The principle of male hormonal contraception has been investigated for the past 20 years.
This thesis reviews what is known already from the literature and presents the results of
three new clinical trials investigating different aspects of this approach.These trials were undertaken by myself as a member of the Contraceptive Development
Network research group at the University of Edinburgh.MOIS: A clinical trial of male hormonal contraception with a treatment period of 48
weeks. Subjects (n=29) were randomised to receive either 2 MENT Ac implants or
600mg per 12 weeks testosterone pellets in conjunction with 2 etonogestrel implants and
outcome measures of sperm count, and reproductive hormone data were collected to
assess contraceptive effects. Haematology and biochemistry parameters, prostate volume,
PSA, bone density and blood pressure measurements were recorded to assess safety and
the effects on androgen dependent tissues. The spermatogenic suppression achieved was
similar and effective in both groups. Thereafter, the MENT group failed to maintain
suppression and 6 men nnoted loss of libido due to a decline in the release rate of the
MENT implants. No adverse effects of MENT on the prostate or bone mass were
demonstrated. A small but significant increase in systolic blood pressure was observed in
the MENT group and the implications of this remain to be further qualified. In the
testosterone group profound and consistent spermatogenic suppression was demonstrated
and azoospermia was achieved in all men. An increase in haemoglobin and prostate size
and reduction in HDL-C were noted. MENT with progestogen can achieve rapid suppression of spermatogenesis similar to testosterone, but this promising result was not
sustained due to a reduction in the MENT release from the implants. This dose of
testosterone, compared with previous studies using lower dose with a higher dose of
etonogestrel, had non-reproductive side effects without any increase in spermatogenic
suppression.Conclusion: These data indicate the importance of the doses of progestogen and
testosterone for optimum spermatogenic suppression while minimizing side effects.M016: A randomised controlled trial investigating the effects of gonadotrophin
withdrawal and progestogen administration on hormone production, metabolism and
action in the human testis. Thirty subjects were randomised to no treatment or
gonadotrophin suppression by GnRH antagonist with testosterone (CT) +/- additional
administration of the progestogen desogestrel (CTD) for 4 weeks before testicular biopsy.
Gene expression was quantified by PCR. Both treatment groups showed similar
suppression of gonadotrophins and sperm production and markedly reduced expression of
steroidogenic enzymes. Addition of progestogen resulted in expression of 5a-reductase
type 1 compared with both controls and the CT group. Inhibin-a and the spermatocytes
marker acrosin-binding protein were significantly lower in the CTD but not CT groups,
compared with controls, but did not differ between treated groups. Men who showed
greater falls in sperm production also showed reduced expression of these three genes but
not of the spermatid marker protamine 1.Conclusion: These data provide evidence for direct progestogenic effects on the testis and
highlight steroid 5a-reduction and disruption of spermiation as important components of
the testicular response to gonadotrophin withdrawal.M017: Investigation of testicular function in normal men and those receiving a male
hormonal contraceptive regimen. 20 subjects were recruited and hourly blood samples
were taken over 24 hours for measurement of testosterone, inhibin B, LH, FSH and
Cortisol. Urinary excretion of testosterone and the testicular steroid epitestosterone was
also measured. In the controls, a diurnal variation in serum testosterone and LH but not
FSH was detected. The treated group had similar testosterone concentrations but showed
no diurnal variation. Periodicity was detected in inhibin B concentrations in 5 controls
and in 9 of the treated group. Urinary testosterone excretion did not show a diurnal
variation in either group, but this was apparent for epitestosterone with a morning peak in
both groups despite the markedly lower excretion in the treated men.Conclusion: The diurnal variation of testosterone in normal men is due to change in
secretion rather than clearance and is largely LH driven. An endogenous rhythm in both
testicular steroidogenesis (epitestosterone) and Sertoli cell function (Inhibin B) is also
present
