Adrenal Gland

16.3.1 Introduction

The adrenal gland located cranially on each kidney consists of an outer cortex and inner medulla, functions as two dis­crete endocrine glands with distinct embryological origins and endocrine activities.

Fig. 16.12 Adrenal gland and its histology. [The adrenal gland comprises two distinct regions, i.e., cortex and medulla, attributed to secrete corticosteroids and catecholamines, respectively. The adrenal cortex has three layers, which are functionally and histologically different]

metabolism, electrolyte balance, and antagonize stressors. Hence, appropriate functioning of the adrenal gland is essen­tial for an animal’s survival.

16.3.2 Adrenal Cortex: Histology

The adrenal cortex has three different histological zones, namely: the outer zona glomerulosa, the central zona fasciculata, and the inner zona reticularis (Fig. 16.12). The presence of zone-specific hydroxylases in adreno-cortical cells helps in converting cholesterol to different classes of zone-specific steroid hormones. The corticosteroids are not stored in the cortical cells but their synthesis is rapidly stimulated in response to specific stimuli (Table 16.3).

16.3.3 MechanismofSynthesis

of Corticosteroids

The cholesterol required for the synthesis of corticosteroids is primarily derived from the circulation although a smaller proportion is derived from the de novo synthesis. The abun­dant lipid stores, mitochondria, and smooth endoplasmic reticulum are the major characteristics of cortical cells.

16.3.4 Zona Glomerulosa: Site of Synthesis for Mineralocorticoids

The zona glomerulosa is a thin outermost layer with colum­nar cells arranged in irregular cords. They are responsible for the secretion of a class of hormones known as mineralocorticoids, which are implicated in regulating major electrolytes (Na⁺, K⁺) present in the blood. Aldoste­rone is the potent and major mineralocorticoid secreted across different species of animals. In addition, corticoste­rone and 11-deoxycorticosterone have slight mineralocorti­coid activity. Within these cortical cells, pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydroge­nase (3βHSD). Then the subsequent conversion of progester­one by 21β-hydroxylase results in the production of 11-deoxycorticosterone. Further, the

11-deoxycorticosterone is converted to corticosterone by 11 β-hydroxylase. Finally, the aldosterone synthase that is present exclusively in the zona glomerulosa converts

Table 16.3 List of hormones secreted from the adrenal gland, their chemical nature, effect, and half-life in circulation

Fig.

corticosterone to aldosterone (Fig. 16.13). The enzymatic activity of aldosterone synthase is regulated by angiotensin-II. Furthermore, the inability of zona glomerulosa cells to secrete cortisol or other androgens is due to the absence of 17 α-hydroxylase.

16.3.4.1 MechanismofAction

Aldosterone exerts its biological effects mainly by binding to intracytoplasmic mineralocorticoid receptors (MR). Once the hormone-receptor complex is formed, it migrates to the nucleus and stimulates the transcription of Na⁺-K⁺ ATPase and epithelial sodium channels (ENaC) genes. Hence, the effects of aldosterone are not evident soon after its release and require a brief period. Most importantly, the principal cells (PC) and intercalated cells (IC) are recognized as the major cellular targets of aldosterone.

16.3.4.2 Biological Effects

The restoration of normal circulatory levels of Na⁺ and K⁺ by inhibiting natriuresis with a concomitant rise in potassium secretion from kidneys is regarded as the crucial biological effects. In addition, the rise in systemic circulatory volume and arterial blood pressure are secondary effects due to increased reabsorption of water from the renal tubules.

16.3.4.3 Effect on Principal Cells

The principal cells are present in the late distal tubule and effectively contribute to the reabsorption of Na⁺ and secre­tion of K⁺. The Na⁺-K⁺ ATPase located on the basolateral membrane pumps Na⁺ ions in exchange for K⁺ ions from blood, resulting in the establishment of low Na⁺ and high K⁺ concentrations inside.

16.3.4.4 Effect on Intercalated Cells

Intercalated cells (IC) are the other type of distal tubular cells affected by aldosterone. It stimulates the H⁺ ATPase/H⁺-K⁺ ATPase pumps present on the apical membrane to secrete H⁺ ions and reabsorb K⁺ ions. Thus, this particular activity of IC is critical for the excretion of H⁺ ions and imparting a regu­latory role in acid-base balance. In addition, there is an interdependency between the functioning of IC and PC.

16.3.4.5 Regulation of Secretion

Although ACTH is necessary for the production of aldoste­rone, the circulatory concentration of K⁺ ions is by far the most potent stimulator for its secretion. The angiotensin-II is the second most potent stimulator of aldosterone production. It increases the secretion of aldosterone by directly acting on the zona glomerulosa cells and by stimulating the production of ACTH from the anterior pituitary. The initiation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating the circulatory volume and arte­rial pressure. Moreover, an increase in the circulatory con­centration of Na⁺ ions suppresses the secretion of aldosterone.

