J I

Vitamin D metabolites

FIGURE 2-19 Relationship between stimulatory peptide hormones and the production of steroid hormones. For each of the six classes of steroid hormones, the specific stimulatory or tropic peptide hormone is indicated as well as specification of the organ or cell upon which it acts. Also, in males, FSH is known to act upon the Sertoli cells of the seminiferous tubules to increase the production not of a steroid hormone but of sperm proteins, androgen-binding protein, and inhibin, a peptide hormone.

It is important to appreciate that the production of each steroid hormone is dependent upon the stimulation of its cells of origin by a specific tropic (stimulatory) peptide hormone.

The purpose of the following section is to review the metabolic pathways by which the six classes of steroid hormones are produced. All discussions of the endocrine systems for each of the steroid hormone classes as well as of their biological properties and modes of action are deferred to subsequent chapters in this book.

B. Biosynthesis of Pregnenolone and Progestins

Figure 2-20 illustrates the various steps involved in the production of progesterone. As indicated in Figure 2-18, the conversion of cholesterol into pregnenolone and then progesterone is a common pathway leading to the production of the five classes of steroids.

The conversion of cholesterol into pregnenolone is carried out by one P450-containing enzyme known as the cholesterol side chain cleavage enzyme or P450scc. Once pregnenolone (72) is produced from cholesterol (3), it may undergo one of two conversions: it may undergo 17a-hydroxylation, ultimately leading in the adrenals to Cortisol (13), or it may be converted to progesterone (12), which is a significant steroid hormone produced by the corpus luteum and placenta. Progesterone is also an intermediate in the synthesis of aldosterone in the adrenals. The two-step transformation of pregnenolone into progesterone is also catalyzed by one enzyme that carries out the 3/8-steroid dehydrogenase oxidation of the 3/6-OH and also the movement of the A5,A4-double bond (isomerase).

The principal progestational steroid in humans is progesterone. It is produced by both the corpus luteum of the ovaries and the placenta. The physiological actions of progesterone are described in Chapter 13.

C. Biosynthesis by the Adrenal Cortex of Glucocorticoids, Mineralocorticoids, and Some Androgens

Figure 2-21 presents the structures of the adrenal cortex steroids that lead to the biosynthesis of glucocorticoids, mineralocorticoids, and the androgen dehy-droepiandrosterone (DHEA). As discussed in Chapter 10 and Table 2-6, the adrenal cortex is anatomically divided into three zones that produce different major classes of the adrenal steroids; these are the zona glomerulosa (mineralocorticoids), zona fasciculata (glucocorticoids), and zona reticularis (androgens). Over 45 steroids have been isolated and chemically characterized from adrenal gland extracts. The 21-carbon corticosteroids include the glucocorticoids and the mineralocorticoids; both subclasses are produced by the adrenal cortex (see Chapter 10). The corticosteroids are characterized by (i) an oxo group at carbon-3 and a double bond at carbon-4; (ii) a two-carbon side chain

Hormones, Second Edition

NADP+

• Aldosterone

17-aOH-Pregnenolone (74)

17-aOH-Progesterone (76)

FIGURE 2-20 Biosynthesis of pregnenolone, 17a-pregnenolone, and progesterone. The steps of metabolism are numbered (in circles) according to the reactions described in Figure 2-18 and Table 2-6. The cholesterol side chain cleavage enzyme (csc) carries out three enzymatic steps, comprising two successive hydroxylations followed by scission of the C-20-C-22 carbon-carbon bond. Similarly, the steps marked (2) are mediated by one enzyme that carries out a successive dehydrogenation followed by isomerization.

on carbon-17; and (iii) an oxo group at carbon-20 and a hydroxyl on carbon-21. Glucocorticoids are characterized by (iv) the presence or absence of hydroxyls at both carbon-11 and carbon-17. The principal glucocorticoid in humans is Cortisol. Mineralocorticoids are characterized by (v) a hydroxyl at carbon-11 and (vi) carbon-18 oxidized to an aldehyde.

The principal mineralocorticoid in humans is aldosterone. As a consequence of its carbon-18 aldehyde moiety, aldosterone can form a five-membered hemiac-etal ring utilizing the C-18 aldehyde with the carbon-

FIGURE 2-21 Pathways of glucocorticoid, mineralocorticoid, and dehydroepiandrosterone (DHEA) biosynthesis in the adrenal cortex. The main steps of metabolism are numbered (in circles) according to the reactions described in Figure 2-18 and Table 2-6. The boldface arrows indicate the major pathways of biosynthesis of Cortisol and aldosterone; however, there is no single exclusive pathway. The alternate possibilities are indicated by regular arrows. Under some circumstances, the androgen DHEA can also be produced by the adrenals (see Chapter 10).

Dehydroepiandrosterone (DHEA) (77)

Cholesterol (3) t ho-

Dehydroepiandrosterone (DHEA) (77)

Cholesterol (3) t

Pregnenolone (72)

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