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Two aromatase inhibitors inhibit the ability of a third to promote mating in male rats

Abstract

Aromatase, the enzyme that aromatizes androstenedione (A) to estrone and testosterone (T) to estradiol (E), affects androgen control of male sex behavior in many vertebrates. In male monkeys, rats and quail, E mimics the ability of T to promote mating, and aromatase inhibitors block mating induced by T but not E. Aromatase inhibitors include androgens with different A-rings than T and A, e.g., 1,4,6-androstatriene-3,17-dione (ATD), azoles, e.g., fadrozole, and androgens alpha-halogenated at carbon 6, e.g., 6 alpha-bromoA, 6 alpha-fluoroA and 6 alpha-fluoroT. 6 alpha-FluoroT is the only 6 alpha-halogenated androgen studied in regard to mating. It promotes mating in male rats and quail and was studied, before it was known to inhibit aromatase, because it cannot be aromatized yet has the same A-ring as T. 6 alpha-FluoroT might promote mating by binding estrogen receptors (ER) directly, i.e., unassisted, or by metabolism to an androgen that binds ER. Since neither process would require aromatase, this study tested both hypotheses by determining how mating induced in castrated male rats by 6 alpha-fluoroT is affected by ATD and fadrozole. Both aromatase inhibitors inhibited the effects of 6 alpha-fluoroT on mating. Thus, 6 alpha-fluoroT does not promote mating by direct ER binding or metabolism to another androgen. Since aromatase underlies a process in which 6 alpha-fluoroT, unlike most nonaromatizable androgens, mimics T effects on male sex behavior, the process must involve a feature that 6 alpha-fluoroT shares with T but not other nonaromatizable androgens. A-ring structure is a candidate. A hypothesis is also offered for how aromatase may participate without aromatizing the androgen. (C) 2015 Elsevier Inc. All rights reserved.

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