Male hormonal contraceptives

Commonly known as the “male pill”, a hormonal contraceptive for men would probably not be delivered as a pill. Researchers are coming closer to a marketable male hormonal contraceptive (MHC) delivered by implant or injection, but there is nothing commercially available right now. MHCs today are much like female hormonal contraceptives were in the 1950s; researchers are still seeking the most effective formulation, dosage, and delivery method. Researchers expect that they will be able to provide a contraceptive that is as effective, convenient and safe as the female birth control pill.

Of all the potential male contraceptives, this method is the closest to market in the US and Europe. With the support of the multinational pharmaceutical companies Organon and Schering, MHCs may reach the European market within 10 years. Work outside the private sector is slow because most researchers work for non-governmental organizations and universities with limited budgets. Most studies on new formulations are carried out with very small groups of men (10 or fewer), which makes it difficult to draw generalized conclusions.

Another reason for the slow progress toward market is the standard to which potential MHCs are being held. Regulatory agencies and developers expect MHCs to be better products than female hormonal contraceptives ever were. For women, the desired outcome was no pregnancy, and some side effects were considered acceptable to reach that outcome. For men, desired outcome is normal physiology, psychology and libido; in other words, no side effects whatsoever. This is a significantly higher standard than even modern formulations of female hormonal contraceptives are held to.

How would it work?

Male hormonal contraceptives attempt to block or severely reduce the production of sperm. They accomplish this by stopping the secretion of a man's reproductive hormones in the brain and testes. When levels of testosterone in the testes are low, sperm production slows or halts. Typical MHC formulations provide replacement testosterone to the man’s bloodstream to maintain male characteristics like muscle mass and facial hair. Small scale clinical trials of MHCs have had mixed results so far, with a few notable successes. For a more detailed explanation of the biology at work, see How MHCs work.

How effective would it be?

The ultimate goal of all MHC methods is azoospermia, or the complete absence of sperm in the ejaculate. Researchers agree that severely oligospermic men with fewer than 1 million sperm per milliliter of semen are functionally infertile. For a sense of scale, a normal man has anywhere from 200 to 20 million sperm/ml. The contraceptive efficacy of severe oligospermia is 99%, which is better than the typical use of the female pill.

The effectiveness of each hormonal method varies depending on its formulation, delivery method and dosage. There are many different formulations, each with their own effectiveness. Read more about the different formulations being tested. Researchers are still working toward a MHC formulation that is universally completely effective.

How long would it take?

The fastest possible onset of efficacy that a man taking an MHC could hope for would be 1½ - 2½ months. Once spermatogenesis is halted, it takes an average of 2½ months for the last spermatids produced to travel through and exit the epididymis. For a more detailed explanation of how this works, read a bit about male reproductive biology. Some of the methods partially halt the maturation of these last spermatids through an unknown mechanism, delivering the faster 1½ month onset of efficacy.

How would an MHC be delivered?

The issue of most concern for the convenience of MHCs is how they are delivered, and how frequently. Some of the androgens used in MHCs are only effective when they are injected into muscle tissue. Intramuscular injections must be administered by a qualified nurse or doctor, and therefore require a visit to a clinic. Researchers are aiming for a formulation they could inject every 3-4 months. Between infrequent injections, some formulations provide uneven levels of active androgen in the blood stream, which can result in unpleasant side effects and reduced effectiveness. It is also important to maintain even levels of testosterone because unusually high levels, such as a spike immediately following an injection, are associated with the reappearance of sperm in the ejaculate (McLachlan 2004).

Researchers are investigating alternatives to injections: implants, pills, patches and creams. Implants are active for many months, and deliver a very steady dose of the androgen. They require minor surgery to put in and remove, and there is a 3 - 7% risk of the implant breaking the skin above it. Pills, patches and creams have all had disappointing clinical results. Right now there are no good options for a self-administered formulation like the female pill. Nevertheless, researchers are confident that with further drug development, they will find the right combination of easy delivery and long action.

The World Health Organization and the Population Council have both worked to develop new androgens such as testosterone buciclate and MENT. Both organizations have jumped high hurdles as the regulatory requirements for new drug development have become increasingly stringent. The WHO actually dropped testosterone buciclate development due to the requirement of a chemical evaluation much more rigorous than that required for female hormonal (Waites 2003). Continued work in this field will require the a financial commitment from government health services or the pharmaceutical industry.

What side effects would be expected?

Men taking MHCs in clinical trials experience a range of side effects, including lean muscle weight gain, increased acne and changes in mood. These side effects are caused by the synthetic androgen in the MHC regimen. They could be minimized as researchers tailor the androgen dose and delivery method. However, as is the case with female hormonal contraceptives, it may not be possible to entirely eliminate these side effects for all men.

A more serious side effect of altering a man's androgen metabolism is a depressed level of high-density lipoprotein cholesterol (HDL-C) in the blood. HDL-C is a healthy type of cholesterol which has been correlated with reduced risk of atherosclerosis (hardening of the arteries). Volunteers in clinical trials of certain types of synthetic androgen experience a 15% drop in HDL-C levels. If this side effect can not be mitigated, men with a risk of heart disease should be advised to avoid MHCs (Brady 2002).

