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.