male condom

Every few months, headlines from the media report on the development of a new “male pill” or an exciting new form of male contraception. What is the reality and how can you advise your patients on the availability of reversible male contraceptives?

 

Is a new, reversible male contraceptive about to go on the market?

Unfortunately, no.

Many media reports on new male contraceptives come from preliminary studies that are often years away from being commercially available to men. Many studies report data from animals where a drug or agent has been administered and sperm output is halted. Research at this stage must undergo years of further development and clinical evaluation – with a high risk of failure – before a marketable product is available.

The only effective and reversible male contraception option on the market is the condom, with a “real world’ failure rate of ~13% per year[1].

 

Why has the development of new male contraceptives been so difficult?

One hurdle is a simple mathematical equation; a contraceptive needs to block the production of one egg (oocyte) per month in women compared to approximately one thousand sperm per heartbeat in men. Male contraceptives need to work very effectively at blocking sperm production.

A second major hurdle has been a lack of investment in research and development. Pharmaceutical companies have preferred to invest in the development of therapies to treat diseases, especially chronic disorders for which there is a large market and perceived need, rather than the higher risk and expositive strategy of developing agents to be administered over the long term to otherwise healthy men.

 

Male hormonal contraception is a promising approach

Over the past three decades, a wide variety of hormonal contraceptives have been trialled. These methods involve the administration of hormones, particularly androgen and progestin-like compounds. These suppress the release of gonadotrophins (FSH and LH) from the pituitary, resulting in the suppression of the synthesis of testicular testosterone and the production and release of sperm from the testes. These formulations contain androgenic agents that maintain peripheral androgen action.

The ability of these formulations to suppress sperm output depends on the degree to which gonadotrophins are suppressed. The time it takes for adequate sperm count suppression varies from weeks to months[2]. Formulations that inhibit sperm release at the end of the sperm production process may suppress sperm production quite rapidly[3]. Hormonal methods are fully reversible, although the time taken to fully recover sperm counts can be several months[2].

Many of these formulations are very effective at suppressing sperm output. The complete suppression of sperm counts to undetectable (azoospermia) is achievable in many, but not all, men and has a contraceptive efficacy comparable to the most effective female contraceptives[4]. Suppression of sperm counts to less than one million per mL of ejaculate is achievable in around 95% of men, with a contraceptive efficacy similar to female oral contraceptives[1],[2].

 

Challenges in getting a male hormonal contraceptive to the market

Despite these promising results from many clinical trials, challenges remain.

A small proportion of men fail to achieve adequate sperm count suppression for unknown reasons. Side effects occur and vary with formulation but are generally similar to those experienced by women taking hormonal contraceptives. These include acne, weight gain and impacts on libido (though men tend to report increased libido compared to decreased libido in women). Some formulations are associated with adverse changes in circulating lipoproteins. Effects on depression and mood with some formulations are a cause for concern, and these endpoints need to be monitored carefully in future clinical trials[2].

Male hormonal contraceptive research requires further investment so that formulations with optimal efficacy, safety and acceptability are brought to market. Unfortunately, at present there is little interest from the pharmaceutical industry but work continues in the USA public sector on innovative hormonal methods approaches.

 

What other male contraceptives are in the pipeline and where are they in their development?

Non-hormone-based contraceptive approaches are also being investigated. The Male Contraceptive Initiative is investing in research on a wide range of options to help bring a variety of marketable male contraceptives closer to reality. Various pharmaceutical agents that act on the testis to block sperm production have been investigated, but many have not progressed to further development2. Other approaches aim to reversibly block sperm motility or the transport of sperm into the ejaculate. For example, the injection of a substance into the vas deferens to reversibly block sperm output has been trialled, but a return to normal fertility after removal has been questioned by pre-clinical data[5].

 

Common questions about male contraceptives

Will there be a male contraceptive “pill”?

Maybe. Current approaches to hormonal contraceptives being trialled include implants, long-acting injectables and transdermal gels. Some newer compounds with androgen and progestin activity can be administered orally[2]. The ultimate goal should be the availability of a wide variety of methods so that the consumer can choose what is acceptable to them.

 

Could a male contraceptive harm future fertility?

A major goal for researchers working in male contraception is full reversal of fertility. Hormonal contraceptive approaches work by temporarily halting the process of sperm production, and a return to normal sperm counts after cessation of treatment has been proven in many different formulations. Other non-hormone-based approaches are evaluated on their ability to allow sperm counts to return to baseline.

 

Are side effects, safety and acceptability a concern?

Yes, but these depend on the formulation. Each formulation is evaluated closely for its patient acceptability and safety, with the newer generation formulations being trialled to overcome these issues2. The required clinical efficacy and safety studies involve large numbers of men/couples being assessed over long periods, and considerable investment is necessary to complete these studies.

 

The ultimate goal is to define formulations with the most favourable risk/benefit profiles. It is important to consider that female hormonal contraceptives are also associated with side effects and risks yet are still widely prescribed. Weighing up the risks and benefits for both partners is an important consideration when it comes to deciding on contraceptive method.

 

What to tell your patients about male contraceptives

There is no male contraceptive on the market, yet. Research is ongoing and needs investment and public support.

The leading candidates are based on hormonal contraception and – like female hormonal contraceptives – different methods are being trialled for their safety, efficacy and acceptability. Large, multi-centre trials have established the effectiveness and relative safety of hormonal contraceptives, but much more research needs to be done to identify the ideal formulations. Different methods, including physical barriers and non-hormone-based pharmaceuticals that specifically target sperm production, are also being investigated for their suitability as reversible contraceptives.

Dr Liza O'donnell
Dr Liza O’Donnell

Liza O’Donnell is a senior research scientist at the Hudson Institute of Medical Research and the University of Newcastle. She obtained her PhD from Monash University in reproductive endocrinology. During her career, Liza’s research interests have included the endocrine and molecular regulation of the testis, in particular male hormonal contraception and male infertility causes and treatments. Her work currently focuses on the identification of biomarkers to diagnose testis function and investigating new diagnostics and therapies to support optimal androgen production and fertility in men.

References

[1] Sundaram, A., B. Vaughan, K. Kost, A. Bankole, L. Finer, S. Singh, and J. Trussell, Contraceptive Failure in the United States: Estimates from the 2006-2010 National Survey of Family Growth. Perspect Sex Reprod Health, 2017. 49(1): p. 7-16.

[2] Thirumalai, A. and J.K. Amory, Emerging approaches to male contraception. Fertil Steril, 2021. 115(6): p. 1369-1376.

[3] McLachlan, R.I., L. O'Donnell, P.G. Stanton, G. Balourdos, M. Frydenberg, D.M. de Kretser, and D.M. Robertson, Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive hormones, and germ cell populations in normal young men. J Clin Endocrinol Metab, 2002. 87(2): p. 546-56.

[4] Trussell, J., Contraceptive failure in the United States. Contraception, 2011. 83(5): p. 397-404.

[5] Waller, D., D. Bolick, E. Lissner, C. Premanandan, and G. Gamerman, Reversibility of Vasalgel male contraceptive in a rabbit model. Basic Clin Androl, 2017. 27: p. 8.

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