Adrenal hormones

All adrenal hormones are synthesized from cholesterol. The major hormones of the adrenal glands are shown in the table below.

*CRH for corticotropin releasing hormone.

ACTH activates the enzyme cholesterol desmolase which catalyzes the first step of conversion of cholesterol to pregnenolone.

Cortisol

Cortisol is a glucocorticoid. Only about 10% of circulating cortisol is free. The remaining majority circulates bound to plasma proteins, particularly corticosteroid-binding globulin called transcortin. It is secreted in a pulsatile fashion with higher frequency of bursts in the morning. Cortisol begins rising 1–2 h after sleep onset, peaks within 1 h of morning waking, and declines thereafter across the 24-h day. Cortisol rhythms parallel those of insulin sensitivity, such that high cortisol levels coincide with increased insulin sensitivity and vice versa. Postmeal cortisol secretions decline by 33% from morning to evening. The amplitude of cortisol pulses are diminished with ageing and by irregular and daytime sleep. CRH from the paraventricular nucleus of the hypothalamus stimulates the release of ACTH from the anterior pituitary which then activates the zona fasciculata to release cortisol. Cortisol regulates its own secretion by negative feedback on the hypothalamus and pituitary resulting in decreased CRH and ACTH secretions respectively.

Cortisol binds to the glucocorticoid receptor (GR) in the cytoplasm and the hormone-receptor complex is then translocated into the nucleus, where it binds to its nuclear receptor and modulates transcription from a large battery of genes. Genomics analysis indicates that 29% of human genes have a glucocorticoid response element, which explains the huge number of effects glucocorticoids have on physiology. The DNA binding domain of GR has zinc finger motifs through which the GR binds to hormone response elements or HREs. The immunosuppressant effects of cortisol may result from binding and inhibition of NF-kB.

Almost all cells have glucocorticoid receptors. It has profound effects on metabolism. It stimulates hepatic gluconeogenesis and promotes lipolysis thus helping to maintain the blood glucose levels in fasting. Glucocorticoids have potent anti-inflammatory and immunosuppressive properties. They increase the synthesis of lipocortin which inhibits phospholipase A2 which is required for the synthesis of prostaglandins and leukotrienes. Cortisol also inhibits the production of IL2 and release of histamine and serotonin. They facilitate the maturation of fetal lungs and surfactant production. Glucocorticoids have a permissive action with catecholamines as they upregulate alpha 1 receptors.

Cortisol inhibits bone formation by decreasing the synthesis of type I collagen, decreasing osteoid deposition and decreasing intestinal Ca++ absorption. Glucocorticoids have been implicated in the process of bone loss through their ability to block 1,25-(OH)2-vitamin D-induced osteocalcin synthesis. They prevent attachment of osteoblasts to matrix proteins, including osteonectin, possibly through down-regulation of β 1-integrin and other cell surface attachment factors.

Aldosterone

It is a mineralocorticoid hormone synthesized by the zona glomerulosa. Aldosterone synthase is the rate limiting enzyme for aldosterone synthesis. Angiotensin II stimulation of the zona glomerulosa leads to increased transfer of cholesterol to the inner mitochondrial membrane and increased conversion of cholesterol to pregnenolone and corticosterone to aldosterone. Potassium directly increases aldosterone secretion by the adrenal cortex and aldosterone then lowers serum potassium by stimulating its excretion by the kidney. High serum K+ causes depolarization of adrenal cells, opening of voltage sensitive Ca++ channels and rise in intracellular calcium causing aldosterone secretion. High dietary potassium intake increases plasma aldosterone. ACTH increases aldosterone secretion by binding to glomerulosa cell-surface melanocortin-2 receptor, activating adenylate cyclase, increasing intracellular cAMP. Vasopressin increases aldosterone secretion by activating the V2 receptor. Dopamine and ANP inhibit aldosterone secretion.

Mineralocorticoid receptor or MR is located in the cytoplasm. It has a nuclear binding domain composed of zinc finger motifs. On ligand i.e. aldosterone binding, MR translocates into the nucleus and binds to HREs, modulating the transcription of genes involved in the synthesis of aldosterone regulated ion channels.

Aldosterone increases Na+ reabsorption and potassium secretion by the principal cells and H+ secretion by alpha intercalated cells. It acts on the mineralocorticoid receptor or MR resulting in the activation of ENaC sodium channels, K+ channels and Na+K+ATPase pump. Sodium channels responsive to aldosterone are present in the late distal tubules and collecting ducts , colon, sweat glands, lungs and tongue. Aldosterone action on blood vessels is through a G protein coupled receptor or GPCR. Activation of GPCR causes vasodilation while activation of the mineralocorticoid receptor causes vasoconstriction.

Adrenal androgens

They are steroid hormones with weak androgenic activity produced in the zona reticularis. They include dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, 11-ketotestosterone and 11β-hydroxyandrostenedione. Adrenal androgens can be converted into testosterone and estrogen in the peripheral tissues. Testosterone is converted to dihydrotestosterone (DHT) by 5 alpha reductase enzyme while androgens are converted to estrone in the peripheral tissues by the enzyme aromatase. Estradiol-17-β-hydroxysteroid dehydrogenase (17β-HSD) converts estrone to the biologically active estradiol. About 90% of adrenal androgens are bound to albumin and 3% approximately are bound to sex hormone-binding globulin.

Adrenal androgens are mainly regulated by ACTH. They are secreted synchronously with cortisol. Hormone levels vary depending on episodic secretion and the circadian rhythm of ACTH, effect of stress on HPA axis and feedback inhibition of ACTH secretion by cortisol which will also decrease androgen production. Synthesis of adrenal androgens is increased by prolactin. IL 8 and MCP 1 or monocyte chemotactic protein 1 increase adrenal androgen synthesis.

The androgen receptor is activated by binding to testosterone or DHT in the cytoplasm and then translocates into the nucleus. Androgen receptors are encoded by the AR gene located on the X chromosome. AR are widely expressed on the adrenal cortex.

Adrenal cortex normally secretes androgens in increasing amounts beginning at about 6-7 years of age in girls and 7-8 years of age in boys. This rise continues until late puberty. Adrenarche or the secretion of adrenal androgens occurs years before gonadarche (secretion of gonadal sex steroids). The appearance of pubic hair (pubarche) results from a rise in adrenal androgen concentration. In women, increased adrenal androgen production may be manifested as cystic acne, hirsutism, male type baldness, menstrual irregularities, oligoovulation or anovulation, infertility, and/or frank virilization leading to PCOS and insulin resistance. Excessive adrenal androgen secretion in prepubertal or pubertal girls can cause precocious puberty. Women with poor ovarian reserve, after DHEA supplementation 4 to 12 weeks prior an in vitro fertilization (IVF) cycle, had a 50-80% reduction in miscarriages. Androgens have a protective effect on bone mineral density.