Ebook Endocrine physiology (4th edition): Part 2

(BQ) Part 2 book Endocrine physiology presents the following contents: Adrenal gland, endocrine pancreas, male reproductive system, female reproductive system, endocrine integration of energy and electrolyte balance.

6 Adrenal Gland OBJECTIVES Y Y Y Y Y Y Y Y Y Y Identify the functional anatomy and zones of the adrenal glands and the principal hormones secreted from each zone Describe and contrast the regulation of synthesis and release of the adrenal steroid hormones (glucocorticoids, mineralocorticoids, and androgens) and the consequences of abnormalities in their biosynthetic pathways Understand the cellular mechanism of action of adrenal cortical hormones and identify their major physiologic actions, particularly during injury and stress Identify the major mineralocorticoids, their biologic actions, and their target organs or tissues Describe the regulation of mineralocorticoid secretion and relate this to the regulation of sodium and potassium excretion Identify the causes and consequences of oversecretion and undersecretion of glucocorticoids, mineralocorticoids, and adrenal androgens Identify the chemical nature of catecholamines and their biosynthesis and metabolic fate Describe the biologic consequences of sympatho-adrenal medulla activation and identify the target organs or tissues for catecholamine effects along with the receptor types that mediate their actions Describe and integrate the interactions of adrenal medullary and cortical hormones in response to stress Identify diseases caused by oversecretion of adrenal catecholamines The adrenal glands are important components of the endocrine system They contribute significantly to maintaining homeostasis particularly through their role in the regulation of the body’s adaptive response to stress, in the maintenance of body water, sodium and potassium balance, and in the control of blood pressure The main hormones produced by the human adrenal glands belong to different families based on their structure; these are the steroid hormones including the glucocorticoids, mineralocorticoids and androgens; and the catecholamines norepinephrine and epinephrine The adrenal gland, like the pituitary, has different embryologic origins, which as we will discuss, influence the mechanisms that control hormone production by each of the components 129 130 / CHAPTER FUNCTIONAL ANATOMY AND ZONATION The adrenal glands are located above the kidneys They are small, averaging 3–5 cm in length, and weigh 1.5–2.5 g and as mentioned above, consist of different components; the cortex and the medulla (Figure 6–1), each with a specific embryologic origin The outer adrenal cortex is derived from mesodermal tissue Cortex Zona glomerulosa Aldosterone Zona fasciculata Cortisol & androgens Medulla Zona reticularis Epinephrine & norepinephrine Cortex Medulla Figure 6–1 Adrenal glands The adrenal glands are composed of a cortex and a medulla, each derived from a different embryologic origin The cortex is divided into 3 zones: reticularis, fasciculata, and glomerulosa The cells that make up the zones have distinct enzymatic capacities, leading to a relative specificity in the products of each of the adrenal cortex zones The adrenal medulla is made of cells derived from the neural crest ADRENAL GLAND / 131 Adrenal cortex (steroid) hormones CH2OH CH2OH C=O C=O .OH HO HO O O O HCO HO Dehydroepiandrosterone Cortisol Aldosterone Glucocorticoid Mineralocorticoid Androgen Adrenal medulla hormones (Catecholamines) HO HO HO H C H CH2 OH Epinephrine N H C HO CH3 CH2 OH Catechol group NH2 Amino group Norepinephrine Figure 6–2 Adrenal gland hormones The principal hormones synthesized and released by the adrenal cortex are the glucocorticoid cortisol, the mineralocorticoid aldosterone, and the androgen dehydroepiandrosterone (DHEA) These steroid hormones are derived from cholesterol The principal hormones synthesized and released by the adrenal medulla are the catecholamines epinephrine and norepinephrine These catecholamines are derived from L-tyrosine and accounts for approximately 90% of the weight of the adrenals The cortex synthesizes the adrenal steroid hormones called