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Introduction

With the exception of retinoic acid, the steroid hormones are all derived from cholesterol. Moreover, with the exception of vitamin D, they all contain the same cyclopentanophenanthrene ring and atomic numbering system as cholesterol. The conversion of C-27 cholesterol to the 18-, 19-, and 21-carbon steroid hormones involves the rate-limiting, irreversible cleavage of a 6-carbon residue from cholesterol, producing pregnenolone (C-21) plus isocaproaldehyde.
Common names of the steroid hormones are widely recognized, but systematic nomenclature is gaining acceptance and familiarity with both nomenclatures is increasingly important. Steroids with 21 carbon atoms are known systematically as pregnanes, whereas those containing 19 and 18 carbon atoms are known as androstanes and estranes, respectively. The important mammalian steroid hormones are shown below along with the structure of the precursor, pregneolone. Retinoic acid and vitamin D are not derived from pregnenolone, but from vitamin A and cholesterol respectively.

Pregnenolone: produced directly from cholesterol, the precusor molecule for all C-18, C-19 and C-21 steroids
Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstral cycle, differentiation factor for mammary glands
Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake
Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone
Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics
Cortisol: dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system

All the steroid hormones exert their action by passing through the plasma membrane and binding to intracellular receptors. The mechanism of action of the thyroid hormones is similar; they interact with intracellular receptors. Both the steroid and thyroid hormone-receptor complexes exert their action by binding to specific nucleotide squences in the DNA of responsive genes. These DNA sequences are identified as hormone response elements, HREs. The interaction of steroid-receptor complexes with DNA leads to altered rates of transcription of the associated genes.
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Steroid Hormone Biosynthesis Reactions

The particular steroid hormone class synthesized by a given cell type depends upon its complement of peptide hormone receptors, its response to peptide hormone stimulation and its genetically expressed complement of enzymes. The following indicates which peptide hormone is responsible for stimulating the synthesis of which steroid hormone:
The first reaction in converting cholesterol to C-18, C-19 and C-21 steroids involves the cleavage of a 6-carbon group from cholesterol and is the principal committing, regulated, and rate-limiting step in steroid biosynthesis. The enzyme system that catalyzes the cleavage reaction is known as P450-linked side chain cleaving enzyme (P450SSC), or desmolase, and is found in the mitochondria of steroid-producing cells, but not in significant quantities in other cells.
Mitochondrial desmolase is a complex enzyme system consisting of cytochrome P450, and adrenadoxin (a P450 reductant). The activity of each of these components is increased by 2 principal cAMP- and PKA-dependent processes. First, cAMP stimulates PKA, leading to the phosphorylation of a cholesteryl-ester esterase and generating increased concentrations of cholesterol, the substrate for desmolase. Second, long-term regulation is effected at the level the gene for desmolase. This gene contains a cAMP regulatory element (CRE) that binds cAMP and increases the level of desmolase RNA transcription, thereby leading to increased levels of the enzyme. Finally, cholesterol is a negative feedback regulator of HMG CoA reductase activity (see regulation of cholesterol synthesis). Thus, when cytosolic cholesterol is depleted, de novo cholesterol synthesis is stimulated by freeing HMG CoA reductase of its feedback constraints. Subsequent to desmolase activity, pregnenolone moves to the cytosol, where further processing depends on the cell (tissue) under consideration.
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Steroids of the Adrenal Cortex

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 that of steroids produced by the male gonads. Adrenal insufficiency is known as Addison disease, and in the absence of steroid hormone replacement therapy can rapidly cause death (in 1--2 weeks).
The adrenal cortex is composed of 3 main tissue regions: zona glomerulosa, zona fasciculata, and zona reticularis. 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 depending on the enzymes present in the cells of each zone.
Zona glomerulosa cells lack the 17-a-hydroxylase that converts pregnenolone and progesterone to their C-17 hydroxylated analogs. Thus, the pathways to the glucocorticoids (deoxycortisol and cortisol) and the androgens (dehydroepiandosterone and androstenedione) are blocked in these cells. 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. 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.
Cells of the zona fasciculata and zona reticularis lack the C-18 hydroxylase that converts corticosterone to aldosterone, and thus these tissues produce only the weak mineralocorticoid corticosterone. However, both these zones do contain the 17-a-hydroxylase missing in zona glomerulosa and thus produce the major glucocorticoid, cortisol. Zona fasciculata and zona reticularis cells also contain the 17-20 lyase, whose activity is responsible for producing the androgens, dehydroepiandosterone and androstenedione. Thus, fasciculata and reticularis cells can make corticosteroids and the adrenal androgens, but not aldosterone.
As noted earlier, P450SSC is a mitochondrial activity. Its product, pregnenolone, moves to the cytosol, where it is converted either to androgens or to 11-deoxycortisol and 11-deoxycorticosterone by enzymes of the endoplasmic reticulum. The latter 2 compounds then reenter the mitochondrion, where the enzymes are located for tissue-specific conversion to glucocorticoids or mineralocorticoids.
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Regulation of Adrenal Steroid Synthesis

