The pathways of the biosynthesis of progesterone and estradiol from cholesterol are shown in Figure 1. The amounts of estradiol, estrone, and progesterone produced by the ovary and circulating during different phases of the menstrual cycle are shown in Table 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).. For each of the steroid enzyme transformations, the seven letter/number acronym is shown in magenta next to the arrow.
Table1. Production Rates and Plasma levels of Ovarian Steroid Hormones
The specific manner in which estradiol synthesis is accomplished in the pre-ovulatory follicle is shown in Figure 2 and involves the cooperation of two cell types and the activity of two gonadotrophins. The cells of the theca interna contain cholesterol side chain cleavage activity (CYP11A1/P450scc). These are the ovarian cells that express receptors for LH, the response to which is an increase in steroid acute regulatory protein (StAR) and the cleavage of the side chain of cholesterol. In the endoplasmic reticulum of the thecal cells, pregnenolone is converted to androstenedione by the removal of carbons 20 and 21 and the isomerization of the double bond from the B to the A ring of the steroid nucleus (Figure 1). Androstenedione diffuses across the basement membrane of the follicle into the follicular fluid from which it is taken up by granulosa cells. These cells express the FSH receptor which, when activated by FSH, brings about, through adenyl cyclase activation, the synthesis of Cyp19A1 (P450arom), the aromatase that converts androstenedione to estrone. Action of 17β-hydroxysteroid dehydrogenase (17-ketosteroid reductase; HSD17B1) converts estrone to estradiol (Figure 1). Thus, in order for sufficient amounts of estrogen to be synthe sized for maturation and ovulation of the follicle, both granulosa cells and thecal cells must be functional and both gonadotrophins must be secreted in appropriate amounts.
Fig2. Estrogen synthesis in the ovary. The two-cell model for estrogen synthesis in the pre-ovulatory follicle is depicted. Under the stimulation of LH (luteinizing hormone), mediated by adenyl cyclase (AC) activation leading to increased StAR (steroid acute regulatory protein), cholesterol (Chol.) is converted by Cyp 11A1 (cholesterol side chain cleavage; also known as P450scc) to pregeneolone (Preg.) in the mitochondria of the thecal cell. Pregnenolone is converted to androstenedione (A-dione) which crosses the basement membrane surrounding the follicle and enters the granulosa cells. Cyp 19A1 (aromatase), elevated by FSH stimulation of the granulosa cells, converts A-dione to estrone (see Figure 1). Finally, estrone is converted to estradiol by 17β-hydroxysteroid dehydrogenase (HSD17B1).
Following ovulation the major steroid produced by the luteinized cells of the corpus luteum is progesterone, although estrogen continues to be synthesized and secreted as well. Steroidogenesis in the corpus luteum is dependent on stimulation of the cholesterol side chain cleavage step by LH and the conversion of the resulting pregnenolone to progesterone (Figure 1).
