Oral Methods of Male Contraception

Gossypol

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.

Tripterygium wilfordii (TW)

The Chinese herbal medicine Tripterygiumwilfordii (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). (For other sources of information on the potential risks of TW, click here.)

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.

Nifedipine

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 and barriers to its testing, see MaleContraceptives.org.

Miglustat (NB-DNJ, trade name Zavesca®)

The compound N-butyldeoxynojirimycin (NB-DNJ), trade name Zavesca®, uses a similar approach to nifedipine, but administrators at the National Institutes of Health hope that it will be more sperm-specific in its action.

Studies in mice at the University of Oxford show that low doses of miglustat interfere with sperm development, and that the effects are reversible. Miglustat impairs sperms’ ability to swim by causing irregular mitochondrial sheaths, poor attachment of tails, and deviant head shapes. It also removes sperms’ ability to fertilize an egg once they get to it due to the deviant head shapes and lack or malformation of the acrosomes. These effects are reversible, and fertility returns three weeks after stopping the drug (van der Spoel et al., 2002). Miglustat does not affect the genetic integrity of the sperm, allaying concerns about birth defects in cases of failed contraception (Suganuma et al., 2005).

Miglustat is particularly exciting because it has passed safety tests and has recently been approved in both the United States and the European Union for treatment of Gaucher Disease, a rare genetic disorder (Actelion Ltd., 2004). However, four questions remain:

1. Will miglustat have the same effect in humans as in mice? It is expected to, given the similarity of spermatogenesis in the two species and the experience so far in humans. Zavesca’s prescribing information states rather bluntly that “Zavesca® may also harm a man’s sperm” (Actelion Ltd., 2003).
2. Will miglustat be safe for men who do not have Gaucher Disease? Those with type 1 Gaucher Disease lack an enzyme that breaks down a chemical in the body called glucosylceramide. Buildup of glucosylceramide causes liver and spleen enlargement, blood changes, and bone disease. Miglustat can help slow the production of glucosylceramide (Actelion Ltd., 2003). The question then becomes what will happen to people with a normal amount of glucosylceramide when they take the medicine. Luckily, mouse studies show infertility at one tenth the dosage required for treatment of Gaucher Disease, so safety issues may be minimal.
3. Will miglustat’s side effects be tolerable? In Gaucher Disease treatment, miglustat causes diarrhea in at least 80% of patients due to its interference with intestinal sucrase and isomaltases. Abdominal pain, flatulence, and weight loss are also seen in many patients (one third to two thirds), with generalized weakness, tremor, and peripheral neuropathy (nerve disturbance in the arms and legs) also frequently reported (Actelion Ltd., 2003). These effects are mostly reversible (Zimran & Elstein, 2003) but would obviously be unacceptable to men who are not forced to take the medication by a hereditary disease. Miglustat will only be a promising contraceptive if, as hoped, the contraceptive dosage is so low that the side effects disappear. If the side effects do not disappear, the research will be another example of the wisdom of targeted vas-based rather than systemic oral approaches.

These first three questions can be answered by research. Miglustat is fortunate to be receiving research attention and support through the U.S. National Institute of Child Health and Human Development’s Cooperative Research Program on Male Fertility Regulation (Contraception and Reproductive Health Branch (CRH), 2004). Frances M. Platt and Aarnoud van der Spoel of Oxford Glycosciences are helping to coordinate a confirmatory trial in seven men at the University of Washington in Seattle . The trial has already started recruiting volunteers (ClinicalTrials.gov, 2005). However, a fourth question remains:

4. Will miglustat be affordable? Since Gaucher Disease is rare, Zavesca’s maker Actelion maximizes profit on each patient. Prices range from $80-90 per pill, with Canada having negotiated the cheapest price, about $240 U.S., for a daily dose of three pills (PJ Online, 2004; PMPRB, 2004; RX USA, 2005). This would mean that at current prices, a contraceptive dose would cost at least $8,700 per year. This would be prohibitive for most people and would certainly not be covered by health insurance, since cheaper contraceptives exist.

Zavesca grosses roughly $100,000 per year per patient, and an estimated 30,000 people worldwide have Gaucher Disease. That adds up to a billion-dollar-plus market. If Zavesca’s maker lowered prices to sell Zavesca as a male contraceptive, it would have to be convinced that the male contraceptive sales would more than make up for the lost profit on Gaucher Disease sales. That would require almost a million customers at a more typical contraceptive price of $50 per month: more than are currently using the NuvaRing vaginal ring (Azko Nobel, 2005).

It remains to be seen whether this price barrier can be addressed. However, the U.S. NICHD and the Glycobiology Institute at Oxford deserve credit for pursuing these studies and seeking to determine the drug’s potential.

CatSper

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, 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.

Binding/Penetration Enzymes

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.

The researchers are hoping to computer-design an even more potent enzyme inhibitor by early 2006. After safety testing, they hope to partner with a larger company to run a small human trial in Europe in 2006 or 2007. Based on past experience, this is an optimistic timetable. However, 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, so progress may accelerate (Associated Press, 2005). If researchers design a potent enough enzyme inhibitor, safety testing will be the crucial next hurdle.

For further details on this research, see MaleContraceptives.org.

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).

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.

Next section: Other Nonhormonal Approaches to Male Contraception