When studying orally administered compounds, one must be prepared for a large percentage of leads to eventually demonstrate toxicity. However, in an ideal world, promising oral compounds would be pursued aggressively despite this, and alternative delivery systems (such as transdermal patches) would be investigated to avoid metabolism by the liver and allow a reduction of dose below toxic levels.
The newest approach in the press is the work of Prof. Haim Breitbart in Israel and is based on a discovery about sperm published in a 2006 paper. However, it has so far only been shown to work in mice; as the cautionary tale about Zavesca (below, “Graveyard”) shows, this is only the first step on a long journey. Prof. Breitbart’s work takes its place next to other oral approaches known to work in mice, such as Dr. Debra Wolgemuth’s work on RAR-antagonists at Columbia University, and Dr. Joseph Tash’s work on gamendazole at the University of Kansas. Many potential oral methods have now passed this first test and are competing for further funding. More on a few of them:
Retionoic-acid receptor antagonists (RAR-antagonists)
Columbia University researchers have taken advantage of the importance of vitamin A to design a new contraceptive approach. Men who are extremely low in vitamin A lose their fertility– but they also become extremely sick, so avoiding vitamin A doesn’t work as a contraceptive. Instead, Professor Debra Wolgemuth discovered a drug that had been abandoned by a pharmaceutical company precisely because it interfered with vitamin A receptors in the testes. Her team tested it in mice, and it worked with no health effects. “The receptors are everywhere, but the testis is exquisitely sensitive to the drug. So we can use a dose that is so low it has no effect on the rest of the body,” she reports. She is now seeking funding to test it in monkeys.
Our main concern with this method, which seems quite promising (given that it can be effective at such low doses), is to make sure that it truly affects only the testes. Continued safety testing should give more information on that point.
In this work supported by the NIH (National Institute of Child Health & Human Development), researchers have been able to achieve 100% infertility with full recovery in mating trials in rats and have shown reversible drops in sperm count in monkeys with no side effects. More details are expected to be presented in October 2011.
Indonesian pill (Justicia gendarussa)
This nonhormonal pill, derived from the plant Justicia gendarussa, could be the first new male contraceptive to market, but with a caveat: just the Indonesian market. But men outside Indonesia will probably be doing whatever they can to get ahold of it.
Antara News reported on August 18, 2013 that research on Gandarusa had been completed by scientists at Airlangga University and the purified plant extract has been handed over to state pharmaceutical company Indofarma for stability testing and securing the production and distribution licenses. The process is expected to take less time because Gandarusa is considered a herbal medicine, and the pill may be available to Indonesians by prescription in 2014.
Research on the contraceptive properties of the Justicia gendarussa plant has been ongoing since 1985. The active ingredient was isolated and chemically synthesized, then manufactured into pill form. The scientist heading up the research, Dr. Bambang Projogo, reported that phase two studies included 120 couples who used the pills daily for 108 days with no pregnancies. Phase three studies were recently concluded in 350 couples taking the pill for 30 days with a reported 99.96% success rate. He intends to conduct a fourth phase of study to reduce the dosage to 15 days per month.
While the Justicia gendarussa plant’s anti-inflammatory properties have been studied extensively, published information is difficult to obtain on its effects on male contraception. Scientists involved in the research report that the active ingredient in Gandarusa disrupts an enzyme in the sperm head, which weakens the ability of the sperm to penetrate the ovum. The effect is short term and reversible – having no effect on male hormones. The scientist even report increased libido in some patients.
Approval for other countries would take longer, depending on how much of the Indonesian research meets those countries’ study protocols. To our knowledge, no Western organizations have teamed up with the Indonesian researchers so far.
We expect that given how long the approvals process would take in other countries, some highly-motivated men outside Indonesia won’t be waiting and will be finding a way to get the pill from Indonesia (or get themselves to Indonesia) once it is on the market there.
To learn more:
August 2013 Antara News story on Gandarusa: Newly Invented Family Planning Pills For Men To Be Produced Soon
2011 PBS Newshour special on Gandarusa: Indonesian Plant Shows Promise for Male Birth Control
2011/2012 news coverage: Global Post, Elements
Facebook discussion of justicia gendarussa by men trying it or trying to get it
Tripterygium wilfordii (TW)
The Chinese herbal medicine Tripterygium wilfordii (TW, or lei gong teng) has been used for millennia to treat everything from rheumatoid arthritis to lupus. What at first seems like an odd set of indications makes more sense when one realizes that arthritis and lupus are both autoimmune diseases and TW has an immunosuppressive effect. For many years TW has also been recognized to have an antifertility effect in men at the doses used in Chinese medicine.
Infertility has been known for many years as a side effect of TW, but TW’s other main side effect — gastrointestinal distress — would be undesirable in a contraceptive, as would immune suppression. Fortunately, only about a third of the dose used in Chinese medicine appears to be needed for contraception (Qian, 1987).
