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 in converting cholesterol to pregnenolone.

Cortisol

Cortisol is a glucocorticoid. Only about 10% of circulating cortisol is free; most circulates bound to plasma proteins, especially corticosteroid-binding globulin (CBG), also called transcortin.

Cortisol is secreted in a pulsatile pattern, with more frequent bursts in the morning. It begins rising 1-2 h after sleep onset, peaks within 1 h of morning waking, and then declines 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 secretion declines by 33% from morning to evening. The amplitude of cortisol pulses is diminished with ageing and by irregular and daytime sleep.

CRH from the paraventricular nucleus of the hypothalamus stimulates ACTH release from the anterior pituitary. ACTH then stimulates the zona fasciculata to release cortisol. Cortisol regulates its own secretion through negative feedback on both the hypothalamus and pituitary, decreasing CRH and ACTH secretion, respectively.

Cortisol binds to the glucocorticoid receptor (GR) in the cytoplasm. The hormone-receptor complex then translocates into the nucleus, where it binds to hormone response elements (HREs) and modulates transcription of a large set of genes. Genomic analysis indicates that 29% of human genes have a glucocorticoid response element, which helps explain the wide range of glucocorticoid effects. The DNA-binding domain of GR contains zinc finger motifs that mediate binding to HREs. The immunosuppressant effects of cortisol may result from binding and inhibition of NF-kB.

Almost all cells have glucocorticoid receptors. Cortisol has profound metabolic effects:

• It stimulates hepatic gluconeogenesis.
• It promotes lipolysis, helping maintain blood glucose levels during fasting.

Glucocorticoids also have potent anti-inflammatory and immunosuppressive actions:

• They increase synthesis of lipocortin, which inhibits phospholipase A2 (required for prostaglandin and leukotriene synthesis).
• Cortisol inhibits IL2 production and the release of histamine and serotonin.

Other important effects include:

• Facilitating fetal lung maturation and surfactant production.
• A permissive interaction with catecholamines by upregulating alpha 1 receptors.

Cortisol inhibits bone formation by:

• Decreasing synthesis of type I collagen.
• Decreasing osteoid deposition.
• Decreasing intestinal Ca++ absorption.

Glucocorticoids have been implicated in 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

Aldosterone is a mineralocorticoid synthesized by the zona glomerulosa. Aldosterone synthase is the rate-limiting enzyme for aldosterone synthesis.

Angiotensin II stimulation of the zona glomerulosa increases transfer of cholesterol to the inner mitochondrial membrane and increases conversion of cholesterol to pregnenolone and corticosterone to aldosterone.

Potassium directly increases aldosterone secretion by the adrenal cortex. Aldosterone then lowers serum potassium by stimulating its excretion by the kidney. High serum K+ depolarizes adrenal cells, opening voltage-sensitive Ca++ channels and increasing intracellular calcium, which triggers aldosterone secretion. High dietary potassium intake increases plasma aldosterone.

ACTH increases aldosterone secretion by binding to the glomerulosa cell-surface melanocortin-2 receptor, activating adenylate cyclase and increasing intracellular cAMP. Vasopressin increases aldosterone secretion by activating the V2 receptor. Dopamine and ANP inhibit aldosterone secretion.

The mineralocorticoid receptor (MR) is located in the cytoplasm and has a nuclear binding domain composed of zinc finger motifs. When aldosterone binds, MR translocates into the nucleus and binds to HREs, modulating transcription of genes involved in the synthesis of aldosterone-regulated ion channels.

Aldosterone increases Na+ reabsorption and potassium secretion by principal cells, and H+ secretion by alpha intercalated cells. It acts through MR, resulting in activation of:

• ENaC sodium channels
• K+ channels
• 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 (GPCR). Activation of GPCR causes vasodilation, while activation of the mineralocorticoid receptor causes vasoconstriction.

Adrenal androgens

Adrenal androgens 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 peripheral tissues:

• Testosterone is converted to dihydrotestosterone (DHT) by 5 alpha reductase.
• Androgens are converted to estrone by aromatase.
• Estradiol-17-β-hydroxysteroid dehydrogenase (17β-HSD) converts estrone to biologically active estradiol.

About 90% of adrenal androgens are bound to albumin, and approximately 3% are bound to sex hormone-binding globulin.

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

The androgen receptor is activated when testosterone or DHT binds in the cytoplasm; the receptor 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.

The 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 (the increase in adrenal androgen secretion) 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.