Aromatization of androgens

Estrogens are formed by the aromatization of androgens in a complex process that involves three hydroxyla-tion steps, each of which requires O2 and NADPH. The aromatase enzyme complex is thought to include a P450 monooxygenase. Estradiol is formed if the substrate of this enzyme complex is testosterone, whereas estrone results from the aromatization of androstenedione. 

Significant amounts of estrogens are produced by the peripheral aromatization of androgens. In human males, the peripheral aromatization of testosterone to estradiol (Ej) accounts for 80% of the production of the latter. In females, adrenal androgens are important... 

Estrogens are also neuroprotective against ischemic damage [13], and aromatization of androgens to estrogens plays a role even in females, where knockout of the aromatase gene increases the vulnerability of female mice to stroke damage by a process that is prevented by estradiol administration [33]. 

Miyairi, S. and J. Fishman (1983). Novel method of evaluating biological 19-hydroxylation and aromatization of androgens. Biochem. Biophys. Res. Commun. 117, 392-398. 

Local production of estrogens by the aromatization of androgens may play a causal role in the development or progression of diseases such as breast cancer. Estrogens also may be produced from androgens by CYPI9 in the central nervous system (CNS) and other tissues and exert local effects near their production site fe.g., in bone they increase bone mineral density). 

Anastrozole (Fig. 46.11) is a potent and highly selective, nonsteroidal aromatase inhibitor utilized in the treatment of advanced breast cancer that is hormone-responsive. It is considered to be second-line therapy (after tamoxifen) in the treatment of postmenopausal breast cancer. Anastrozole. a benzyltriazole derivative, competes with the natural substrate for binding to the active site of the aromatase. The mechanism of enzyme inhibition resides in the coordination of the triazole ring with the heme iron atom of the aromatase enzyme complex (161,162). This coordination ultimately prevents aromatization of androgens into estrogens and, therefore, deprives the tumor of estrogen. This effect is reversible. In the presence of anastrozole. estradiol levels are reduced to undetectable levels, with no adverse effects on levels of any other hormone, including cortisol and aldosterone. 

Fig. 9.27 Known reactions of human P450 19A1 (in addition to aromatization of androgens) [1373, 2300]...

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