Studies in male hormonal contraception

Abstract

Early studies aimed at producing a reversible contraceptive for men involved treatments with injectable testosterone esters which induce azoospermia in only a proportion of subjects. Androgens remain a central part of any hormonal contraceptive for men although understanding the heterogeneity of the suppression response within populations may be pivotal and require consideration of other hormonal regulatory systems. Development of minimally invasive, long acting androgen formulations is also necessary to provide an acceptable, convenient and reliable form of androgen delivery which men themselves can administer. The first study describes a clinical trial employing a wholly subject administered, non-invasive hormonal contraceptive regime which combined transdermal T patches with the oral progestin desogestrel (DSG). The study shows that oral DSG combined with transdermal T produces suppression of gonadotrophins and spennatogenesis but is less effective than regimens incorporating injectable T and serves to further emphasise the critical role of T delivery. Studies in animals have established pro lac tin as a progonadal hormone in the testis and accessory glands. To explore the role of prolactin in men we first investigated the localization of prolactin receptor expression in the human testis and accessory tissues by immunohistochemistry and found it to be localized to the Leydig cells and differentiating cells of the testis, the epithelium of vas deferens, epididymis, prostate and seminal vesicles. Expression of prolactin receptor mRNA was identified in human testis and vas deferens by RT-PCR. Functional activation of prolactin receptor was demonstrated in human vas deferens by examination of the Janus Kinase/Signal Transducer and Activator of Transcription and Mitogen Activated Protein kinase and Extracellular signal-Regulated Kinase signalling pathways. The demonstration of function and localization of the prolactin receptor presented here suggests multiple roles for prolactin in the human male reproductive tract. The final study investigated whether concomitant suppression of PRL with the non-ergot, dopamine receptor agonist quinagolide (Q) in healthy male volunteers , would enhance spermatogenic suppression by testosterone (T). The results suggest that inhibition of PRL does not confer additional efficacy in spermatic suppression by T although difficulty in consistently suppressing PRL in eugonadal men did not allow unequivocal testing of the hypothesis. It is hoped that these studies address some of the challenges in this area and contribute toward the ambition of a safe, reversible contraceptive for men.