Biosynthesis of oestrogens

Although it has long been known that C19 steroids, such as 4-androstenedione, give rise to oestrogens, the mechanism of this conversion has been the focus of intense study [52,97]. In pre-menopausal women the major source of oestrogen are the ovaries but, in many species, the testes make a significant contribution. The adrenals seem only to produce small quantities. However, it has been known for some years that, in post-menopausal women, most of the oestrogen formed is derived 

The first step in the conversion of 4-androstenedione to oestrone is the hydrox-ylation at C-19, a reaction associated with the ER and which requires NADPH and 02. It was thought earlier that the 19-hydroxy derivative was then converted to the 19-aldehyde, which gave rise to oestrone or oestradiol-17/3 (from 4-androstenedi-one or testosterone, respectively) as rupture of the bond between C-10 and the angular methyl group at C-19 occurred through C-10,19-lyase action (Fig. 12). More recent studies [42,52] have resulted in the proposal of at least three mechanisms, which all involve a second stereospecific hydroxylation at C-19 (requiring a second 

19-d i hydroxy-4 -androstenedione (hydrated form of thel9-aldehyde derivative) 

Further work by Stevenson et al. [105] has shown that 16a-hydroxytestosterone can be aromatized to oestriol via the 19-dihydroxy and 19-oxo derivatives, these changes being identical to those indicated above [104], in which an enzyme-peroxide intermediate was postulated (Fig. 14). Since the aromatase system is known to be catalysed by cytochrome P-450 [106], it is feasible that involvement of a P-450-peroxide species could be envisaged, not only in the C-10,19 cleavage but also in the preceding hydroxylations (Fig. 15). 

There is evidence [52] that there are at least two forms of cyt P-450 involved with aromatization. Likewise, there is evidence for different aromatases in human placenta which catalyse the production of oestrone and oestriol from 4-androstenedi-one and 16a-hydroxytestosterone, respectively. Each enzyme system has been subfractionated into its own cyt P-450 and cyt P-450 reductase [107]. This has been supported recently by Purohit and Oakey [108], who measured aromatase activity for 16a-hydroxy-4-androstenedione and 4-androstenedione in the presence or absence of the other substrate. 4-Androstenedione competitively inhibited aromatization of the 16a-hydroxy derivative, with apparent K, essentially the same as its apparent Km, suggesting that both substrates bind and are aromatized independently of each other. The 16a-hydroxy derivative competitively inhibited the aromatization of 4-androstenedione, thus presumably lowering the affinity of the aromatase for the latter. 

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