Estradiol biosynthesis

The estrogens are a family of hormones synthesized in a variety of tissues. 17P-Estradiol is the primary estrogen of ovarian origin. In some species, estrone, synthesized in numerous tissues, is more abundant. In pregnancy, relatively more estriol is produced, and this comes from the placenta. The general pathway and the subcellular localization of the enzymes involved in the early steps of estradiol synthesis are the same as those involved in androgen biosynthesis. Features unique to the ovary are illustrated in Figure 42-7. 

Steroids are a class of lipids that have in common a system of four linked carbon rings. Cholesterol, shown in Figure 13.14, is the most abundant steroid by far, and it serves as the starting material for the biosynthesis of most all other steroids, including the sex hormones estradiol and testosterone, also shown in Figure 13.14. Hormones are chemicals produced by one part of the body to influence other parts of the body. For example, estradiol, produced by the ovaries, and testosterone, produced by the testes, are responsible for the development of secondary sex characteristics in other parts of the body. Cholesterol is... 

The step-by-step synthesis of the steroid hormones pregnenolone and progesterone from cholesterol (C27) was presented in chapter 20 (see fig 20.22). Note that pregneno-lone (C2i) and progesterone (table 20.4) (C2 ) are intermediates in the biosynthesis of all of the major adrenal steroids, including cortisol (C2i), corticosterone (C21), and aldosterone (C21). The same two compounds are intermediates in the synthesis of the gonadal steroid hormones, testosterone (C,9) and 17/3-estradiol (CI8). Because the synthesis of all these hormones follows a common pathway, a defect in the activity or amount of an enzyme along that pathway can lead to both a deficiency in the hormones beyond the affected step and an excess of the hormones, or metabolites, prior to that step. 

Steroid hormones bear a remarkable structural similarity to one another (see Fig. 29-1). The precursor for steroid biosynthesis is cholesterol. Consequently, all of the steroid hormones share the same basic chemical configuration as their parent compound. This fact has several important physiologic and pharmacologic implications. First, even relatively minor changes in the side chains of the parent compound create steroids with dramatically different physiologic effects. For instance, the addition of only one hydrogen atom in the sex steroid pathway changes testosterone (the primary male hormone) to estradiol... 

FIGURE 29-1 Pathways of adrenal steroid biosynthesis. Cholesterol is the precursor for the three steroid hormone pathways. Note the similarity between the structures of the primary mineralocorticoid (aldosterone), the primary glucocorticoid (cortisol), and the sex hormones (testosterone, estradiol). See text for further discussion. 

FIGURE 12.1 Biosynthesis of estrogens. Abbreviations DHEA, dehydroepiandrosterone El, estrone E2, estradiol T, testosterone DHT, dihydrotestosterone. Letrozole is an aroma-tase inhibitor, Finasteride is a 5a-reductase inhibitor. Androstane-3p,17P-diol (SPO) is an estrogenic steroid and its synthesis is blocked by 5a-reductase inhibitor, but not affected by aromatase inhibitor."... 

Cholesterol, the most abundant steroid, is an important constituent of cell membranes and the starting material for biosynthesis of other steroids. This includes the sex hormones, such as progesterone, estradiol, testosterone, and androsterone, adrenocortical hormones such as aldosterone and cortisone, bile salts, and vitamin D. 

Fig. 45.3. Biosynthesis of androgens and other sex steroid hormones. The enzymes involved in this biosynthesis are (a) side-chain cleavage, (b) 17a-hydroxylase (c) 5-ene-3(3-hydroxysteroid dehydrogenase, (d) 3-oxosteroid-4,5-isomerase, (e) 17,20-lyase, (f) 17(3-hydroxysteroid dehydrogenase, (g) aromatase, (h) estradiol dehydrogenase, and (i) 5a-reductase.

Estrogens are biosynthesized in the maturing dominant foiiicle and in the corpus luteum in premenopausal women. During pregnancy, the placenta becomes the primary location of estrogen biosynthesis (5,6). Approximately 50% of estrone production occurs in the ovaries. The remaining estrone is biosynthesized from estradiol as well as from the conversion of estrone sulfate to estrone in the adrenal gland and the aromatization of androstenedione. In contrast to premenopausal women, in whom the natural estrone to estradiol ratio is 1 2, postmenopausal women have an estrone to estradiol ratio of 2 1, which reflects the loss of ovarian function. 

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