In the 1980s and 1990s the World Health Organization helped coordinate a program to look for extracts of Tripterygium wilfordii that might have contraceptive effect without the side effects (Waites, 2003). At least six extracts with contraceptive effect were purified (Zhen, Ye, & Wei, 1995). Like nifedipine (discussed next), the extracts seem to incapacitate sperm partly by blocking the calcium channel (Shi, Bai, & Wang, 2003).
Unfortunately, triptolide, an extract studied at the University of California , Los Angeles with much excitement, did not work out. It was not reliably effective at one dose in rats (Lue et al., 1998) and not reliably reversible at twice that dose when used long term (Huynh et al., 2000). Studies at other doses have not been funded, and researchers are less than optimistic that they will find a sweet spot with that small a margin of error available. Triptolide as a potentially permanent contraceptive (a nonsurgical alternative to vasectomy) was not pursued. However, the study produced valuable information by showing that triptolide did not affect hormone levels.
More research is needed to understand TW’s immunosuppressive effect. Most studies showing immunosuppression use doses five to 12 times the antifertility dosage, which may be significantly different than what happens at contraceptive dosage (Zhen et al., 1995). Tantalizingly, in one study an even more refined TW extract, tripchlorolide (or T4), seemed to enhance rather than suppress the immune system at contraceptive doses (Lou & Xu, 1990). (It is not unheard-of for a compound to have opposite effects in large versus small doses. A similar principle is seen in cancer research, where low doses of estrogen can stimulate breast cancer cells while higher doses kill them.) T4 also does not seem to cause genetic mutations in rats (Zhang et al., 2002).
Two additional commonly used variants of TW — a botanical cousin (T. hypoglaucum) and a root extract in pill form (Glycosides of T. wilfordii, or GTW) — also provide reversible contraception in men at doses lower than typically used in Chinese medicine to treat arthritis and skin conditions. These variants are available in every Chinatown or, in the case of the root extract, even online (under the name Lei Gong Teng Pian). In a study of 26 Chinese men treated with 20 mg/day of the root extract (two tablets), there were no significant effects on the immune system or any other parameters (Zhen et al., 1995 citing Qian 1989). This contraceptive dosage is several times lower than the 60-90 mg/day (1-1.5 mg/kg of body weight) recommended for arthritis treatment.
Rat studies of the root extract also showed no effect on body weight, hormones, or mating behavior (Qian, Zhong, & Xu, 1986). However, extensive studies of its use in Chinese medicine provide reminders that it is a powerful drug at higher doses and should not be used without full information (NHI ondemand Professional Data, 2005).
Other sources of information on the potential risks of TW:
- Lei Gong Teng (Radix Tripterygii Wilfordii): A Blessing or a Time Bomb? Acupuncture Today
- In-depth review of male contraceptive research on TW and its extracts on MaleContraceptives.org
TW and its extracts are perfect examples of the difference that a concerted effort on male contraceptive research could make. In a perfect world, each of the six extracts would be the subject of a dose-finding animal study, while the three preparations already used by humans for centuries would also be the subject of large clinical trials. The current haphazard, underfunded approach to male contraceptive development leads to a situation where one piece of bad news (such as triptolide’s uncertain reversibility at the studied dose) can cast a shadow over an entire line of research.
Other Oral Substances
Plant-derived substances, such as chloroform extract of Carica papaya seeds, continue to receive research attention in India and China (Kamal, Gupta, & Lohiya, 2003). Research in South Africa is investigating oleanolic acid, a plant-derived substance found in cloves. The substance causes reversible infertility in rats and monkeys and has passed preliminary safety tests in monkeys (Mdhluli, 2003; Mdhluli & van der Horst, 2002). In another approach, the New York-based Population Council is using U.S. NICHD funding to try to produce a nontoxic derivative of a substance called lonidamine (Contraception and Reproductive Health Branch (CRH), 2004; Nass, Strauss, & Institute of Medicine (U.S.). Committee on New Frontiers in Contraceptive Research., 2004).
CatSper (short for cation channel of sperm) is promising but is in very early-stage research. Briefly, researchers have found a protein dubbed CatSper that sperm need in order to beat their tails energetically and move forward. This protein serves as a “gate” in the sperm tail that allows electrically charged calcium ions to enter (Fliesler, 2003). These ions are like fuel for the sperm, causing fiber-like proteins in the tail to contract rapidly, resulting in the hyperactivation (the powerful lashing of the tail) that sends the sperm bursting forward (Carlson et al., 2003).
Scientists can produce mice that lack the gene needed for CatSper (Ren et al., 2001). In these mice, the sperm not only don’t swim forcefully, but they can’t tunnel through the outer coating of an egg even if they are put right next to it (Cromie, 2001).
If one could just remove single genes in humans, contraception using CatSper would be easy. Unfortunately, it is not that simple. One must find a drug that blocks CatSper’s action, and then test it for safety.
