Adrenal Cortical Hormones
المؤلف:
Marcello Ciaccio
المصدر:
Clinical and Laboratory Medicine Textbook 2021
الجزء والصفحة:
p346-348
2025-09-25
210
Biochemistry and Transport
Adrenal steroids share cyclopentanoperhydrophenanthrene in their chemical structure and may contain 19 or 21 carbon atoms. Hormones with 19 carbon atoms (C19) have androgenic activity and may have a ketone group at position 17 (17-ketosteroids). Steroids with 21 atoms (C21) regulate intermediate metabolism (glucocorticoids) or sodium homeostasis (mineralocorticoids).
Dehydroepiandrostenedione (DHEA) represents the primary adrenal androgen, cortisol among the glucocorticoids, and, finally, aldosterone among the mineralocorticoids.
The precursor of steroid hormones is cholesterol; it is taken up by adrenal cortical cells via the combined ApoB- 100/ ApoE ligand on low-density lipoprotein (LDL). The synthesis of all adrenal steroids begins with transforming cholesterol into a common precursor, pregnenolone. Most of the biosynthetic steps of steroidogenesis are catalyzed by enzymes belonging to the supergene family of cytochrome P450 oxidases (Fig.1).
Fig1. Adrenal steroidogenesis. (Copyright EDISES 2021. Reproduced with permission)
The specificity of synthesis in the various adrenocortical zones depends on specific receptors for ACTH and on the distribution of specific enzyme systems. Indeed, cells in the glomerular zone, which lack 17α-hydroxylase, do not participate in the synthesis of cortisol and androgens, for which this enzyme is essential. In contrast, the fasciculate and reticular zone cells, not possessing the 18-hydroxylase enzyme, cannot synthesize aldosterone. However, cells in the three zones can synthesize deoxycorticosterone, as the initial steps are common to both enzymatic pathways.
Almost all testosterone and cortisol (98%) circulate bound to plasma proteins, while only 60–65% of aldosterone circulates bound to nonspecific plasma proteins (15–20% corticosteroid-binding globulin [Corticosteroid-Binding Globulin, CBG] and 40–50% albumin). Testosterone binds with high affinity to sex hormone–binding globulin (SHBG) and low affinity to albumin. The transport protein with a higher binding affinity for cortisol is cortisol-binding globulin (CBG), an α-globulin that can bind up to 25 μg/dL of circulating hormone. When plasma cortisol concentrations exceed this concentration, the excess is distributed partly by binding to albumin and partly by increasing the free fraction.
Metabolism The daily cortisol secretion is about 25–30 mg (8–10 mg/m2) and follows a circadian rhythm, peaking in the first hours after waking up and decreasing during the day until reaching its lowest point at night. Cortisol metabolism strictly depends on the activity of the enzyme 11β- hydroxysteroidodehydrogenase (11β-HSD), of which two isoforms are known: 11β- HSD- 1 and 11β-HSD-2. The first is liver-based and con verts cortisone into cortisol (active corticosteroid); the second mediates the reverse transformation in the kidney and other tissues. At the hepatic level, cortisol and cortisone are conjugated with glucuronic acid (95%) or sulfuric acid and subsequently excreted renally.
A small portion of the cortisol produced (up to about 150 μg per day) is excreted and represents circulating cortisol in free form, filtered out by the kidney (urinary free cortisol).
The average daily aldosterone secretion is 100–200 μg/ day, of which 30% is in free form, and 70% binds weakly to plasma transport proteins, CBG, and albumin.
Metabolism of aldosterone is characterized by an initial hepatic passage that considerably reduces its concentration (≈75%), followed by renal excretion; under adequate dietary salt intake, daily excretion of the hormone is approximately 50–250 μg.
Adrenal androgens are secreted as DHEA and its ester with phosphate (DHEA-S), 15–30 mg/day. The adrenal gland also secretes small amounts of androstenedione, 11β-hydroxyandrostenedione, and testosterone, from which the female urinary 17-ketosteroids originate. About one- third of them, in the male, is of testicular origin.
Glucocorticoid (GR) and steroid (MR) receptors are intra cellular, and hormone binding activates or inhibits transcription factors. While GR binds only corticosteroids, MR binds both with equal affinity. Alterations in GR result in glucocorticoid resistance syndromes characterized by silent hypercortisolism.
Physiology
The synthesis and secretion of glucocorticoids and mineralocorticoids occur in very different homeostatic contexts. Cortisol secretion is an expression of the control exerted on the adrenal gland by the hypothalamic-pituitary endocrine axis; aldosterone, on the other hand, is secreted in response to the stimulus of angiotensin II, a potent vasoconstrictor regulated by the renin-angiotensin system.
Glucocorticoids
Plasma cortisol is secreted in response to pituitary corticotropin (ACTH) stimulation, which, in turn, responds to stimulation by the hypothalamic release factor (CRH). This mechanism of regulation of the endocrine axis is defined as positive feedback and is common to all the glands under hypothalamic-pituitary control. The inhibition by plasma cortisol on ACTH and CRH represents negative feedback. The resultant integration of these inhibition or release stimuli by each glandular product represents the basis for the foundation of the hypothalamic-pituitary-target gland endocrine axis. However, numerous other factors are involved in modulating these feedbacks, such as stress and hypoglycemia (Fig. 2).
Fig2. Regulation of cortisol secretion. (Copyright EDISES 2021. Reproduced with permission)
Cortisol exerts negative feedback on ACTH in two ways: rapid, entrusted to GR, and delayed, due to suppressing syn thesis of the precursor, pro-oppiomelanocortin (POMC). POMC is also a precursor of melanocyte-stimulating hormone (MSH) and endogenous opioids (met-enkephalins and β-endorphins).
It is helpful to remember that CRH also exerts a feedback control on the sympathetic nervous system, stimulating the locus coeruleus and inhibiting this activation by plasma cortisol.
Mineralocorticoids
Aldosterone secretion is regulated primarily by activation of the renin-angiotensin system. Renin, a hormone produced and secreted by the juxtaglomerular cells surrounding the glomerulus’s afferent arteriole, mediates the circulation of angiotensinogen, produced in the liver, into angiotensin I, which becomes angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II is a potent arteriolar vasoconstrictor that stimulates the biosynthesis and release of aldosterone from cells in the glomerular zone of the corticosurrene. Aldosterone secretion also follows a circadian rhythm, simi lar to that of cortisol.
Aldosterone regulates extracellular volume by inducing changes in renal hemodynamics and tubular sodium reabsorption. In addition to hypovolemia, other stimuli to renin secretion are activation of sodium load-sensitive macula densa chemoreceptors, orthostatism, and atrial natriuretic peptides. Intrarenal pressure and sodium load sensors increase renin secretion; natriuretic peptides reduce it.
Although to a lesser extent, potassium levels and ACTH are also involved in regulating aldosterone secretion.
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