Biosynthesis, Localization, and Mechanism of Action
Mineralocorticoids belong to the group of hydrophobic steroid hormones (corticosteroids). The general pathway of corticosteroid biosynthesis is: cholesterol → pregnenolone → progesterone → corticosteroids.
- Site of synthesis: The zona glomerulosa (zona glomerulosa) of the adrenal cortex. The cortex forms the bulk of the gland, has a yellowish-brown color, and is covered by a fibrous capsule.
- Primary hormone: Aldosterone.
- Endogenous precursor of aldosterone: Deoxycorticosterone.
- Target organ: Kidneys.
- Mechanism of action: Induction of specific transport protein synthesis in the renal tubules.
Physiological Effects:
- Electrolyte balance: Enhancement of $Na^+$ reabsorption from the primary urine in exchange for $K^+$ and $H^+$ excretion.
- Fluid retention: Increased salt concentration in the blood stimulates antidiuretic hormone (ADH) release, leading to water retention in the body.
- Effect on inflammation: During the proliferative phase of inflammation, mineralocorticoids promote tissue regeneration (in contrast to glucocorticoids, which inhibit it at low doses).
Regulation of Secretion
Secretion by the zona glomerulosa is controlled by the renin-angiotensin-aldosterone system (RAAS). This cascade includes the following steps:
- The kidneys secrete the enzyme renin.
- Renin cleaves a fragment from angiotensinogen (a blood plasma protein), producing angiotensin I.
- Angiotensin-converting enzyme (ACE) converts it into angiotensin II.
- Angiotensin II stimulates aldosterone production.
Adrenocorticotropic hormone (ACTH) also plays a regulatory role in mineralocorticoid secretion.
Secretory Metrics and Pharmacokinetics
Under normal dietary salt intake, the following parameters are maintained:
- Daily secretion:
- Aldosterone: 100–200 mcg.
- Deoxycorticosterone: 200 mcg.
- Half-life ($t_{1/2}$):
- Aldosterone: 15–20 min (short half-life).
- Deoxycorticosterone: 70 min.
- Transport and excretion: In the blood, hormones bind to plasma proteins. Excretion occurs via the urine: 70% of aldosterone is excreted as a conjugate (tetrahydroaldosterone), and 30% in free form or as 3-oxoglucuronide.
Clinical Significance and Pathology
- Adrenal insufficiency (Addison's disease): Characterized by hypotension and muscle wasting.
- Congenital adrenal hyperplasia (CAH): Mineralocorticoid administration and/or dose adjustment are indicated in the salt-wasting form. In CAH due to 11$\beta$-hydroxylase deficiency, exogenous mineralocorticoids are not given because this form accumulates deoxycorticosterone, which inherently possesses mineralocorticoid activity.
- Adrenocortical carcinoma: Hormonal hypersecretion occurs in 50–60% of cases. The spectrum of secreted hormones includes mineralocorticoids: aldosterone, corticosterone, and deoxycorticosterone.
Key pharmacological mineralocorticoid agents include desoxycorticosterone acetate and fludrocortisone.