If this research sounds similar to nifedipine research (discussed below), it is no coincidence: CatSper (like nifedipine) belongs to the large family of proteins that serve as ion channels in various parts of the body. Its advantage compared to nifedipine is that it appears to be only in the sperm tail (Quill et al., 2001), and not the heart or countless other places in the body. A CatSper-targeted drug would affect only that protein and might have fewer side effects. CatSper’s disadvantage compared to nifedipine is that CatSper is not a drug, but a target for a drug. Nifedipine is an approved and safety-tested calcium channel-blocking drug, which just happens to also block calcium channels in sperm; CatSper is a specific protein that could be temporarily blocked by an as-yet-unknown drug.
Researchers at Harvard have formed the company Hydra Biosciences, which is hard at work looking for compounds that block only CatSper and not other ion channel proteins. They thus hope to avoid side effects such as lowering blood pressure (the same effect which, ironically, brought nifedipine to market).
Their research is to be applauded. However, if they find such a drug, it must then undergo toxicity testing — a point at which many promising drugs fail. If the drug passes these initial toxicity tests, at least another decade of safety testing is likely to be necessary before such a drug would reach the market.
When penetrating an egg, enzymes in sperm recognize and eat through the sugary coating of the egg. Researcher Joseph C. Hall at Norfolk State University has identified more than one (possibly four) of these enzymes (personal communication, Dr. Joseph C. Hall , Feb. 14, 2005).
Dr. Hall and colleagues have achieved 92% contraceptive success rates in rats by feeding them a substance similar to the sugary coating, which then binds to the sperm while they are still in the epididymis. Once sperm bind with the mimic, they can no longer bind with the egg.
Dr. Hall’s work got a big boost in October 2005 when his research center received a large grant from the National Institutes of Health (Associated Press, 2005). The researchers were then hoping to computer-design an even more potent enzyme inhibitor by early 2006. After safety testing, they were hoping to partner with a larger company to run a small human trial in Europe in 2006 or 2007. Based on past experience (the work has been reported to be “close” for more than a decade), this was an optimistic timetable, and we haven’t heard any news from the team since then. We won’t be placing our bets on this one to win the race.
For further details on this research, see MaleContraceptives.org.
Interested in one of these methods?
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Nifedipine is a widely used high blood pressure medication thought to have contraceptive effect in some men (Benoff et al., 1994). By blocking the calcium channels in sperm membranes, it impacts fertility without affecting a man’s hormones. Dr. S. Benoff of North Shore University Hospital in New York was one of the first to bring public attention to questions about nifedipine’s impact on fertility.
Nifedipine has been on the market for more than 20 years, and its side effect profile is quite well understood (Opie, Yusuf, & Kubler, 2000). With hypertension in more than a third of American men age 45-54 and in more than 10% of men as young as 20-34, nifedipine already has a potential market, including many men who may be using it already and are unaware of its possible contraceptive effect (American Heart Association, 2005).
The antifertility effects of nifedipine and similar calcium channel blockers are well-understood in the lab dish (Kanwar, Anand, & Sanyal, 1993; Kirkman-Brown, Barratt, & Publicover, 2003, 2004; Saha et al., 2000; Triggle, 2003; Yeung, Barfield, & Cooper, 2005). However, scientists have yet to systematically study what percentage of nifedipine users become infertile. Another crucial area of research is nifedipine’s contraceptive reliability (Enders, 1997). In a study of two men using a drug similar to nifedipine, both were able to achieve pregnancy (Katsoff & Check, 1997). The author of that study challenges the idea that nifedipine prevents fertilization, though acknowledging that racial differences might explain varying results.
When men taking nifedipine are infertile, their infertility could be caused by the drug or by health problems from their high blood pressure. How, then, can one separate the potential contraceptive effect of the drug from hypertension complications? Dr. Benoff proposes to test the fertility of men attending a colleague’s headache clinic, since nifedipine is also used for migraine treatment (personal communication, Dr. S. Benoff , Sept. 22, 2004). However, funding for this study has not been forthcoming, and Dr. Benoff is now pursuing other avenues of research.
For more information on nifedipine, see MaleContraceptives.org.
Turns out that Zavesca – a medication already approved for treating a rare genetic disorder – is a great male contraceptive for a particular strain of laboratory mouse, but not for men or even other mammals! Exactly how Zavesca acts as a contraceptive for the mice is not known. It’s possible that discovering that mechanism might lead to new avenues of male contraceptive research. But for the moment, research on Zavesca as a male pill has stopped. Want to know more? See MaleContraceptives.org.
Over the years many oral compounds have been tested, but they usually are found to have toxicity issues. Probably the most famous is the plant-derived compound gossypol, which has been abandoned by the World Health Organization but continues to be studied in Brazil and elsewhere. The main concerns about gossypol are reversibility (almost 40% of men did not regain fertility) and lingering questions about toxicity (Anderson & Baird, 2002; Meng et al., 1988). More information on gossypol status and concerns can be found at MaleContraceptives.org.
Last update: 2011, except gandarusa August/2013
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