Adrenocorticotropic hormone (ACTH) of the hypothalamus regulates the hormone production of the zona fasciculata and zona reticularis. ACTH receptors in the plasma membrane activate adenylate cyclase with production of the second messenger, cAMP. The effect of ACTH on the production of cortisol is particularly important, with the result that a classic feedback loop is prominent in regulating the circulating levels of corticotropin releasing hormone, (CRH), ACTH, and cortisol.
Mineralocorticoid secretion from the zona glomerulosa is stimulated by an entirely different mechanism. Angiotensins II and III, derived from the action of the kidney protease renin on liver-derived angiotensinogen, stimulate zona glomerulosa cells by binding a plasma membrane receptor coupled to phospholipase C. Thus, angiotensin II and III binding to their receptor leads to the activation of PKC and elevated intracellular Ca2+ levels. These events lead to increased P450SSC activity and increased production of aldosterone. In the kidney, aldosterone regulates sodium retention by stimulating gene expression of mRNA for the Na+/K+-ATPase responsible for the reaccumulation of sodium from the urine.
The interplay between rennin from the kidney and plasma angiotensinogen is important in regulating plasma aldosterone levels, sodium and potassium levels, and ultimately blood pressure. Among the drugs most widely employed used to lower blood pressure are the angiotensin converting enzyme (ACE) inhibitors. These compounds are potent competitive inhibitors of the enzyme that converts angiotensin I to the physiologically active angiotensins II and III. This feedback loop is closed by potassium, which is a potent stimulator of aldosterone secretion. Changes in plasma potassium of as little as 0.1 millimolar can cause wide fluctuations (+/- 50%) in plasma levels of aldosterone. Potassium increases aldosterone secretion by depolarizing the plasma membrane of zona glomerulosa cells and opening a voltage-gated calcium channel, with a resultant increase in cytoplasmic calcium and the stimulation of calcium-dependent processes.
Although fasciculata and reticularis cells each have the capability of synthesizing androgens and glucocorticoids, the main pathway normally followed is that leading to glucocorticoid production. However, when genetic defects occur in the 3 enzyme complexes leading to glucocorticoid production, large amounts of the most important androgen, dehydroepiandrosterone (DHEA), are produced. These lead to hirsutism and other masculinizing changes in secondary sex characteristics.
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Gonadal Steroid Hormones

Although many steroids are produced by the testes and the ovaries, the two most important are testosterone and estradiol. These compounds are under tight biosynthetic control, with short and long negative feedback loops that regulate the secretion of follicle stimulating hormone (FSH) and leutinizing hormone (LH) by the pituitary and gonadotropin releasing hormone (GnRH) by the hypothalamus. Low levels of circulating sex hormone reduce feedback inhibition on GnRH synthesis (the long loop), leading to elevated FSH and LH. The latter peptide hormones bind to gonadal tissue and stimulate P450SSC activity, resulting in sex hormone production via cAMP and PKA mediated pathways. The roles of cAMP and PKA in gonadal tissue are the same as that described for glucocorticoid production in the adrenals, but in this case adenylate cyclase activation is coupled to the binding of LH to plasma membrane receptors.
The biosynthetic pathway to sex hormones in male and female gonadal tissue includes the production of the androgens---androstenedione and dehydroepiandrosterone. Testes and ovaries contain an additional enzyme, a 17b-hydroxysteroid dehydrogenase, that enables androgens to be converted to testosterone
In males, LH binds to Leydig cells, stimulating production of the principal Leydig cell hormone, testosterone. Testosterone is secreted to the plasma and also carried to Sertoli cells by androgen binding protein (ABP). In Sertoli cells the D-4 double bond of testosterone is reduced, producing dihydrotestosterone. Testosterone and dihydrotestosterone are carried in the plasma, and delivered to target tissue, by a specific gonadal-steroid binding globulin (GBG). In a number of target tissues, testosterone can be converted to dihydrotestosterone (DHT). DHT is the most potent of the male steroid hormones, with an activity that is 10 times that of testosterone. Because of its relatively lower potency, testosterone is sometimes considered to be a prohormone.
Testosterone is also produced by Sertoli cells but in these cells it is regulated by FSH, again acting through a cAMP- and PKA-regulatory pathway. In addition, FSH stimulates Sertoli cells to secrete androgen-binding protein (ABP), which transports testosterone and DHT from Leydig cells to sites of spermatogenesis. There, testosterone acts to stimulate protein synthesis and sperm development.
In females, LH binds to thecal cells of the ovary, where it stimulates the synthesis of androstenedione and testosterone by the usual cAMP- and PKA-regulated pathway. An additional enzyme complex known as aromatase is responsible for the final conversion of the latter 2 molecules into the estrogens. Aromatase is a complex endoplasmic reticulum enzyme found in the ovary and in numerous other tissues in both males and females. Its action involves hydroxylations and dehydrations that culminate in aromatization of the A ring of the androgens.
Aromatase activity is also found in granulosa cells, but in these cells the activity is stimulated by FSH. Normally, thecal cell androgens produced in response to LH diffuse to granulosa cells, where granulosa cell aromatase converts these androgens to estrogens. As granulosa cells mature they develop competent large numbers of LH receptors in the plasma membrane and become increasingly responsive to LH, increasing the quantity of estrogen produced from these cells. Granulosa cell estrogens are largely, if not all, secreted into follicular fluid. Thecal cell estrogens are secreted largely into the circulation, where they are delivered to target tissue by the same globulin (GBG) used to transport testosterone.
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Michael W. King, Ph.D / Medical Biochemistry / Terre Haute Center for Medical Education / memwk@thcme.indstate.edu
Last modified:   Wednesday, 12-Apr-00 15:36:33