The development of new male contraceptive methods seems to move at an agonizingly slow pace. Despite years of research, no modern contraceptive drug currently exists for men, whose most effective choices are limited to condoms or vasectomy.
Even the more promising experimental male methods are at least a decade away from general use. Experts say a lack of commercial interest and funding have held back research. Progress also has been slow because of the challenging physiological task of controlling the male reproductive system. Simply put, a woman's ovulation is easier to interrupt than a man's sperm production. A woman produces one egg a month; a man produces hundreds of millions of sperm daily. And, while an adult woman is only fertile until menopause, a man continues to produce sperm throughout his adult life.
Nevertheless, a number of intriguing research projects are seeking new modern methods for men. These experimental prototypes typically use one of two mechanisms of action. One approach is aimed at suppressing the production of sperm, either by hormonal or non-hormonal means. Another seeks to inhibit the fertilizing ability of sperm, usually by disrupting a key step in the complex process of conception.
Most research is focusing on suppressing sperm production. The basic idea is to inhibit or neutralize gonadotropins, hormones that control such reproductive functions as sperm production. Already, studies have shown the contraceptive efficacy in men of a variety of testosterone derivatives, which work by suppressing sperm production. While some of these derivatives have drawbacks that make them undesirable for general use, they have provided an important foundation of knowledge that may lead to more successful contraceptive prototypes.
Hormonal approaches
Ways to suppress sperm production through hormonal means include an experimental injection developed by the Population Council that seeks to stimulate an immune response to gonadotropin hormone-releasing hormone (GnRH), a hormone that is essential to sperm production.
The New York-based Population Council is conducting a preliminary study among 20 volunteer men in Santiago, Chile in a trial that will take about two years to complete. A single injection is expected to produce effective contraception for up to one year and, when discontinued, should allow a return to fertility. The experimental injectable is composed of GnRH that is combined with a much larger protein, which acts as a delivery system. In this case, the protein is tetanus toxoid, which is widely used throughout the world as a tetanus immunization.
When injected into the body, the GnRH-carrying tetanus toxoid stimulates a man's immune system to produce antibodies. These antibodies then inactivate GnRH produced naturally in the man's body, resulting in sperm suppression. As an additional benefit, men using this combination would also be protected from tetanus infections.
One drawback of neutralizing GnRH, however, is the suppression of testosterone, a hormone that in men generates libido and secondary sexual characteristics. Thus, men who use the GnRH injection also must use a substitute for testosterone called 7-alpha methyl-19-nortestosterone, or MENT, which is slowly released into a man's body using an implant rod inserted under the skin of a man's upper arm, similar to the Norplant system used by women. This helps to restore normal sexual drive and secondary sexual characteristics, such as the growth of facial hair.
The current study in Chile is designed to examine safety issues. If results are encouraging, the immunocontraceptive's efficacy will then be studied in a trial expected to enroll up to 150 subjects, says Dr. J.F. Catterall, director of reproductive physiology at the Population Council.
While initial Population Council investigations focused on using MENT only to maintain libido, this agent used alone may also provide successful sperm suppression. "That MENT alone could suppress sperm production while maintaining libido came as a surprise to us and others in the field,'' says Dr. Elof Johansson, biomedical research director of the Population Council, who adds that long-term toxicology testing in animals remains to be done and clinical trials among men are in the early stages. Under this approach, MENT would probably be delivered via one to several implants. If MENT proves to be an effective and safe contraceptive, "it would make the development of an implant both simpler and cheaper than we once thought," he says.
MENT, which is chemically similar to testosterone, is 10 times more potent than testosterone. It has the advantage of being effective via gradual, constant release at small doses that do not overstimulate the prostate or affect muscle mass. The MENT implant being developed by the Population Council is expected to be effective for one year and should be reversible.
Testosterone derivatives
Suppressing sperm production by administering testosterone derivatives has been studied for many years. Although testosterone produced naturally in a man's body is essential for sperm production, an excess amount inhibits gonadotropins, thus causing a large decrease in natural testosterone levels in the testes and hampering sperm manufacture.
