Biosynthesis of Steroid Hormones
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Biosynthesis of Steroid Hormones
Steroid hormones are crucial substances for the proper functioning of the body. They mediate a wide variety of vital physiological functions ranging from anti-inflammatory agents to regulating events during pregnancy. Typically, endocrinologists classify steroid hormones into five major groups, based primarily on the receptor to which they bind, and the physiological outcomes: (i) Glucocorticoids (Anti-Stress Hormones), Cortisol is the major representative in most mammals; Mineralocorticoids (Ion Uptake Regulators), Aldosterone being most prominent; Androgens (Male Sex Hormones), such as Androstenedione and Testosterone; Estrogens (Female Sex Hormones), including Estrodiol and Estrone; and, Progestogens (progestational hormones), such as Progesterone. The steroid hormones are synthesized and secreted into the bloodstream by endocrine glands, such as the Adrenal Cortex and the Gonads (Ovary and Testes). Once released into the bloodstream, these hormones travel to other parts of the body where they bring about specific responses from specific cells. The Glucocorticoids affect carbohydrate, protein, and lipid metabolism, and influence a wide variety of other vital functions including inflammatory reactions and the capacity to cope with stress. The Mineralocorticoids largely function to regulate the excretion of salt and water by kidney. Both Androgens and Estrogens affect sexual development and function. They regulate sexual differentiation, the secondary sex characteristics, and sexual behavior patterns. Progestogens help mediate the menstrual cycle and pregnancy (Ref.1).

Steroid hormones are all characterized by the steroid nucleus which is composed of three six member rings and one five member ring. Steroid hormones are derivatives of Cholesterol, the major animal sterol. While cholesterol can be synthesized in many body tissues, further differentiation into steroid hormones takes place only in the Adrenal Cortex and in its embryological cousins, the Ovaries and the Testes. The parent compound Cholesterol contains a ring system composed of 27 Carbons. It is made up of three hexagonal carbon rings and a pentagonal carbon ring to which a side-chain (Carbons 20-27) is attached (at position 17 of the polycyclic hydrocarbon). Two angular methyl groups are also found at position 18 and 19. Removal of part of the side-chain gives rise to C21-compounds of the Pregnane series (Progestogens and Corticosteroids). Total removal of the side chain produces C19-steroids of the Androstane series (including the Androgens), whereas loss of the 19-Methyl group followed by aromatization yields the Estrane (C18) series, to which Estrogens belong. Individual compounds are characterised by the presence or absence of specific functional groups (mainly Hydroxy, Keto (oxo) and Aldehyde functions for the naturally occurring steroids) at certain positions of the Carbon skeleton (particularly at positions 3, 5, 11, 17, 18, 20 and 21). The Adrenals produce both Androgens and Corticosteroids (Mineralocorticoids and Glucocorticoids), the Ovaries (depending on the stage of the Ovarian Cycle) can secrete Estrogens and Progestogens, and the Testes mainly Androgens. However, the biochemical pathways involved are strikingly similar in all tissues, the difference in secretory capacity being mostly due to the presence or absence of specific enzymes. It is therefore possible to give a general outline of the major biosynthetic pathways which is applicable to all Steroid-secreting glands (Ref.2 & 3).

The Cholesterol precursor comes from Cholesterol synthesized from Acetate, from Cholesterol Ester stores in intracellular lipid droplets or from uptake of Cholesterol-containing LDLs (Low Density Lipoproteins). Lipoproteins taken up from plasma are most important. Biosynthesis of steroid hormones requires a battery of oxidative enzymes located both in Mitochondria and ER (Endoplasmic Reticulum). Within Mitochondria, Cholesterol is converted to Pregnenolone by a CYP450 (Cytochrome P450) enzyme in the inner membrane called CYP11A1 (Cytochrome P450 Family-11, Subfamily-A Polypeptide-1). Pregnenolone is derived from Cholesterol by two hydroxylations at C20 and C22, followed by cleavage between C20 and C22 as catalyzed by the mitochondrial enzyme CYP11A1, the net result being the removal of six Carbons from the C17 side chain. Pregnenolone itself is not a hormone, but is an intermediate for the synthesis of all Steroid hormones. Pregnenolone is converted to Progesterone by the enzyme, HSD3B (Hydroxy-Delta-5-Steroid Dehydrogenase, 3Beta- and Steroid Delta-isomerase), one of the few non-CYP450 enzymes involved in steroidogenesis that is found in both Mitochondria and ER. Progesterone, made from Pregnenolone, is the primary progestogen. Progesterone is made by the Corpus Luteum and the Placenta, induces development of endometrium and mammary glands, mediates menstrual cycle and is needed for preparing the uterus for implantation of the ovum, and maintenance of pregnancy (Ref.2, 3 & 4).

