PHI Research Team
Dr Bianca St John
Developing new reversible male contraceptives
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.
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 exploring the relative gonadotrophin and intratesticular androgen dependence of germ cell subtypes. Our work has 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). We are now focussing on the mechanism of spermiation failure including the gene and proteins involved in cell remodelling and cell-cell junction.
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.
We were one of eight sites world-wide involved in the World Health Organisation (WHO)-sponsored multi-centre clinical trials of a male reversible contraceptive. This phase IIb trial involved several hundred couples from seven studies aimed to determine the safety and efficacy of a bi-monthly injection of testosterone and a synthetic hormone, progestin. The formula used in the trial lowered pituitary hormones known to initiate spermatogenesis in the testis without impacting normal testosterone levels in the blood needed for sexual function and general health. This study as brought to an end by WHO in early 2011 after the enrolment of close to 300 couples. Final participants in our study ceased treatment in April 2011 and are benig monitored until sperm production has returned.
We are continuing our study to understand the underlying mechanisms that enable this type of contraception to interrupt sperm production both in vivo and using cultured testicular cells and tubules.
- Contraceptive Research and Development Agency (CONRAD), USA
- World Health Organisation
- National Health and Medical Research Council
- 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.
- Identified pathways of hormone action of sertoli and germ cells and cell junction involved in spermatogensis.
- One of only 8 centres worldwide participating in the recently completed 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.
O'Donnell L, Nicholls PK, O'Bryan MK, McLachlan RI, Stanton PG. Spermiation: The process of sperm release. Spermatogenesis (2011) 1(1):14-35.
Nicholls PK, Harrison CA, Walton KL, McLachlan RI, O'Donnell L, Stanton PG. Hormonal regulation of sertoli cell micro-RNAs at spermiation. Endocrinology (2011) 152(4):1670-83.
Liu PY, McLachlan RI. Male hormonal contraception: so near and yet so far. Journal of Clinical Endocrinology & Metabolism (2008) 93:2474-2476.
Matthiesson KL, McLachlan RI, O'Donnell L, Frydenberg M, Robertson DM, Stanton PG, Meachem SJ. The relative roles of FSH and LH in maintaining spermatogonial populations and spermiation in normal men. Journal of Clinical Endocrinology & Metabolism (2006) 91:3962-9.
Matthiesson K and McLachlan RI. Male Hormonal Contraception: concept proven, product in sight? Human Reproduction Update (2006) 12:463-82.
Matthiesson KL, Stanton PG, O'Donnell L, Amory JK, Berger R, Bremner WJ, McLachlan RI. 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 (2005) 90:5647-5655.
Matthiesson KL, Amory JK, Berger R, Ugoni A, McLachlan RI, Bremner WJ. 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 (2005) 90:91.
McLachlan RI, Robertson DM, Pruysers E, Ugoni A, Matsumoto AM, Anawalt BD, Bremner WJ, Meriggiola C. Relationship between serum gonadotropins and spermatogenic suppression in men undergoing steroidal contraceptive treatment. Journal of Clinical Endocrinology & Metabolism (2004) 89:142-9.