Male hormonal contraception: the effects of progestogens on the hypothalamic-pituitary-gonadal axis in the human male

Abstract

With a third of the World's population relying on male methods of contraception, there is a need to expand choice for couples relying on male methods. Combined testosterone and progestogen preparations suppress gonadotrophin secretion and spermatogenesis, and are a promising approach to male hormonal contraception. The Edinburgh cohort (20 subjects) of a multicentre study investigating the efficacy in suppression of spermatogenesis and gonadotrophins with 300μg oral etonogestrel (ENG) and intramuscular testosterone decanoate (TD) (400mg 4 or 6 weekly) over 48 weeks is reported. Despite persisting sub-physiological trough testosterone concentrations, profound spennatogenic and gonadotrophin suppression was observed and was greater in Group I receiving 400mg TD every 4 weeks than Group II (400mg TD every 6 weeks)

Depot gestagen preparations may permit 'dose-sparing' thus minimising adverse metabolic effects, and allowing a more convenient dose interval. This regime was further investigated using ENG implants and i.m. TD for 48 weeks in a multi-centre study (130 subjects). Subjects received 204mg ENG implants (equivilent to 3 Implanon®) and either 400mg TD every 4 weeks, 6 weeks or 600mg 6 weekly for a period of 48 weeks. A similar profound suppression of spermatogenesis and gonadotrophins was observed again, with a lesser suppression in the lower testosterone group receiving 400mg TD 6 weekly

The effects of the same dose of etonogestrel implants was investigated in a further study (15 subjects) with a different testosterone preparation, 400mg pellets at 12 weekly intervals. Suppression of spermatogenesis was greater than the other regimes investigated with sperm concentrations of <1 x 10₆M/ml in all men by 16 weeks of treatment and eventual azoospermia in all subjects. Testosterone levels remained in the physiological range throughout. In contrast to the other regimes, there were no adverse metabolic effects with no weight gain, change in body composition, or decline in HDL-C concentrations.

The underlying mechanisms of the antigonadotrophic effects of gestogens in the male were investigated. Gestogens have affinity for both androgen and progesterone receptors but the relative contribution of action at these two receptors in gonadotrophin suppression remains unclear. The effects of progesterone, with no significant androgen-receptor affinity were compared to desogestrel, with relatively low affinity for the androgen receptor, on gonadotrophin secretion in normal men. Twenty healthy men were randomly allocated to the two treatment groups receiving either 50mg progesterone i.m. or 300μg desogestrel p.o. daily for 7 days. Frequent blood sampling over 12 hrs was undertaken before and after drug administration. GnRH (lOOμg i.v.) was administered 2 hrs before the end of the frequent sampling period. Both progesterone and desogestrel administration resulted in decreases in the concentration of both LH and FSH secretion, as well as testosterone. Analysis of the pulsatile nature of LH secretion indicated that both treatments reduced LH pulse amplitude, and that progesterone reduced LH pulse frequency. Progesterone but not desogestrel treatment also reduced the increase in LH secretion in response to GnRH. The effects of progesterone were at least as marked as those of a maximally-effective dose of desogestrel. As progesterone has negligible affinity for the androgen receptor, these results suggest that the suppressive effects of synthetic gestogens on gonadotrophin secretion in the male are not due solely by nature of their androgenicity but are mediated via the progesterone receptor.