Glucocorticoids originate in the Adrenal Cortex and affect mainly metabolism in diverse ways; decrease inflammation and increase resistance to stress. 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/CYP17A1 (Cytochrome P450, Family-17, Subfamily-A, Polypeptide-1). 17Alpha-Hydroxypregnenolone is then converted to 17Alpha-Hydroxyprogesterone. The conversion step is catalyzed by the enzyme HSD3B. 17Alpha-Hydroxyprogesterone is also derived from Progesterone by hydroxylation at its 17Alpha position by CYP17. CYP17 is responsible for the 17Alpha-hydroxylations and the C17-20 lysis of steroid structures, which take place in the ER. Both activities appear to be due to distinct catalytic sites on the enzyme. CYP17 hydroxylates the 17Alpha position of Pregnenolone or Progesterone to form the respective 17Alpha-Hydroxysteroids. 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. Corticosterone, an intermediate in the conversion of Progesterone to Aldosterone, is a minor Glucocorticoid in humans, but important in other species. The Glucocorticoid biosynthesis needs precise regulation. Cushings Syndrome, characterized by a moon-shaped face caused by edema, is produced by excessive Glucocorticoids as induced by pituitary tumors. Addisons Disease, characterized by weight loss, hypoglycemia, weakness, and hyperpigmentation is caused by insufficient amounts of Glucocorticoids (Ref.5, 6 & 7).

Mineralocorticoids originate in Adrenal Cortex and maintain salt and water balance. The mineralcorticoid Aldosterone is derived from Progesterone, in three steps: Progesterone®11-Deoxycorticosterone®Corticosterone®Aldosterone. These steps are catalyzed by the enzymes, CYP21A2, CYP11B1, and Aldosterone Synthase/CYP11B2 (Cytochrome P450, family 11, subfamily B, polypeptide-2) respectively. Hydroxylation of Progesterone at Carbon-21 yields 11-Deoxycorticosterone, and Corticosterone after another hydroxylation step at Carbon-11. Corticosterone is a major Glucocorticoid in rats and other species which do not produce Cortisol. Further hydroxylation and oxydoreduction at Carbon-18 catalyzed by CYP11B2 results in the formation of Aldosterone. A deficiency in Aldosterone can occur by itself or, more commonly, in conjunction with a Glucocorticoid deficiency, and is known as Hypoadrenocorticism or Addisons disease. Excess Aldosterone produces primary Aldosteronism, or Conn Syndrome. Symptoms include Na+ (Sodium) and water resorption, hypertension, and loss of Potassium (Ref.6 & 7).

Androgens originate in the Adrenal Cortex and Gonads and primarily affect maturation and function of secondary sex organs (male sexual determination). Androgens are derived from the two 17Alpha-Hydroxylated Steroids: 17Alpha-Hydroxypregnenolone and 17Alpha-Hydroxyprogesterone. These two Steroids can be converted by CYP17 to the weak Androgens DHEA (Dehydroepiandrosterone) and Androstenedione, respectively. DHEA is converted to Androstenedione, by HSD3B. Androgen formation in the adrenals is limited to DHEA and Androstenedione, whereas in the testes the presence of HSD17B (Hydroxysteroid (17-beta) Dehydrogenase) in Leydig cells ensures the formation of Testosterone, the principal "male" hormone. Estrogens originate in the Adrenal Cortex and Gonads and primarily affect maturation and function of secondary sex organs (female sexual determination). Estrogen formation requires another P450 enzyme, the Aromatase complex: CYP19A1 (Cytochrome P450 Family-19 Subfamily-A Polypeptide-1)/Estrogen Synthetase. The substrate is either Androstenedione (for Estrone) or Testosterone (for Estradiol). Estrone and Estradiol are interconvertible through a reversible reaction involving HSD17B, as in the Androstenedione-Testosterone conversion. Aromatase activity is present in the Ovary and the Placenta (Ref.8, 9, 10, 11 & 12).

The Steroid hormones are released into the blood circulation as soon as they are formed, travel to various parts of the body, and act on specific cells to bring about specific responses. All the Steroid hormones exert their action by passing through the plasma membrane and binding to intracellular receptors. The steroid hormone-receptor complexes exert their action by binding to specific nucleotide squences in the DNA of responsive genes. These DNA sequences are identified as HREs (Hormone Response Elements). The interaction of Steroid-Receptor complexes with DNA can induce or repress the transcription of their associated genes. A number of endocrine disorders are also attributed to defects in steroid biosynthesis due to specific enzyme defects. Inability to secrete normal levels of adrenal steroids may result in CAH (Congenital Adrenal Hyperplasia). In the majority of cases, this syndrome is due to CYP21A2 deficiency, and is associated with increased adrenal androgen secretion and partial virilization in girls. Defects in testicular Androgen synthesis (CYP17 or HSD17B deficiency) can lead to male Pseudohermaphroditism (Ref.13, 14 & 15).