Steroid Biosynthesis in Adrenal Cortex
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Steroid Biosynthesis in Adrenal Cortex

Steroid hormones are lipophilic, low-molecular weight compounds derived from Cholesterol that play important physiological roles. The steroid hormones are synthesized mainly by Endocrine Glands such as the the Adrenal Cortex and the Gonads (Ovary and Testes), and are then released into the blood circulation. There are five major classes of steroid hormones. They are the (i) Glucocorticoids (Anti-Stress Hormones), Cortisol is the major representative in most mammals; Mineralocorticoids (Na+ Uptake Regulators), Aldosterone being most prominent; Androgens (Male Sex Hormones), such as Testosterone; Estrogens (Female Sex Hormones), including Estrodiol and Estrone; and, Progestogens (Progestational hormones), such as Progesterone. The Adrenal Cortex is responsible for production of 3 major classes of steroid hormones: Glucocorticoids, which regulate carbohydrate metabolism; Mineralocorticoids, which regulate the body levels of sodium and potassium; and Androgens, whose actions are similar to those of steroids produced by the male gonads. Once released into the bloodstream, these hormones travel to other parts of the body where they bring about specific responses from specific cells (Ref.1 & 2). 

Adrenal Glands are Endocrine Glands which are located on top of both the kidneys. Each gland consists of a Medulla (the center of the gland) which is surrounded by the cortex. The medulla is responsible for production of Epinephrine and Norepinephrine.  The Adrenal Cortex secretes steroid hormones. The Cortex is composed of 3 main tissue regions: Zona Glomerulosa, Zona Fasciculata, and Zona Reticularis. Although the Adrenal Cortex is capable of synthesizing all the steroid hormones produced by the body, only three of them: Mineralocorticoids (which are secreted from the zona glomerulosa); Glucocorticoids (which are synthesized and released both from the Zona Fasciculata and Zona Reticularis), and the Androgens (released from Zona Reticularis) are produced in appreciable doses. All the Adrenal steroid hormones are derived from Cholesterol. The first committed step in steroid biosynthesis is the conversion of the 27-carbon skeleton of Cholesterol to a C21-compound, Pregnenolone. This conversion step is the same in all zones of the Cortex. This critical step is subject to hormonal control by the ACTH (Adrenocorticotropic Hormone) in the Adrenals, catalysed by a P450 enzyme, the cholesterol side-chain cleavage enzyme CYP11A1 (Cytochrome P450 family-11 subfamily- A, Polypeptide-1)/ P450SCC (Cytochrome P450 Side-Chain Cleavage Enzyme). Pregnenolone itself is not a hormone, but is an intermediate for the synthesis of all Steroid hormones. Although the pathway to pregnenolone synthesis is the same in all zones of the cortex, the zones are histologically and enzymatically distinct, with the exact steroid hormone product dependent on the enzymes present in the cells of each zone (Ref.3, 4, & 5).

The Zona Glomerulosa region of the Adrenal Cortex is the site for the the synthesis of the Mineralocorticoid, Aldosterone. In the Zona glomerulosa cells, Aldosterone is synthesized from Pregnenolone in four steps: Pregnenolone¨ Progesterone¨ 11Deoxycorticosterone¨ Corticosterone¨ Aldosterone. Pregnenolone is converted to Progesterone by the enzyme HSD3B (Hydroxy-Delta-5-Steroid Dehydrogenase 3Beta- and Steroid Delta-isomerase). HSD3B is present in all the three zones of the Adrenal Cortex. The enzyme CYP21A2 (Cytochrome P450, family-21 subfamily-A polypeptide-2) present in the Glomerulosa cells catalyzes the conversion of Progesterone to 11-Deoxycorticosterone.  The weak Mineralocorticoid, Corticosterone is synthesized from 11-Deoxycorticosterone and the synthesis is catalyzed by the enzyme CYP11B1 (Cytochrome P450 family-11 subfamily-B Polypeptide-1). Zona Glomerulosa cells are unique in the Adrenal Cortex in containing the enzyme responsible for converting Corticosterone to Aldosterone, the principal and most potent Mineralocorticoid. This enzyme is CYP11B2 (Cytochrome P450 family-11 Subfamily B polypeptide-2), also called ALDOS (Aldosterone Synthase). The result is that the Zona Glomerulosa is mainly responsible for the conversion of Cholesterol to the weak Mineralocorticoid, Corticosterone and the principal Mineralocorticoid, Aldosterone. Zona Glomerulosa cells lack the CYP17/CYP17A1 (Cytochrome P450, family-17 subfamily-A, Polypeptide-1) enzyme, that converts Pregnenolone and Progesterone to their C17 hydroxylated analogs. Thus, the pathways to the Glucocorticoids (Deoxycortisol and Cortisol) and the Androgens [DHEA (Dehydroepiandrosterone) and Androstenedione] are blocked in these cells (Ref.6 & 7).  

