Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception

Abstract

Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoospermia or severe oligozoospermia, commensurate with contraceptive efficacy. We tested here, using hypogonadal luteinizing hormone/choriongonadotropin receptor (LHCGR) knockout (LHR−/−) mice, the basic principle of the T-based male contraceptive method, that a specific T dose could maintain extragonadal androgen actions without simultaneously activating spermatogenesis. LHR−/− mice were treated with increasing T doses, and the responses of their spermatogenesis and extragonadal androgen actions (including gonadotropin suppression and sexual behavior) were assessed. Conspicuously, all dose responses to T were practically superimposable, and no dose of T could be defined that would maintain sexual function and suppress gonadotropins without simultaneously activating spermatogenesis. This finding, never addressed in clinical contraceptive trials, is not unexpected in light of the same androgen receptor mediating androgen actions in all organs. When extrapolated to humans, our findings may jeopardize the current approach to hormonal male contraception and call for more effective means of inhibiting intratesticular T production or action, to achieve consistent spermatogenic suppression.—Oduwole, O. O., Vydra, N., Wood, N. E. M., Samanta, L., Owen, L., Keevil, B., Donaldson, M., Naresh, K., Huhtaniemi, I. T. Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception.

Mouse models of altered gonadotrophin action: insight into male reproductive disorders

“…This suggests that spermatogenesis can proceed qualitatively to completion with support of the basal LH-independent low intra-testicular testosterone present in the LuRKO testis (Zhang et al 2003), though a much higher threshold of testosterone may be required to induce qualitatively and quantitatively full spermatogenesis (Huhtaniemi et al 2006). This finding was confirmed and extended in our recent study (Oduwole et al 2014), observing that a narrow margin separated the testosterone doses that activated peripheral male sexual androgen action and spermatogenesis. When extrapolated to humans, this may jeopardise the current approach to hormonal male contraception, as it will be practically impossible to define a single dose of testosterone that can suppress gonadotrophins and attain azoospermia.…”

A short evolutionary history of FSH-stimulated spermatogenesis

“…Hence, some Leydig cell factor(s) other than T can promote the proliferation and/or survival of spermatogonia. However, high-dose T supplementation seems to fully restore the number of mature spermatids in LuRKO 18,19 and hpg 16 mice. Furthermore, transcriptome analysis of testes of wildtype LuRKO and T-treated LuRKO mice showed that most of the defects in gene expression in the absence of LH action were corrected by T treatment.…”

Gonadotoropin actions on spermatogenesis and hormonal therapies for spermatogenic disorders [Review]

“…On the other hand, Pakarainen et al reported that 5-10 % of normal ITT is enough to initiate and maintain spermatogenesis [32]. Using LuRKO mice, Oduwole et al reported that exogenous testosterone administration with 5 mg but not 2.5 mg increased ITT level up to 20 nmol/L, which is still lower than control (120 nmol/L) and could restored sperm production [33]. In other words, the testosterone level in testes has a variety of effective ranges, and spermatogenesis is thought to be executed within a wide range with a varied extent of sperm production.…”