Researchers were originally concerned that high levels of T might over stimulate the prostate gland, but in trials up to 18 months long no one has observed this side effect (McLaclan 2000). Each new MHC formulation approaching market will likely undergo this type of screening.

How long would it take to reverse?

The contraceptive effect of all MHC regimens is completely reversed within 3½ to 5 months (Liu 2006). Once treatment stops, it takes a while for a man's body to begin making hormones in pretreatment quantities. Once the pretreatment levels of hormones are restored, the first immature sperm are produced in the seminiferous tubules. It takes 2½ months for these first immature sperm to become fully functional as they travel through the epididymis. For a more detailed explanation of how this works, read a short overview of male reproductive biology.

It’s a mystery: Some men do not respond to MHCs

Researchers have a major problem to solve before they can bring male hormonal contraceptives to market: some men simply do not respond to hormonal contraceptive regimens. Non-response rates range from 5 to 20%, depending on the formulation and delivery method.

There are many theories about what might cause this non-response, but the mechanism remains unknown. So far, researchers have found that non-responders have the same daily and monthly gonadotropin and testosterone levels as responders. They have found that non-responders have higher levels of 5-alpha-reductase, an enzyme which converts testosterone to the potent androgen dihyrdotestosterone (DHT). However, men given a drug to suppress the action of this enzyme do not respond any better than before. New evidence shows that non-responders have a higher level of insulin-like factor-3 (INSL3) than responders, but whether this is a causal relationship remains unclear (Amory 2007).

One interesting clue in the non-response mystery is the striking difference in the response levels of men of different ethnicities. Asian men in the WHO and other studies ”consistently show… a higher prevalence of azoospermia than Caucasian men“ (Brady 2002). Dr. John Amory, a leading MHC researcher at the University of Washington, has suggested that this difference could be of genetic origin (2001). Slight differences in the genes encoding various aspects of a man’s hormonal system ”could allow for continued intratesticular testosterone production or activity of testosterone or gonadotropins, thereby enabling spermatogenesis to persist“.

The non-response mystery will probably be resolved with a better overall understanding of how the male reproductive system works. Dr. Amory (2002) calls for further ”understanding of the hypothalamic-pituitary-testicular axis“ which ”will be possible only with continued clinical and basic investigation.“

 

References

• Amory, JK, and WJ Bremner (2000) "Newer agents for hormonal contraception in the male." Trends in Endocrinology and Metabolism 11(2): 61-66.
• Amory, JK, BD Anawalt, WJ Bremner and AM Matsumoto (2001) "Daily testosterone and gonadotropin levels are similar in azoospermic and nonazoospermic normal men administered weekly testosterone: Implications for male contraceptive development." Journal of Andrology 22(6): 1053-1060.
• Amory, JK, and WJ Bremner (2002) "Endocrine regulation of testicular function in men: Implication for contraceptive development." Molecular and Cellular Endocrinology 186: 205-209.
• Amory, JK, ST Page, BD Anawalt, AD Coviello, AM Matsumoto and WJ Bremner (2007) "Elevated end-of-treatment serum INSL3 is associated with failure to completely suppress spermatogenesis in men receiving male hormonal contraception." Journal of Andrology Epub ahead of print Feb 21.
• Anawalt, BD, and JK Amory "Advances in male hormonal contraception." Annals of Medicine 33: 587-595.
• Brady, BM, and RA Anderson (2002) "Advances in male contraception." Expert Opinion on Investigational Drugs 11(3): 333-344.
• Liu, PY, RS Swerdloff, PD Christenson, DJ Handelsman, C Wang and other members of the Hormonal Male Contraception Summit group (2006) "Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis." The Lancet 367(9520): 1412-20.
• Mahler, K (1996) "Testosterone injections suppress sperm production, providing effective level of contraceptive protection" Family Planning Perspectives 28(4): 84-85.
• McLachlan, RI (2000) "Male hormonal contraception: a safe, acceptable and reversible choice." Medical Journal of Australia 172: 254-255.
• McLachlan, RI, DM Robertson, E Pruysers, A Ugoni, AM Matsumoto, BD Anawalt, WJ Bremner and C Merrigiola (2004) "Relationship between serum gonadotropins and spermatogenic suppression in men undergoing steroidal contraceptive treatment." Jornal of Endocrinology and Metabolism 89(1): 142-9.
• Nieschlag, E (2002) “Sixth Summit Meeting Consensus: Recommendations for regulatory approval for hormonal male contraception.” International Journal of Andrology 25: 375.
• Nieschlag, E, GF Weingauer and HM Behre (1995) "Male contraception based on testosterone in combination with other agents." in Proceedings of the 2nd International Androgen Workshop. Eds. S. Bhasin et al. New York : Wiley-Liss.
• Swerdloff, R, B Steiner, C Callegari and S Bhasin (1995) "GnRH analogues and male contraception." in Proceedings of the 2nd International Androgen Workshop. Eds. S. Bhasin et al. New York : Wiley-Liss.
• Waites, GMH (2003) "Development of methods of male contraception: impact of the World Health Organization Task Force." Fertility and Sterility 80(1): 1-15.
• World Health Organization Task Force on Methods for the Regulation of Male Fertility (1996) "Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men." Fertility and Sterility 65(4): 821-829.