glucocorticoids, mineralocorticoids, and androgens (eg, cortisol, aldosterone, and dehydroepiandrosterone [DHEA]) in response to hypothalamic-pituitary-adrenal hormone stimulation (Figure 6–2) The inner medulla is derived from a subpopulation of neural crest cells and makes up the remaining 10% of the mass of the adrenals The medulla synthesizes catecholamines (eg, epinephrine and norepinephrine) in response to direct sympathetic (sympatho-adrenal) stimulation Several features of the adrenal glands contribute to the regulation of steroid hormone and catecholamine synthesis, including the architecture, blood supply, and the enzymatic machinery of the individual cells Blood supply to the adrenal glands is derived from the superior, middle, and inferior suprarenal arteries 132 / CHAPTER Branches of these arteries form a capillary network arranged so that blood flows from the outer cortex toward the center area, following a radially oriented sinusoid system This direction of blood flow controls the access of steroid hormones to the circulation and concentrates the steroid hormones at the core of the adrenals, thus modulating the activities of enzymes involved in catecholamine synthesis The venous drainage of the adrenal glands involves a single renal vein on each side; the right vein drains into the inferior vena cava and the left vein drains into the left renal artery HORMONES OF THE ADRENAL CORTEX The adrenal cortex consists of zones that vary in both their morphologic and functional features and thus, the steroid hormones they produce (see Figure 6–1) • The zona glomerulosa contains abundant smooth endoplasmic reticulum and is the unique source of the mineralocorticoid aldosterone • The zona fasciculata contains abundant lipid droplets and produces the glucocorticoids, cortisol and corticosterone, and the androgens, DHEA and DHEA sulfate (DHEAS) • The zona reticularis develops postnatally and is recognizable at approximately age years; it also produces glucocorticoids and androgens The products of the adrenal cortex are classified into general categories: glucocorticoids, mineralocorticoids, and androgens (see Figure 6–2) which reflect the primary effects mediated by these hormones This will become clear when their individual target organ effects are discussed Chemistry and Biosynthesis Steroid hormones share an initial step in their biosynthesis (steroidogenesis), which is the conversion of cholesterol to pregnenolone (Figure 6–3) Cholesterol used for steroid hormone synthesis can be derived from the plasma membrane or from the steroidogenic cytoplasmic pool of cholesteryl-esters Free cholesterol is generated by the action of the enzyme cholesterol ester hydrolase Cholesterol is transported from the outer mitochondrial membrane to the inner mitochondrial membrane, followed by the conversion to pregnenolone by P450scc enzyme; an inner mitochondrial membrane present in all steroidogenic cells This is considered the rate-limiting step in steroid hormone synthesis and requires the STeroid Acute Regulatory (STAR) protein STAR is critical in mediating cholesterol transfer to the inner mitochondrial membrane and the cholesterol side chain cleavage enzyme system This conversion of cholesterol to pregnenolone is the first step in a sequence of multiple enzymatic reactions involved in the synthesis of steroid hormones Because the cells that constitute the different sections of the adrenal cortex have specific enzymatic features, the synthetic pathway of steroid hormones will result in preferential synthesis of glucocorticoids, mineralocorticoids, or androgens, depending on the region ADRENAL GLAND / 133 Cholesterol Pregnenolone Progesterone 11-deoxycorticosterone 17-alpha hydroxypregnenolone 17-alpha hydroxyprogesterone Corticosterone 11-deoxycortisol Androstenedione Aldosterone Cortisol Testosterone Mineralocorticoid Estradiol-17β Dehydroepiandrosterone 17-alpha hydroxyprogesterone 11-deoxycortisol Androgens Androstenedione Cortisol Testosterone Glucocorticoid Estradiol-17β Figure 6–3 Adrenal steroid hormone synthetic pathway Cholesterol is converted to pregnenolone by the cytochrome P450 side-chain cleavage enzyme Pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydrogenase or to 17α-OH-pregnenolone by 17α-hydroxylase Thereafter, 17α-OH-pregnenolone is converted to 17α-OH-progesterone by 3β-hydroxysteroid dehydrogenase, 17α-OHprogesterone is converted to 11-deoxycortisol by the enzyme 21-hydroxylase, and 11-deoxycortisol is converted to cortisol by 11β-hydroxylase In addition, 17α-OH-progesterone can be converted to androstenedione Both 17α-OHpregnenolone and 17α-OH-progesterone can be converted to the androgens dehydroepiandrosterone (DHEA) and androstenedione, respectively DHEA is converted to androstenedione Cells in the zona glomerulosa not have 17α-hydroxylase activity Therefore, pregnenolone can be converted only into progesterone The zona glomerulosa possesses aldosterone synthase activity, and this enzyme converts deoxycorticosterone to corticosterone, corticosterone to 18-hydroxycorticosterone, and 18-hydroxycorticosterone to aldosterone, the principal mineralocorticoid produced by the adrenal glands The line denotes which steps occur outside the adrenal glands 134 / CHAPTER GLUCOCORTICOID HORMONE SYNTHESIS Cells of the adrenal zona fasciculata and zona reticularis synthesize and secrete the glucocorticoids cortisol or corticosterone through the following pathway (see Figure 6–3) Pregnenolone exits the mitochondria and is converted to either progesterone or 17α-OH-pregnenolone Conversion of pregnenolone to progesterone is mediated by 3β-hydroxysteroid dehydrogenase Progesterone is converted to 11-deoxycorticosterone by 21-hydroxylase; then 11-deoxycorticosterone is converted to corticosterone by 11β-hydroxylase Conversion of pregnenolone to 17α-OH-pregnenolone is mediated by 17α-hydroxylase; 17α-OH-pregnenolone is converted to 17α-OH-progesterone by 3β-hydroxysteroid dehydrogenase; 17α-OH-progesterone is converted to either 11-deoxycortisol or androstenedione The enzyme 21-hydroxylase mediates the conversion of 17α-OH-progesterone to 11-deoxycortisol, which is then converted to cortisol by 11β-hydroxylase Both 17α-OH-pregnenolone and 17α-OH-progesterone can be converted to the androgens DHEA and androstenedione, respectively DHEA is converted to androstenedione by 3β-hydroxysteroid dehydrogenase MINERALOCORTICOID HORMONE SYNTHESIS The adrenal zona glomerulosa cells preferentially synthesize and secrete the mineralocorticoid aldosterone The cells of the zona glomerulosa not have 17α-hydroxylase activity Therefore, pregnenolone can be converted only to progesterone The zona glomerulosa possesses aldosterone synthase activity, and this enzyme converts 11-deoxycorticosterone to corticosterone, corticosterone to 18-hydroxycorticosterone, and 18-hydroxycorticosterone to aldosterone, the principal mineralocorticoid produced by the adrenal glands ADRENAL ANDROGEN HORMONE SYNTHESIS The initial steps in the biosynthesis of DHEA from cholesterol are similar to those involved in glucocorticoid and mineralocorticoid hormone synthesis The product of these initial enzymatic conversions, pregnenolone, undergoes 17α-hydroxylation by microsomal P450c17 and conversion to DHEA 17α-pregnenolone can also be converted to 17α-OH-progesterone, which in turn can be converted to androstenedione in the zona fasciculata Regulation of Adrenal Cortex Hormone Synthesis As already mentioned, the initial steps in the biosynthetic pathways of steroid hormones are identical regardless of the steroid hormone synthesized The production of the hormones can be regulated acutely and chronically Acute regulation results in the rapid production of steroids in response to immediate need and occurs within minutes of the stimulus The biosynthesis of glucocorticoids to combat stressful situations and the rapid synthesis of aldosterone to rapidly regulate blood pressure are examples of this type of regulation Chronic stimulation, such as that which occurs during prolonged starvation and chronic disease, involves the synthesis of enzymes involved in steroidogenesis to enhance the synthetic capacity of the cells Although both glucocorticoids and mineralocorticoids are released in ADRENAL GLAND / 135 response to stressful conditions, the conditions under which they are stimulated differ, and the cellular mechanisms responsible