Fig. 16.14 Biological effects of aldosterone [Aldosterone acts on the principal and intercalated cells in the distal convoluted tubules to increase the tubular reabsorption of Na⁺ along with water and tubular excretion of K⁺ ions.

RAS renin-Angiotensin system; Na⁺ sodium ion; K⁺ potassium ion; HCO₃ bicarbonate ion; ENaC epithelial sodium channels; H₂CO₃ car­bonic acid; CA carbonic anhydrase; BM basal membrane; LM luminal membrane; # decrease; " increase]

16.3.5 Zona Fasciculata: Site of Synthesis for Glucocorticoids

The zona fasciculata is the middle and broadest layer of adrenal cortex comprising polyhedral cells. They secrete a group of hormones known as glucocorticoids, which are implicated in regulating metabolic pathways that enable the animals to endure various stressors. The presence of 17 α-hydroxylase in fascicular cells converts pregnenolone to 17-hydroxypregnenolone. Then, it is further converted to 17-hydroxyprogesterone by the enzyme 3βHSD. Consequent action of 21β-hydroxylase results in the conversion of 17 hydroxy-progesterone to 11-deoxycortisol. Finally, the 11-deoxycortisol is converted by 11 β-hydroxylase to pro­duce cortisol, the predominant glucocorticoid in animals. Additionally, pregnenolone is converted to progesterone and further to 11-deoxycorticosterone and corticosterone, both of which are found in the circulation as minor glucocorticoids (Fig. 16.15). Cortisol then secreted will be bound to transcortin (corticosteroid-binding globulin) present in the circulation.

16.3.5.1 MechanismofAction

Glucocorticoids exert their effects on the target tissues by binding to glucocorticoid receptors (GCR) localized in the cytoplasm. Generally, the GCRs in their inactive state are bound with heat shock protein 90 (Hsp90). Upon their inter­action with glucocorticoids will result in the dissociation of Hsp90 with a simultaneous translocation of the hormone- receptor complex to the nucleus. In the nucleus, hormone- receptor complexes dimerize and bind to DNA (glucocorti­coid response element) to regulate the transcription of genes.

16.3.5.2 Biological EffectsofGlucocorticoids

The glucocorticoids have a prominent role in maintaining energy homeostasis by regulating metabolic pathways in the liver, adipose tissue, and skeletal muscles.

Fig. 16.15 Biosynthesis of glucocorticoids in zona fasciculata. [The cholesterol taken up by the fascicular cells is enzymatically converted to produce glucocorticoids such as corticosterone and cortisol. [ACTH adrenocorticotropic hormone; StAR steroidogenic acute regulatory

protein; OMM outer mitochondrial membrane; IMM inner mitochon­drial membrane; CYP11A1 cholesterol side-chain cleavage enzyme; 3βHSD 3β-hydroxysteroid dehydrogenase]

Fig. 16.16 Effects of cortisol on intermediary metabolism and its regulation of secretion [Glucocorticoids increase the catabolism of lipids and amino acids for cellular metabolism, thereby maintain a constant elevated blood glucose levels to combat stressful conditions. [CRH corticotropin-releasing hormone; ACTH adrenocorticotropic hormone; PEPCK phosphoenolpyruvate carboxykinase; G6Pase glucose 6-phosphatase; GLUT4 glucose transporter 4; FAS fatty acid synthase; ACC acetyl-CoA carboxylase (ACC); FBP fructose-1, 6-bisphosphatase; GP glycogen phosphorylase; GP glycogen synthase; HSL hormone-sensitive lipase, (-) negative feedback inhibition; IL-2 interleukin 2; IL-3 interleukin 3; IL-5 interleukin 5; GM-CSF granulocyte-macrophage colony-stimulating factor; # decrease; " increase]

16.3.5.2.1 Effect on Hepatic Metabolism

Glucocorticoids stimulate gluconeogenesis and glycogenoly­sis, respectively, by stimulating the transcription of key genes such as PEPCK and G6Pase. This helps in increased hepatic glucose production and released into the circulation. They also upregulate FAS and ACC genes, which leads to increased lipogenesis. Along with lipogenesis, simultaneous inhibition of the β-oxidation of fatty acids leads to an increase in hepatic lipid accumulation (hepatic steatosis).

