There are many potential methods of male contraception that are not reported on in depth here. For the most part, the research on such methods is too preliminary to warrant a full description. However, these methods do appear in the news, and we regularly receive questions about them.
Retinoic acid receptor antagonist (BMS-189453)
In the 1980s, researchers at the pharmaceutical company Bristol-Meyers Squibb developed a drug they designated BMS-189453. They investigated whether it could be used to treat skin and inflammatory diseases, and found that rats treated with 100 milligrams per kilogram of body weight became infertile. That was an unexpected side effect – the researchers decided not to study the drug further. It remained on a shelf until a group of scientists at Columbia University came knocking in 2007.
BMS-189453 is a pan-retinoic acid receptor antagonist. What does that mean? Let’s take it one piece at a time. “Retinoic acid” is the metabolic product of the vitamin A in food. The “receptor” here is a molecule in a cell that picks up retinoic acid. The receptor is in the nucleus of cells, and functions there as a transcription factor, making proteins that turn on target genes. “Antagonist” means that this drug binds to the retinoic acid receptor and prevents it from picking up retinoic acid. “Pan” means that this drug affects all three known types of retinoic acid receptors, named alpha (α), beta (β) and gamma (γ).
Scientists have known since the 1920s that dietary vitamin A is necessary for normal production of sperm in men (Wolbach 1925). It turns out that retinoic acid is necessary in specific amounts inside the testes for normal sperm production. Blocking retinoic acid receptors in Sertoli cells and developing sperm cells results in disrupted sperm maturation and, ultimately, infertility.
The researchers at Columbia University have now shown that this drug works as a reversible contraceptive in mice (Chung 2011a). Mice given the drug mixed into a solution orally for 7 days were infertile after 4 weeks, at doses of 1mg/kg body weight and 5 mg/kg. The mice all sired healthy litters after 14 weeks, and the offspring had normal fertility. The researchers also found that fertility returned when mice had been treated with 1mg/kg for 16 weeks, and that those offspring were also healthy (Chung 2011b). Their next steps are to:
• extend the dosing regimen for even longer periods,
• test the drug in primates,
• and develop a drug specific to only the alpha (α) retinoic acid receptor, because that’s the one critical for making sperm.
Neem extracts (Azadirachta indica)
Neem is a tree common to India with many medicinally valuable parts. The potential use of neem leaf extracts as contraceptives is not a new idea; research on its use as a spermicide has been underway since the 1960s. The injection of minute quantities of neem oil into the vas deferens (the tubes that carry sperm) has been successfully tested as an alternative to surgical vasectomy (Upadhyay 1993).
Various forms of neem have been studied as potential reversible male contraceptives. Male mice fed water crushed with fresh neem leaves impregnated fewer female mice and had smaller average litter sizes (Deshpande 1980). Researchers obtained similar results in rats (Sadre 1983). Within 11 weeks, the animals in this study had 100% effective contraception. The effects were reversed within 6 weeks. An equivalent body weight dosage was tested in guinea pigs and rabbits, but this dosage was toxic. After 6 weeks of treatment, 75 and 90% of the respective animals had died.
Studies of various forms of neem for male contraception in different types of mammals have reported no changes in libido or hormonal function (Jensen 2002). Neither neem leaf extract in water nor neem leaf oil alters the rate spermatogenesis. The contraceptive effect of these two forms of neem comes from a reduction in the motility of the sperm. However, neem bark extract and neem seed oil caused arrest of spermatogenesis within 2 months, with a decrease in the number of Leydig cells (responsible for the manufacturing of testosterone) (Randhawa 1996). Although neem treatment does not trigger a systemic autoimmune response to sperm, researchers speculate that a local immune response of some kind is responsible for its contraceptive effects (Lohiya 2001).
Reports of neem oil use by 20 Indian Army soldiers as a low dose, orally administered male contraceptive are erroneous. Neem oil was indeed administered as a successful post-coital contraceptive to the wives of 20 soldiers (National Research Council 1992), but it was not a formal study. There have been no studies of neem as a contraceptive in men.
Papaya seed extracts (Carica papaya)
The contraceptive qualities of papaya seed extract have been known since the early 1970s. When the crude extract of papaya seeds was fed to male rats, the quantity and quality of the sperm they produced deteriorated. At higher doses, this provided 100% effective contraception, but it also resulted in weight loss, possibly due to toxicity (Udoh 1999, Kusemiju 2002, Lohiya 2005). When a chloroform extract of papaya seeds was tested in langur monkeys for 1 year, they showed a steady decrease in sperm production with no evidence of toxicity. The chloroform extract had no effect on testosterone levels. Within 3 months all the monkeys were azoospermic (no sperm in the ejaculate). Once treatment stopped, full recovery occurred within 5 months. The researchers postulate that the potential inconvenience of this relatively long recovery time is offset by the minimal side effects (Lohiya 2002).
This plant compound is extracted from the flowers of a myrtle family tree native to southern Asia, Eugenia jambolana. The tree has been naturalized in Hawaii, southern Florida, Australia, the Philippines, Zanzibar and Kenya. Studies of oleanolic acid in rats show that low, sustained doses result in reversible infertility (Rajasekaran, 1988). The studies reported no changes in body weight or libido. The compound alters the way sperm pass through the epididymis. Normally, immature spermatids are converted in the epididymis to fully functioning, motile sperm. The sperm of rats treated with oleanolic acid emerged from the epididymis with decreased forward motility. Rats treated for 30 days became infertile; the contraceptive effect was reversed 14 days after ending treatment (Mdhluli 2002). Doses within an order of magnitude of the therapeutic contraceptive dose showed immunosuppressive side effects in mice (Dai 1989). A group of researchers in South Africa are working towards studies of oleanolic acid in male monkeys.
