Leydig Cells as a Target for Male Contraception

Current approaches to fertility control are predominantly targeted to women. However, men have traditionally and historically played an important role in contraception. Thus, until the second half of the 20th century, periodic abstinence, coitus interruptus, condoms, and vasectomy, all of which are male-directed or male-oriented methods, were the only means for couples to limit family size. However, all of these methods are associated with limited effectiveness, lower acceptability, and partial irreversibility. Therefore, protracted efforts have been made to develop an endocrine male contraceptive regimen. Although our limited understanding of the complex regulatory mechanisms underlying normal spermatogenesis makes it difficult to identify specific testicular targets for pharmacological disruption, both T and FSH are required for complete spermatogenesis in humans. Therefore, to suppress spermatogenesis, the pituitary gonadotropic stimulus is inhibited, thereby abrogating Leydig cell steroidogenesis and nullifying FSH simultaneously. The consequent depletion of intratesticular testosterone and loss of FSH action result in a collapse of spermatogenesis without affecting stem cells. Maintenance of the spermatogonial stem cell population ensures that hormonal suppression of spermatogen-esis is reversible. Because testosterone is necessary for spermatogenesis (133), Leydig cells represent an obvious target for hormonal contraception.

Hormonal contraception targets Leydig cells, suppressing their androgenic function. How much testosterone is needed for normal spermatogenesis in humans remains to be determined. In rats, intratesticular testosterone concentrations as low as 5% of normal support the complete spermatogenic process, whereas in the nonhuman primate, testic-ular androgen levels of 30% of baseline do not prevent complete suppression of germ cell development (134,135). Therefore, testosterone levels must be reduced below a threshold for successful interruption of spermatogenesis. In primates, however, the selective suppression of Leydig cell testosterone production is not sufficient to accomplish the goal of fertility regulation, and the additional inhibition of FSH secretion is necessary (136). One effective approach may be to suppress both LH and FSH secretion and, simultaneously, supply androgen to avoid peripheral androgen deficiency (137).

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