16.3.5.2.2 Effect on Skeletal Muscle

Glucocorticoids inhibit the insulin secretion from β-cells, insulin-dependent uptake of glucose and amino acids by inhibiting the insulin-mediated PI3K/Akt signaling pathway. Thus, the inhibition of the PI3K/Akt pathway results in reduced glucose uptake and glycogenesis due to declined translocation of GLUT4 and downregulation of the glycogen synthase gene respectively. Furthermore, glucocorticoids increase the protein degradation by the proteasome, cathepsin-L, and ubiquitin C to produce free amino acids required for generating energy and glucose. Altogether, glucocorticoids produce a catabolic effect on skeletal muscles characterized by the exhaustion of glycogen and protein reserves.

16.3.5.2.3 EffectonAdiposeTissue

They activate hormone-sensitive lipase (HSL) in peripheral adipocytes, this leads to increased lipolysis and FFA produc­tion. In addition, they inhibit PEPCK and insulin-dependent glucose uptake to decrease triglyceride formation. Whereas, the same glucocorticoids stimulate the differentiation and hypertrophy of central adipocytes. Altogether, glucocorticoids redistribute lipids from peripherally located adipose tissues to central adipose depots, especially in the abdomen.

16.3.5.2.4 Effect on the Immune System

Glucocorticoids inhibit the production of cytokines like inter­leukin 3(IL-3), interleukin 5 (IL-5), GM-CSF which regulate maturation, differentiation, and survival of eosinophils. Their effect on inhibiting IL-2 and T-cell growth factor results in the inhibition of T cell proliferation and with a concurrent increase in T-cell apoptosis. Furthermore, glucocorticoids inhibit the migration of leucocytes by downregulating the expression of adhesion molecules and chemokines from the inflammatory site.

16.3.5.2.5 Hypothalamo-Pituitary-Adrenal (HPA

Axis)

The secretion of glucocorticoids is primarily regulated through CRH and ACTH released from the hypothalamic- pituitary axis. The release of CRH is stimulated during phys­ical stress, physiological stress, or behavioral stress. Further, the increased circulatory levels of glucocorticoids have nega­tive feedback on the secretion of CRH and ACTH. The circadian rhythm also affects the secretion of cortisol, attaining peak secretion during the early morning.

16.3.6 Zona Reticularis and Adrenal Androgens

The dehydroepiandrosterone (DHEA) and androstenedione are the two adrenal androgens secreted from the innermost zona reticularis in response to ACTH (Fig. 16.17). The 17-hydroxypregnenolone produced from cholesterol is converted by the action of 17, 20 lyase to DHEA. Further, DHEA is converted to androstenedione by 3βHSD. They bind to albumin and sex hormone-binding globulin (SHBG) in circulation. These weak adrenal androgens cannot bind to androgen receptors and require transformation to potent forms such as testosterone and dihydrotestosterone to elicit target effects. Although the amount of adrenal androgens produced in male animals is negligible, they might play a role in producing an anabolic effect on muscle mass, bone density, and estrous behavior in female animals.

Fig. 16.17 Biosynthesis of adrenal androgens. [Zona reticularis is bestowed with the production of androgens from cholesterol, which are further converted in to active or more potent forms in the gonads. [DHEA dehydroepiandrosterone; ACTH adrenocorticotropic hormone;

StAR steroidogenic acute regulatory protein; OMM outer mitochondrial membrane; IMM inner mitochondrial membrane; CYP11A1 cholesterol side-chain cleavage enzyme; 3βHSD 3β-hydroxysteroid dehydrogenase; " increase]

Know More...

• Addison’s disease: Also known as

hypoadrenocorticism, characterized by reduced secretion of corticosteroids.

• Cushing’s disease: Pathological condition due to the hyperactivity of adrenal cortex.

• Fetal cortisol is the hormone that initiates the par­turition reflex in animals.

• Circulatory cortisol levels are often used as a stress marker and useful assess well-being of animals.

• In birds, mice, and rats, corticosterone is the major glucocorticoid secreted from adrenal cortex.

• Aldosterone escape: The expansion of circulatory volume due to aldosterone triggers the release of atrial natriuretic peptide (ANP) from heart to induce natriuresis and diuresis.

16.3.6 Adrenal Medulla: Histology

The adrenal medulla is the innermost part of the adrenal gland, it forms one-fifth of the adrenal mass. Generally con­sidered an extension of the sympathetic system, the adrenal medulla comprises postganglionic sympathetic cells that can secrete hormones. When stimulated by pre-ganglionic sym­pathetic neurons, they synthesize and secrete epinephrine (adrenaline) and norepinephrine (noradrenaline). Since these neuroendocrine cells display a high affinity toward chromium salts, they are also known as chromaffin cells.

