Estradiol, from testosterone 6/3-hydroxylation

Fig. 1. Estrogens. Biosynthesis of estradiol from testosterone. Cip and C2(t hydrogens are lost, and C19 is removed as formate. Oxygen incorporated in the first hydroxylation is retained during subsequent oxidations until it appears in the product formate. Oxygen incorporated in the final hydroxylation also appears in the product formate. [J. Fishman Cancer Research (Suppl.) 42 (1982) 3277s-3280is]...

In the biosynthesis of estrone from J -androstenedione, or estradiol from testosterone, or estriol from 17a-hydroxytestosterone (Ryan, 1959), the aromatization of ring A is initiated by reactions designed to remove the angular C-19 methyl group (Meyer, 1955). It is now well-established that the first step is the hydroxylation of this carbon. The progression of reactions beyond this point is not yet clearly defined. However, from information available to date a pathway which appears most probable has been proposed (Fig. 16) (Longchampt et al., 1960b). 

Steroids are good substrates for microbiological reductions however, the reductions often lead to unwanted side reactions of desired transformations such as hydroxylations. The first report in 1937 291 dealt with baker s yeast reduction of the 3- and 17-groups and led to the synthesis of estradiol from estrone and testosterone from androstenedione. 

These experiments demonstrate that the C-19 carbon atom detaches itself as formaldehyde from the 19-oxo compound leaving a double bond at C-1 (Fig. 1, pathway a). There could, however, be two other ways in which formaldehyde arises in the eourse of aromatization (1) It is conceivable that formaldehyde is removed from the 19-hydroxy compound (Fig. 1, pathway b) the resulting 19-nor steroid could aromatize after hydroxylation at C-1 or C-2 and subsequent loss of the elements of water. This route, however, does not appear to be followed in placental microsomes, since after incubation in this stem, the relative yield of estradiol-17/8 from 19-nortestosteronc is only one-fifth of that from testosterone (Ryan, 1959a). If 19-nortestosterone is actually an intermediate in this reaction, this compound should give at least the same yield of estradiol-17j8 as that observed with testosterone. (2) The second possibility which does not involve the 19-oxo compound requires the introduction of a double bond into the 19-hydroxy compound (Fig. 1, pathway c). As has been shown by Khrenstein and Otto (1959), the A -19-hydroxy compound aromatizes... 

The answer is d. (Murray, pp 505-626. Scriver, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) Both cortisol and aldosterone contain C-21-hydroxyl groups. Both are also derived from progesterone in the adrenal cortex. In contrast, the sex hormones are synthesized in the ovaries and testicular interstitial cells. In the synthesis of sex hormones, progesterone is converted to 17a-hydroxyprogesterone and then androstenedione, which may either become estrone or testosterone. Testosterone gives rise to estradiol in the ovaries. In the corpus luteum, progesterone is produced. 

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