Basic science research will lead to novel male contraceptives
Scientists’ understanding of the molecular functioning of males’ reproductive tracts is many years behind that of their understanding of females’. There are a number of researchers working to describe the various chemical pathways required for spermatogenesis. Many years from now, the foundation of basic science that these researchers are building could reveal new routes for male contraceptives. You may recognize some of this work from news headlines.
The identification of a set of genes known as Catsper could provide a new route for pharmaceutical male contraception. The Catsper genes encode a series of calcium ion exchange channels which occur exclusively in the male reproductive tract. Calcium ion exchange is an essential mechanism of cellular motion; blocking calcium ion fluxes could block sperm motility. The study of the Catsper genes will help researchers understand the contraceptive mechanisms of calcium channel blocker (CCB) drugs and may lead to the development of more targeted CCBs.
Septin 4 gene
Another gene critical to production of normal sperm has been identified by a team led by Population Council researchers. The gene Septin 4 encodes proteins that help sperm form normal tails. If researchers can develop a drug that blocks the action of the Septin 4 proteins, it could be a nearly side-effect free male contraceptive. A treated man would produce the normal number of sperm, but their bent tails would render them incapable of fertilizing an egg.
Protein required for motion
Researchers at the University of Massachusetts Medical School have entered into a drug development agreement with a Norwegian pharmaceutical company. The researchers have identified another protein found exclusively in sperm. The protein plays an essential role in the sperms’ ability to swim. If they find a drug that deactivates the protein, sperm will be unable to swim or fertilize an egg.
Retinoic acid receptor antagonist references
- Chung, SS, X Wang, SS Roberts, SM Griffey, PR Reczek and DJ Wolgemuth (2011a) “Oral administration of a retinoic acid receptor antagonist reversibly inhibits spermatogenesis in mice.” Endocrinology 152(6): 2492-502.
- Chung, SS, XY Wang and DJ Wolgemuth (2011b) “Meeting Men's Contraceptive Needs: Long-Term Oral-Administered Retinoic Acid Receptor Antagonist Inhibits Spermatogenesis in Mice with a Reversible and Rapid Recovery.” Endocrine Reviews 32 (03): LB-4.
- Wolbach, SB, and PR Howe (1925) “Tissues changes following deprivation of fat-soluble A vitamin.” Journal of Experimental Medicine 42: 753-77.
- Deshpande, VY, KN Mendulkar and NL Sadre (1980) “Male antifertility activity of Azadirachta indica in mice.” Journal of Postgraduate Medicine 26: 167-70.
- Jensen, JT (2002) “Male contraception.” Current Women's Health Reports 2(5): 338-45.
- Lohiya, NK, B Manivannan, PK Mishra and N Pathak (2001) “Vas deferens, a site of male contraception: an overview.” Asian Journal of Andrology 3(2): 87-95.
- National Research Council (1992) Neem: A tree for solving global problems. National Academy Press: Washington, DC.
- Randhawa NS and BS Parmar (eds.) (1996) Neem. New Age International: New Delhi, India.
- Sadre, NL, VY Deshpande, KN Mendulkar and DH Nandal (1983) “Male antifertility activity of Azadirachta indicain different species.” In Schmutterer, H, and KRS Ascher (eds.) Natural pesticides from the neem tree (Azadirachta indica A. Juss) and other tropical plants: Proceedings of the 2nd International Neem Conference. Deutsche Gesellschaft für Technische Zusammenarbeit : Roßdorf, Germany.
- Upadhyay, SN, S Dhawan and GP Talwar (1993) “Antifertility effects of neem (Azadirachta indica) oil in male rats by single intra-vas administration: an alternate approach to vasectomy.” Journal of Andrology 14(4): 275-81.
Papaya seed extract references
- Kamal, R, RS Gupta and NK Lohiya (2003) “Plants for male fertility regulation.” Phytotherapy Research 17(6): 579-90.
- Kusemiju, O, C Noronha and A Okanlawon (2002) “The effect of crude extract of the bark of Carica papaya on the seminiferous tubules of male Sprague-Dawley rats.” Nigerian Postgraduate Medical Journal 9(4): 205-9.
- Lohiya, NK, B Manivannan, PK Mishra, N Pathak, S Sriram, SS Bhande and S Panneerdoss (2002) “Chloroform extract of Carica papaya seeds induces long-term reversible azoospermia in langur monkey.” Asian Journal of Andrology 4: 17-26.
- Lohiya, NK, PK Mishra, N Pathak, B Manivannan, SS Bhande, S Panneerdoss and S Sriram (2005) “Efficacy trial on the purified compounds of the seeds of Carica papaya for male contraception in albino rat.” Reproductive Toxicology 20(1): 135-48.
Oleanolic acid references
- Mdhluli, MC, and G van der Horst (2002) “The effect of oleanolic acid on sperm motion characteristics and fertility of male Wistar rats.” Laboratory Animals 36(4): 432-7.
- Rajasekaran, M, JS Bapna, S Lakshmanan, AG Ramachandran Nair, AJ Veliath and M Panchanadam (1988) “Antifertility effect in male rats of oleanolic acid, a triterpene from Eugenia jambolana flowers.” Journal of Ethnopharmacology 24(1): 115-21.
- Dai, Y, BQ Hang, PZ Li and LW Tan (1989) “Effects of oleanolic acid on immune system and type I allergic reaction.” Zhongguo Yao Li Xue Bao 10(4): 381-4.