6.3 Endocrine & Adrenocortical Hormones

Adrenal Cortex

The adrenal cortex is organized histologically and functionally into three zones, remembered as GFR → Salt, Sugar, Sex (from superficial to deep):

All cortical steroids derive from cholesterol delivered by LDL via the StAR protein, which transports cholesterol into mitochondria where desmolase (side-chain cleavage enzyme) converts it to pregnenolone. The rate-limiting step in steroidogenesis is the cholesterol-to-pregnenolone conversion.

Aldosterone

Aldosterone is the principal mineralocorticoid. Its secretion is controlled mainly by the renin-angiotensin-aldosterone system (RAAS) and by serum potassium — not directly by ACTH. Renin, released by juxtaglomerular (JG) cells of the afferent arteriole in response to low renal perfusion, low NaCl at the macula densa, and sympathetic stimulation, cleaves angiotensinogen (liver) to angiotensin I, which is converted by angiotensin-converting enzyme (ACE) in the lung to angiotensin II. Angiotensin II stimulates aldosterone secretion via the AT1 receptor on zona glomerulosa cells.

Aldosterone acts on principal cells of the renal collecting duct via the cytosolic mineralocorticoid receptor (MR). The ligand-receptor complex translocates to the nucleus and upregulates synthesis of ENaC (epithelial Na+ channel) subunits and Na+/K+-ATPase. Net effect: increased Na+ reabsorption, increased K+ and H+ secretion, expansion of extracellular volume, and elevated blood pressure.

A key confounder: 11β-hydroxysteroid dehydrogenase type 2 in the kidney converts cortisol to cortisone (inactive at MR), preventing cortisol from over-stimulating the mineralocorticoid receptor. Deficiency (apparent mineralocorticoid excess) or inhibition (licorice/glycyrrhizin) causes hypertension with low renin and low aldosterone.

Cortisol

Cortisol is secreted by zona fasciculata under ACTH control, which is driven by hypothalamic CRH and follows a diurnal rhythm (peak early morning, nadir around midnight). Cortisol acts through the cytosolic glucocorticoid receptor (GR), producing widespread effects:

• Metabolic — increases blood glucose by stimulating hepatic gluconeogenesis, increasing proteolysis in muscle, and enhancing lipolysis in adipose. It is permissive for glucagon and catecholamine action.
• Anti-inflammatory and immunosuppressive — inhibits phospholipase A2 (reducing prostaglandin/leukotriene synthesis), reduces IL-2 and T-cell proliferation, and decreases capillary permeability.
• Permissive for catecholamines — maintains vascular smooth muscle alpha-1 receptor expression, sustaining blood pressure responsiveness to norepinephrine.
• Stress response — mobilizes fuel substrates during trauma, infection, fasting.

Cortisol excess (Cushing syndrome) produces moon facies, buffalo hump, central obesity, hyperglycemia, thin skin, easy bruising, proximal myopathy, and osteoporosis. Cortisol deficiency (Addison disease) produces hypotension, hyponatremia, hyperkalemia, hypoglycemia, and hyperpigmentation (from elevated ACTH/POMC).

Adrenal Androgens

The zona reticularis produces DHEA and androstenedione, weak androgens converted peripherally to testosterone and estrogens. Excess (e.g., congenital adrenal hyperplasia from 21-hydroxylase deficiency) causes virilization in females and precocious puberty in males, with concomitant salt-wasting from deficient aldosterone and cortisol.

Adrenal Medulla

The adrenal medulla is a modified sympathetic ganglion: chromaffin cells (postganglionic sympathetic neurons without axons) secrete epinephrine (~80%) and norepinephrine (~20%) directly into the blood in response to preganglionic sympathetic (splanchnic) acetylcholine acting on nicotinic receptors. Phenylethanolamine-N-methyltransferase (PNMT), induced by cortisol from the cortex draining into the medulla, converts norepinephrine to epinephrine.

Catecholamines act on alpha-1, alpha-2, beta-1, and beta-2 adrenergic receptors:

• Alpha-1 — vasoconstriction (skin, splanchnic); Gq → IP3/DAG.
• Alpha-2 — inhibits insulin release, platelet aggregation; Gi → ↓cAMP.
• Beta-1 — increases heart rate and contractility; Gs → ↑cAMP.
• Beta-2 — bronchodilation, vasodilation in muscle, glycogenolysis, insulin release; Gs → ↑cAMP.

Pheochromocytoma is a catecholamine-secreting tumor producing episodic hypertension, palpitations, headache, and sweating.

Pancreatic Islet Hormones

The islets of Langerhans contain several cell types:

• Beta cells (~60%) — secrete insulin in response to elevated blood glucose, GLP-1 (incretin), and parasympathetic stimulation. Insulin lowers blood glucose by promoting GLUT4-mediated glucose uptake in muscle and adipose, stimulating glycogenesis, lipogenesis, and protein synthesis. It inhibits glycogenolysis, gluconeogenesis, and lipolysis.
• Alpha cells (~25%) — secrete glucagon in response to hypoglycemia, amino acids, and sympathetic stimulation. Glucagon raises blood glucose via hepatic glycogenolysis and gluconeogenesis (cAMP/PKA pathway).
• Delta cells (~10%) — secrete somatostatin, inhibiting both insulin and glucagon.
• PP cells — secrete pancreatic polypeptide, which regulates pancreatic exocrine secretion and GI motility.

Diabetes mellitus type 1 is autoimmune beta-cell destruction (absolute insulin deficiency); type 2 is insulin resistance with relative deficiency.

Other Endocrine Hormones

• Erythropoietin (EPO) — produced by interstitial fibroblasts in the renal cortex in response to hypoxia (HIF-2α pathway); stimulates red bone marrow erythroid proliferation. Renal failure causes anemia from low EPO.
• Atrial Natriuretic Peptide (ANP) — released by atrial myocytes in response to stretch (volume overload); increases renal Na+ excretion, dilates afferent arteriole, inhibits renin and aldosterone, lowering blood pressure. BNP (brain natriuretic peptide, from ventricles) is similar and used as a heart failure biomarker.
• Renin — secreted by juxtaglomerular cells; not a hormone of action but the rate-limiting enzyme of the RAAS cascade.
• Leptin — adipocyte hormone that suppresses appetite via hypothalamic melanocortin pathway; rises with fat mass.

Comprehensive Hormone Reference Table