The principal progestational steroid in females is progesterone. It is produced from cholesterol by both the corpus luteum of the ovaries and the placenta (see Figure 1).
Fig1. Pathway of the production of progesterone by the corpus luteum and estradiol by the theca and granulosa cells. Cholesterol is the starting point for the production of both progesterone (shown in green color) and estradiol (shown in blue color). There are two pathways from dehydroepiandrosterone (DHEA) to estradiol-17. The major pathway is via androst-4-ene-3, 17dione and estrone. The second pathway via androste-5-ene-3β, 17β-diol and testosterone is only a minor pathway (see three magenta dashed lines). The chemical details of the aromatization of estradiol are described in Figure 2. For each of the steroid enzyme transformations, the seven letter/number acronym is shown in magenta next to the arrow. The enzyme full name for each acronym is tabulated in Table 1.
Fig2. Proposed mechanism of aromatization of estradiol. The aromatase belongs to the cytochrome P450 super family of enzymes. The aromatase is located in the endoplasmic reticulum and is specifically responsible for the production of the steroid hormone estradiol (shown in blue color). The reaction requires one molecule of testosterone (shown in green color), three molecules of NADPH, and three molecules of O2. The initial step is hydroxylation of carbon 19 (the CH3) followed immediately by a second hydroxylation of carbon-19 to yield a gem-diol, which fragments into a C-19 aldehyde. The third oxidative attack (O2) results in the conversion of the C-19 aldehyde into a C-19 carboxyl group that is followed by an immediate elimination of the C-19 methyl group as formic acid which completes the aromatization of the A-ring. Aromatization of estradiol as described by W.L. Miller & R.J. Auchus in Endocrine Rev. 32, 81–151 (2001).
Table1. a Key Human Enzymes Concerned with the Production of Steroid Hormones
The several metabolic pathways for the conversion of either androst-4-ene-3,17-dione (25) or testosterone (15) into estrogens are also summarized in Figure 1; a unique feature of this conversion is the loss of carbon-19.
The estrogens are all 18-carbon steroids. They are produced in females in the ovaries (both the follicle and corpus luteum) and the fetal–placental unit. In males, the testes under some circumstances can produce physiologically significant amounts of both estrone and estradiol (not illustrated). In both males and females, the adrenal cortex zona fasciculata can generate small quantities of estrone from androst-4 ene-3,17-dione (not illustrated).
The estrogens in humans are characterized by (i) loss of carbon-19, (ii) the presence of an aromatic A ring, (iii) absence of the two-carbon side chain on car bon-17, and (iv) presence of a hydroxyl group at both carbon-3 and carbon-17 and, in the instance of estriol, a third hydroxyl at carbon-16. The major naturally occurring steroids with estrogenic activity are estra 3,17β-diol, estra-3,16α,17β-triol.
Figure 2 presents a detailed illustration of the chemistry involved with the conversion of the A-ring of testosterone or androste-4-ene, 3, 17dione into an aromatic ring, which is the hallmark of an estrogen.
Pregnancy is characterized in humans by a massive increase in the production of both progesterone and estrogen. The increase in progesterone and estradiol production occurs only in the placenta
