenteric ganglion. The parasympathetic neurons are located proximal to the organs they innervate and stimulate them individually. They include the cranial ganglia that supply the visceral structures in the head through the (a) III, (b) VII, and (c) IX cranial nerves, and to the organs of the thorax and upper abdomen by the X cranial nerve (vagus). The pelvic nerve originates in the sacral spinal cord and supplies the lower abdomen viscera and the sex organs.

FIGURE 11 Diagram of the efferent pathways of the autonomic nervous system. The two systems, the sympathetic and the parasympathetic, often act antagonistically: for example, sympathetic stimulation usually accelerates the speed of cardiac contraction and increases blood pressure, whereas parasympathetic stimulation decreases both of them. Stimuli from the sympathetic neurons, located in the lateral columns of the spinal cord, are relayed to the paravertebral sympathetic ganglion chain and from the ganglia to the peripheral viscera. In the case of stress, they are activated simultaneously and generate those multiple responses necessary for survival and adaptation. Other sympathetic neurons include the (1) superior, (2) middle, (3) inferior, cervical ganglia (4), celiac ganglion (5), superior mesenteric ganglion (6), inferior mesenteric ganglion. The parasympathetic neurons are located proximal to the organs they innervate and stimulate them individually. They include the cranial ganglia that supply the visceral structures in the head through the (a) III, (b) VII, and (c) IX cranial nerves, and to the organs of the thorax and upper abdomen by the X cranial nerve (vagus). The pelvic nerve originates in the sacral spinal cord and supplies the lower abdomen viscera and the sex organs.

reduction in endoplasmic reticulum activity. In humans and other examined animals (e.g., cattle), such changes are rare.

n Growth Hormone, Growth Hormone-Releasing Hormone, and Somatostatin

Aging is associated with a decrease in protein synthesis of lean body mass and bone formation as well as with an increase in adiposity (fat). This association suggests the involvement of growth hormone (GH) because of its anabolic (i.e., protein synthesis promoting) and metabolic actions (Box 3). Although some studies have reported a decrease in basal levels of GH, the number of somatotropes (i.e., pituitary cells secreting GH), the pituitary content of GH, the basal plasma levels of the hormone, and its clearance remain essentially unchanged into old age.

Obesity lowers circulating GH levels in young individuals, and the presence of obesity in some elderly may contribute to the decreased GH levels. Contradictory changes in GH levels have been reported in the elderly after exposure to stimuli known to cause GH release. In rats, GH elevation after stimulation by a variety of means is less marked in old animals, and, consistent with those findings, in humans after stress, surgical trauma, exercise, and arginine stimulation, the expected increase of GH secretion is often considerably blunted or even entirely lacking (55).

TABLE 3 "Fright, Flight, or Fight" Responses to Stress

Increased blood pressure Increased heart rate Increased force of heart contraction Increased heart conduction velocity

Shift of blood flow distribution away from the skin and splanchnic regions and more to the heart, skeletal muscle, and the brain Contraction of spleen capsule (increased hematocrit i.e., increased proportion of red blood cells to whole blood volume) Increased depth and rate of respiration Mobilization of liver glycogen to glucose (glycogenolysis) Mobilization of free fatty acids from adipose tissue (lipolysis) Mydriasis (widening of pupil)

Accommodation for far vision (relaxation of ciliary muscle) Widening of palpebral fissure (eyelids wide open) Piloerection (erection of hair)

Inhibition of gastrointestinal motility and secretion, and contraction of sphincters (ringlike muscles closing an orifice) Sweating (cold sweats as skin blood vessels are constricted)

GH secretion in humans undergoes a nocturnal peak during the first four hours of sleep, coinciding with stages III and IVof slow-wave sleep. These stages are the most affected in aging (Chapter 7). Studies in older persons have shown a decrease in sleep-related GH secretion and an occasional decrease in the nocturnal peak. The latter finding has been attributed to low levels of growth hormone-releasing hormone (GHRH) and high levels of somatostatin or growth hormone-inhibiting hormone (GHIH) (56). However, the exact nature of the relationship between GH levels and sleep quality over age remains controversial (and so too does the exact nature of the relationship between GH levels and body weight over age).

The effects of GH on growth and protein metabolism depend not only on GH levels, but also on the interaction between GH and somatomedins, which are polypeptide growth factors secreted by the liver and other tissues in response to stimulation by GH. The majority of growth factors act by paracrine communication, that is, they reach their neighboring cells directly without being carried by the blood to distant targets. The principal and, in adult humans, probably the only circulating somatomedins is insulin-like growth factor-1 (IGF-1). Insulin-like growth factor-2 (IGF-2), is present and active primarily during the embryonic/fetal periods. As noted in Chapter 3, suppression of IGF-1 receptors (IGF-1Rs) and, hence, suppression of the actions of this hormone, lengthens the life span in worms, flies, and mice, and has several concomitant actions such as increasing resistance to stress (Chapter 3). In humans, IGF-1 levels decrease with old age, but the functional consequences of their decrease still remain controversial.

FIGURE 12 Diagrammatic representation of the major hormones of the anterior pituitary and the endocrine glands and tissues on which these hormones act. Note that the regulation of hormone levels depends on negative feedback (Box 2) except for the positive feedback of estrogens on LH secretion from the pituitary (Chapter 10). Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone (women); ICSH, interstitial cells-stimulating hormone (men); PL, prolactin; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic hormone; GH, growth hormone; IGF-1, insulin-like growth factor-1.

FIGURE 12 Diagrammatic representation of the major hormones of the anterior pituitary and the endocrine glands and tissues on which these hormones act. Note that the regulation of hormone levels depends on negative feedback (Box 2) except for the positive feedback of estrogens on LH secretion from the pituitary (Chapter 10). Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone (women); ICSH, interstitial cells-stimulating hormone (men); PL, prolactin; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic hormone; GH, growth hormone; IGF-1, insulin-like growth factor-1.

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