Developing new reversible male contraceptives

Summary

Sex hormone treatment is a promising reversible contraceptive that acts by stopping the pituitary hormone drive needed for sperm production. We are assessing its clinical efficacy and also examining other potential target for non-hormonal methods such as the disruption of cell junctions within the seminiferous epithelium.

Description

Men currently play a major role in contraception through natural family planning, condom use and sterilisation but new effective, reversible and acceptable options are needed.

In stable couples, male hormonal contraception (MHC) is a promising approach based on testosterone treatments (usually injection), often in combination with a progestin (a component of the female hormonal methods), acting to suppress the pituitary hormones that drive sperm production. About 95% of men show suppression of sperm count to a degree that will probably provide contraception of the same effectiveness as the female oral contraceptive.

We are studying how MHC affects sperm production and whether there are ways to make it more rapid and universally effective. We undertake sophisticated hormonal and genetic studies using blood and testicular biopsies samples from animal models and men following MHC treatment.

We are also involved in ongoing WHO-sponsored clinical trials that are addressing key practical matters that will determine the wider acceptance of MHC including the most effective and convenient dose and frequency of treatment, and the best way to monitor the possible long-term health effects.

Enrolling men in short-term contraceptive studies prior to vasectomy has allowed us to obtain testicular tissue and thus greatly enhanced our knowledge regarding the effects of male hormonal contraceptives on the spermatogenic process.

Initial work highlighted the two major sites of contraceptive disruption in spermatogenesis, namely the maturation of type B spermatogonia and the realse of mature sperm from the Sertoli cell (spermiation). However more recent work using novel contraceptive combinations (androgens, GnRH antagonists, progestins) has confirmed that whilst intratesticular testosterone and its 5 alpha reduced metabolites were similarly suppressed, the pattern of germ cell suppression remains heterogenous and seemingly unrelated to treatment combination, serum or intratesticular hormone levels.

Further work has explored the relative gonadotrophin and intratesticular androgen dependence of germ cell subtypes. Interestingly, it was found that the selective maintenance of either LH or FSH can maintain spermatogenesis with FSH better able to support pachytene spermatocyte number and LH providing improved conversion to round spermatids.

Taken together these studies emphasise the need for future contraceptive treatment strategies to consider the heterogenous germ cell response and independent regulation of spermatogenesis by FSH and LH/intratesticular androgens for maximum efficacy.

Funding

Contraceptive Research and Development Agency (CONRAD), USA
World Health Organisation
National Health and Medical Research Council

Outcomes

Established the two major sites of hormonal contraceptive disruption in human spermatogenesis (maturation of type B spermatogonia and spermiation).
Described the heterogeneity in germ cell suppression in response to male hormonal contraception and showed that this was seemingly unrelated to treatment combination, serum or intratesticular hormone levels.
Established that selective maintenance of either LH or FSH can maintain human spermatogenesis, with FSH better able to support pachytene spermatocyte number and LH providing improved conversion to round spermatids.
Collaborated with the ANZAC Institute, Sydney, in the first demonstration that an androgen-progestin combination provided effective contraception over a 12 month period in 55 normal couples.
Is currently one of only 8 centres worldwide participating in the WHO-CONRAD sponsored trial of the clinical efficacy of testosterone undecanoate and norethisterone enanthate in 400 couples using this as their sole contraceptive method for 1 year.

Selected Publications

Liu PY, McLachlan RI (2008). Male hormonal contraception: so near and yet so far. J Clin Endocrinol Metab 93:2474-2476.

Matthiesson KL, McLachlan RI, O'Donnell L, Frydenberg M, Robertson DM, Stanton PG, , Meachem SJ. (2006) The relative roles of FSH and LH in maintaining spermatogonial populations and spermiation in normal men. Journal of Clinical Endocrinology & Metabolism 91:3962-9.

Matthiesson K & McLachlan RI. (2006) Male Hormonal Contraception: concept proven, product in sight? Human Reproduction Update 12:463-82.

Matthiesson KL, Stanton PG, O'Donnell L, Amory JK, Berger R, Bremner WJ, McLachlan RI. (2005) Effects of testosterone and levonorgestrel combined with a 5 alpha reductase inhibitor or GnRH antagonist on spermatogenesis and intratesticular steroid levels in normal men. Journal of Clinical Endocrinology & Metabolism 90:5647-5655.

Matthiesson KL, Amory JK, Berger R, Ugoni A, McLachlan RI, Bremner WJ. (2005) Novel male hormonal contraceptive combinations: the hormonal and spermatogenic effects of testosterone and levonorgestrel combined with a 5 alpha reductase inhibitor or GnRH antagonist. Journal of Clinical Endocrinology & Metabolism 90:91.

McLachlan RI, Robertson DM, Pruysers E, Ugoni A, Matsumoto AM, Anawalt BD, Bremner WJ, Meriggiola C. (2004) Relationship between serum gonadotropins and spermatogenic suppression in men undergoing steroidal contraceptive treatment. Journal of Clinical Endocrinology & Metabolism 89:142-9.