Cells of the Zona Fasciculata and Zona Reticularis lack CYP11B2 that converts Corticosterone to Aldosterone, and thus these tissues produce only the weak Mineralocorticoid Corticosterone. However, both these zones do contain the CYP17 enzyme, which is missing in Zona Glomerulosa. CYP17 catalyzes both 17-alpha-hydroxylation and the 17,20-lyase reactions. The 17-alpha-hydroxylation activity catalyzes the conversion of Pregnenolone and Progesterone to their 17-alpha-hydroxylated products and 17,20-lyase activity is responsible for producing the androgens, DHEA (Dehydroepiandrosterone) and Androstenedione. Zona Fasciculata and Zona Reticularis cells are thus capable of producing the major Glucocorticoid, Cortisol, and also the Androgens: DHEA and Androstenedione, but not Aldosterone. Although Fasciculata and Reticularis cells each have the capability of synthesizing androgens and Glucocorticoids, the main pathway normally followed in the Fasciculata cells is that leading to Glucocorticoid production, and that followed in the Reticularis cells is that leading to the production of Androgens (Ref.6 & 8).

In Zona Fasciculata, Cortisol is derived biosynthetically from Pregnenolone with 17Alpha-Hydroxypregnenolone, 17Alpha-Hydroxyprogesterone, and 11-Deoxycortisol as intermediates. Pregnenolone is converted to 17Alpha-Hydroxypregnenolone by the enzyme, CYP17. 17Alpha-Hydroxypregnenolone is then converted to 17Alpha-Hydroxyprogesterone. The conversion step is catalyzed by the enzyme HSD3B. The CYP450 enzyme CYP21A2 (Cytochrome P450 family-21 subfamily-A Polypeptide-2) catalyzes the convertion of 17Alpha-Hydroxyprogesterone to 11-Deoxycortisol, the immediate precursor of Cortisol. 11-Deoxycortisol is then converted to Cortisol by CYP11B1 (Cytochrome P450 family-11 subfamily-B Polypeptide-1). Cortisol is the main Glucocorticoid secreted by human Adrenal Glands. The Mineralocorticoid Corticosterone is also synthesized in the Zona Fasciculata from Pregnenolone in three steps: Pregnenolone¨Progesterone¨11-Deoxycorticosterone¨Corticosterone as in case of Zona Glomerulosa cells, catalyzed by the enzymes: HSD3B, CYP21A2, CYP11B1 respectively. Zona Reticularis is the main site for the synthesis of weak Androgens in the Adrenal Cortex. DHEA is synthesized from the 17Alpha-Hydroxylated product of Pregnenolone, i.e., 17Alpha-Hydroxypregnenolone. The reaction is catalyzed by the enzyme CYP17. DHEA is then converted to Androstenedione by HSD3B. Androgen formation in the Adrenals is limited to DHEA and Androstenedione. Cortisol is also synthesized in small amounts in the Zona Reticularis in a similar manner as in the cells of Zona Fasciculata (Ref.8 & 9).

Small amounts of Testosterone and Estradiol are produced in the Adrenal as well. This is exacerbated if the activity of CYP21A2 is weak, and may result in unusually high Testosterone levels in females who have this deficiency. This inability to secrete normal levels of adrenal steroids results in CAH (Congenital Adrenal Hyperplasia). In the majority of cases, this syndrome is associated with increased Adrenal Androgen secretion and partial virilization in girls. Similarly, when genetic defects occur in the enzyme complexes leading to Glucocorticoid production, large amounts of DHEA are produced. These lead to Hirsutism and other masculinizing changes in secondary sex characteristics. Inconsistency in steroid synthesis in the Adrenal Cortex leads to various other pathological conditions like Addisons Disease (Adrenocortical failure), characterized by weight loss, hypoglycemia, weakness, and hyperpigmentation caused by insufficient amounts of Glucocorticoids, and Cushings Syndrome (Adrenocortical excess), characterized by a moon-shaped face caused by edema, produced by excessive Glucocorticoids (Ref.1, 2 & 10).