16.3.7.1 Mechanism of Synthesis

Derived from the amino acid tyrosine, both epinephrine and norepinephrine are known as adrenal catecholamines. The tyrosine required for their synthesis is derived either from the diet or through the enzymatic conversion of phenylala­nine. The further conversion of tyrosine to dihydroxy­phenylalanine (DOPA) by tyrosine hydroxylase (TH) is the rate-limiting step in the biosynthesis of adrenal catecholamines. Subsequently, DOPA is formed from dopa­mine due to the enzymatic action of L-aromatic amino acid decarboxylase (AAAC). Later, norepinephrine is produced from dopamine under the influence of

dopamine-β-hydroxylase (DBH). Additionally, 80% of chro­maffin cells possess phenylethanolamine

N-methyltransferase (PNMT) enzyme, which converts nor­epinephrine to form epinephrine. Therefore, epinephrine is the major catecholamine to be secreted from the adrenal medulla (Fig. 16.18).

16.3.7.2 Mechanism of Action

Epinephrine and norepinephrine bind to specific adrenergic receptors (AR), which are further classified into two major subtypes α and β. Epinephrine has an equal affinity toward both the receptor types, whereas norepinephrine predomi­nantly excites β type of adrenergic receptors. The adrenergic receptors belong to the GPCRs family, upon activation they either stimulate or inhibit adenylyl cyclase (AC) and phospholipase-C (PLC) systems to produce biological effects in the target organs. Hence, the target effects of adrenal catecholamines depend on the type of receptor expressed on the target tissues.

16.3.7.3 Biological Effects

Even though the adrenal medulla is not essential for life, hormones secreted from it activate physiological and behav­ioral responses collectively known as “fight or flight” to overcome acute stress. The biological effects are predomi­nant in the cardiovascular system, skeletal muscles, energy metabolism, GI tract, and kidneys.

16.3.7.3.1 Effects on the Cardiovascular System

Both epinephrine and norepinephrine directly stimulate the SA node, AV node, and Purkinje conduction system leading to an increased heart rate. In addition, they also increase the strength of myocardial contractions. Both these effects are mediated by the activation of β-ARs and downstream AC system. Furthermore, catecholamines produce α-AR-mediate vasoconstriction in the lungs, kidneys, and GIT. The concur­rent vasodilation occurring in skeletal muscles due to the activation of β-ARs will lead to the redistribution of blood to them. The redistribution and vasoconstrictor effects of catecholamines lead to an increase in the systemic arterial pressure to maintain adequate blood supply to vital organs.

16.3.7.3.2 Effects on the Smooth Muscle System

Adrenal catecholamines have profound effects on smooth muscles present in various organs. The vasoconstrictor effect in different visceral organs is due to the contraction of vascu­lar smooth muscles present in small arterioles and pre-capillary sphincter. They also act on smooth muscles present in bronchioles, GIT, and urinary bladder resulting in bronchodilation, inhibition of GIT motility, and urine reten­tion, respectively.

16.3.7.3.3 Effects on Metabolism

The circulating catecholamines inhibit insulin and stimulate glucagon secretion by activating α-ARs and β-ARs, respec­tively. In addition, they stimulate glucose production through glycogenolysis in the liver and skeletal muscles. They also

hydroxylase; TH tyrosine hydroxylase; AAAD L-aromatic amino acid decarboxylase; DBH dopamine-β-hydroxylase; PNMT phenylethanolamine N-methyltransferase; E epinephrine; NE norepi­nephrine; Na⁺ sodium ion; Ca²⁺ calcium ion; " increase]

Fig. 16.18 Synthesis of adrenal catecholamines [Produced from tyro­sine, the catecholamines are released into the circulation from the adrenal medulla in response to adverse situations such as fear, stress, cold, and apnea. [SNS sympathetic nervous system; PH phenylalanine augment lipolysis by activating triglyceride lipase in adipose tissue to release free fatty acids. The aforementioned effects of adrenal medullary hormones will lead to an increased concentration of glucose and free fatty acids in the blood. The resultant changes in metabolism will help the skeletal muscles, heart, and brain to function normally even during adverse conditions.

16.3.7.3.4 Effect on Skeletal Muscles

The redistribution of blood to skeletal muscles from visceral organs will help in meeting the nutrients required for increased muscular activity seen during flight or fight response. They stimulate glycolysis and β-oxidation of fatty acids for deriving the energy required for muscular contrac­tion (Fig. 16.19).

16.3.7.3.5 Miscellaneous Effects

Other effects of catecholamines include natriuresis, activa­tion of the renin-angiotensin system, mydriasis, and inhibi­tion of micturition. They also play a crucial in learning and memory consolidation.

16.3.7.4 Regulation of Secretion

The secretion of adrenal catecholamines is mainly due to the stimulation of the sympathetic nervous system (SNS) by cold, apnea, physical or environmental stress, and fear.

16.4