for stimulating their release are different Thus, the mechanisms involved in the regulation of their release differ and are specifically controlled as described below GLUCOCORTICOID SYNTHESIS AND RELEASE The pulsatile release of cortisol is under direct stimulation by adrenocorticotropic hormone (ACTH) released from the anterior pituitary ACTH, or corticotropin, is synthesized in the anterior pituitary as a large precursor, proopiomelanocortin (POMC) POMC is processed post-translationally into several peptides, including corticotropin, β-lipotropin, and β-endorphin, as presented and discussed in Chapter (see Figure 3–4) The release of ACTH is pulsatile with approximately 7–15 episodes per day The stimulation of cortisol release occurs within 15 minutes of the surge in ACTH An important feature in the release of cortisol is that in addition to being pulsatile, it follows a circadian rhythm that is exquisitely sensitive to environmental and internal factors such as light, sleep, stress, and disease (see Figure 1–8) Release of cortisol is greatest during the early waking hours, with levels declining as the afternoon progresses As a result of its pulsatile release, the resulting circulating levels of the hormone vary throughout the day, and this has a direct impact on how cortisol values are interpreted according to the timing of blood sample collection ACTH stimulates cortisol release by binding to a Gαs protein–coupled plasma membrane melanocortin receptor on adrenocortical cells, resulting in activation of adenylate cyclase, an increase in cyclic adenosine monophosphate, and activation of protein kinase A (see Figure 3–4) Protein kinase A phosphorylates the enzyme cholesteryl-ester hydrolase, increasing its enzymatic activity; leading to increased cholesterol availability for hormone synthesis In addition, ACTH activates and increases the synthesis of STAR, the enzyme involved in the transport of cholesterol into the inner mitochondrial membrane Therefore, ACTH stimulates the initial and rate-limiting steps in steroid hormone synthesis The release of ACTH from the anterior pituitary is regulated by the hypothalamic peptide corticotropin-releasing hormone (CRH) discussed in Chapter Cortisol inhibits the biosynthesis and secretion of CRH and ACTH in a classic example of negative feedback regulation by hormones Th is closely regulated circuit is referred to as the hypothalamic-pituitary-adrenal (HPA) axis (Figure 6–4) METABOLISM OF GLUCOCORTICOIDS Because of their lipophilic nature, free cortisol molecules are mostly insoluble in water Therefore, cortisol is usually found in biologic fluids either in a conjugated form (eg, as sulfate or glucuronide derivatives) or bound to carrier proteins (noncovalent, reversible binding) The majority of cortisol is bound to glucocorticoidbinding α2-globulin (transcortin or cortisol-binding globulin [CBG]), a specific carrier of cortisol Normal levels of CBG average 3–4 mg/dL and are saturated 136 / CHAPTER Stress Hypothalamus CRF Exogenous glucocorticoids ACTH Anterior pituitary gland Adrenal gland Negative feedback Cortisol Bloodstream Figure 6–4 Hypothalamic-pituitary-adrenal axis Corticotropin-releasing factor (CRF), produced by the hypothalamus and released in the median eminence, stimulates the synthesis and processing of proopiomelanocortin, with resulting release of proopiomelanocortin peptides that include adrenocorticotropic hormone (ACTH) from the anterior pituitary ACTH binds to the melanocortin-2 receptor in the adrenal gland and stimulates the cholesterol-derived synthesis of adrenal steroid hormones Glucocorticoids released into the systemic circulation exert negative feedback inhibition of corticotropin-releasing factor (CRF) and ACTH release from the hypothalamus and pituitary, respectively, in a classic example of negative feedback hormone regulation This closely regulated circuit is referred to as the hypothalamicpituitary-adrenal (HPA) axis ADRENAL GLAND / 137 with cortisol levels of 28 μg/dL The hepatic synthesis of CBG is stimulated by estrogen and decreased by hepatic disease (cirrhosis) Approximately 20%–50% of bound cortisol is bound nonspecifically to plasma albumin A small amount (