Layers of cortex.
The adrenal cortex
|Latin||cortex glandulae suprarenalis|
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, such as aldosterone and cortisol, respectively. It is also a secondary site of androgen synthesis.
The adrenal cortex comprises three main zones, or layers that are regulated by distinct hormones as noted below. This anatomic zonation can be appreciated at the microscopic level, where each zone can be recognized and distinguished from one another based on structural and anatomic characteristics.
- Zona glomerulosa
- The outermost layer, the zona glomerulosa is the main site for the production of aldosterone, a mineralocorticoid. The synthesis and secretion of aldosterone are mainly regulated by the renin–angiotensin–aldosterone system. The zona glomerulosa cells express a specific enzyme aldosterone synthase (also known as CYP11B2). Aldosterone is largely responsible for the long-term regulation of blood pressure. Aldosterone's effects are on the distal convoluted tubule and collecting duct of the kidney where it causes increased reabsorption of sodium and increased excretion of both potassium (by principal cells) and hydrogen ions (by intercalated cells of the collecting duct). Sodium retention is also a response of the distal colon, and sweat glands to aldosterone receptor stimulation. Although sustained production of aldosterone requires persistent calcium entry through low-voltage activated Ca2+ channels, isolated zona glomerulosa cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca2+ channels entry.
- The secretion of aldosterone is also stimulated by ACTH.
- The expression of neuron-specific proteins in the zona glomerulosa cells of human adrenocortical tissues has been predicted and reported by several authors and it was suggested that the expression of proteins like the neuronal cell adhesion molecule (NCAM) in the cells of the zona glomerulosa reflects the regenerative feature of these cells, which would lose NCAM immunoreactivity after moving to the zona fasciculata. However, together with other data on neuroendocrine properties of zona glomerulosa cells, NCAM expression may reflect a neuroendocrine differentiation of these cells.
- Zona fasciculata
- Situated between the glomerulosa and reticularis, the cells of the zona fasciculata synthesize and secrete glucocorticoids, such as 11-deoxycorticosterone, corticosterone, and cortisol in humans. The major hormone that stimulates cortisol secretion in humans is the adrenocorticotropic hormone (ACTH) that is released from the anterior pituitary. It has been shown that the steroidogenic capacity of the zona fasciculata increases during illness in infants.
- Zona reticularis
- The inner most cortical layer, the zona reticularis produces androgens, mainly dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (the precursor to testosterone) in humans. The secretion of DHEAS is also stimulated by ACTH.
The precursor of steroids synthesized in the adrenal cortex is cholesterol that is stored in vesicles. Cholesterol can be synthesized de novo in the adrenal cortex. Yet, the major source of cholesterol appears to be cholesterol that is taken up with circulating lipoproteins. 
The steps up to this point occur in many steroid-producing tissues. Subsequent steps to generate aldosterone and cortisol, however, primarily occur in the adrenal cortex:
- Progesterone → (hydroxylation at C21) → 11-Deoxycorticosterone → (two further hydroxylations at C11 and C18) → Aldosterone
- Progesterone → (hydroxylation at C17) → 17-alpha-hydroxyprogesterone → (hydroxylation at C21) → 11-Deoxycortisol → (hydroxylation at C11) → Cortisol
The primary mineralocorticoid, aldosterone, is produced in the adrenocortical zona glomerulosa by the action of the enzyme aldosterone synthase (also known as CYP11B2). Aldosterone is largely responsible for the long-term regulation of blood pressure. Aldosterone effects on the distal convoluted tubule and collecting duct of the kidney where it causes increased reabsorption of sodium and increased excretion of both potassium (by principal cells) and hydrogen ions (by intercalated cells of the collecting duct). Sodium retention is also a response of the distal colon, and sweat glands to aldosterone receptor stimulation. Although sustained production of aldosterone requires persistent calcium entry through low-voltage activated Ca2+ channels, isolated zona glomerulosa cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca2+ channels entry.
Glucocorticoids are produced in the zona fasciculata. The primary glucocorticoid released by the adrenal gland is cortisol in humans and corticosterone in many other animals. Its secretion is regulated by the hormone ACTH from the anterior pituitary.
They are produced in the zona reticularis. The most important androgens include:
- Testosterone: a hormone with a wide variety of effects, ranging from enhancing muscle mass and stimulation of cell growth to the development of the secondary sex characteristics.
- Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors.
- Androstenedione (Andro): an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically to testosterone and other androgens, they are also the parent structure of estrone.
- Dehydroepiandrosterone (DHEA): It is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone. The reticularis also produces DHEA-sulfate due to the actions of a sulfotransferase, SULT2A1.
- Adrenal insufficiency (e.g. due to Addison's disease)
- Cushing's syndrome
- Cushing's disease
- Conn's syndrome
- Adrenocortical carcinoma
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