The most comprehensive study to demonstrate this relationship was a two-year trial completed in 1994 by the World Health Organization (WHO) of injectable testosterone enanthate (TE), a synthetic derivative of testosterone. The study involved 399 men in nine countries in Asia, Australia, Europe and North America. The agent's contraceptive efficacy proved to be comparable to that of female hormonal methods. In 98 percent of the study subjects, TE weekly injections either totally suppressed sperm production or greatly reduced it, providing effective contraception. Furthermore, the method was reversible, with fertility restored within two to three months after the last injection.
Unfortunately, injections needed to be given weekly to achieve contraception. "Following the trial, many men wanted to continue the contraceptive method and were disappointed when told they could not do so," says David Griffin, a WHO scientist. "However, it was recognized that weekly injections of TE would not be an attractive option to men at large. Thus, research efforts have focused on the development of longer-acting testosterone derivatives that could be injected at intervals of two or three months."
Researchers also realized that TE has other limitations, including an inability to produce total azoospermia in all men, which increases the risk of contraceptive failure.1 Another drawback is that the onset of contraception is relatively slow, usually two to three months. A couple would need to use another method for months after injections began.
There also is some concern about adverse side effects, chief among them the effects from suppressing high density lipoprotein cholesterol (HDL) levels. HDL is important in cholesterol removal from arterial walls, and epidemiological data have shown an association between low levels of HDL and an increased risk for coronary artery disease. Significant decreases in HDL have been observed in large-scale studies of healthy men receiving weekly injections of TE 200 mg for periods of one to two years.2 However, it is uncertain whether lowered HDL alone is a direct cause of coronary disease. Some researchers have noted that TE's effect on HDL probably reflects the relatively high peak levels and fluctuations of plasma testosterone produced by weekly TE administration. The effect, they have hypothesized, might be avoided by using long-acting preparations of testosterone.3
The contraceptive ability of another derivative, testosterone buciclate (TB), was tested in a WHO-supported study conducted in Germany in 1993 and 1994, but an appropriate dosage to achieve azoospermia or severe oligozoospermia in all men has not yet been identified.4 Higher doses of TB will be the focus of further studies. TB can be injected at three-month intervals.
Meanwhile, some of the concerns arising from administration of androgens (such as TE) alone have been addressed in studies of progestogen-androgen combinations. Among the advantages of such combinations are: the combined regimen appears to suppress spermatogenesis more rapidly and perhaps more effectively than androgen-alone treatment; progestogen doses necessary to suppress gonadotropin secretion and inhibit spermatogenesis are much lower than androgen doses; the androgen's role is primarily to replace the endogenous testosterone inhibited due to gonadotropin suppression by the progestogen; thus, the androgen can be given less frequently and at lower doses.5
A six-month study comparing weekly injections of TE (100 mg) alone and the weekly injections with daily oral doses of levonorgestrel (500 µg) showed that the combination was a more effective and quicker-acting contraceptive method (approximately five weeks faster) than testosterone alone.6 Another study in which TE (100 mg) injected weekly was combined with the progestogen cyproterone acetate (CPA) in a daily oral dose of either 25 mg or 12.5 mg showed suppression of sperm production without detectable adverse effects.7
Trials of an injectable combination of TB and the long-acting progestogen levonorgestrel butanoate, two compounds jointly developed by WHO and the National Institutes of Health (NIH), are likely to begin this year or next after reformulation and stability tests of the compounds are completed, says Dr. Michael Mbizvo, manager of male contraceptive research in the WHO Human Reproduction Programme. The combination regimen is expected to provide contraception for three months at a time.
Other studies supported by WHO will investigate the contraceptive efficacy and acceptability of another injectable -- testosterone undecanoate (TU). Efficacy studies with TU alone, injected monthly, are being done in China with funding from WHO, the Andrew W. Mellon Foundation and the United Nations Population Fund, says Griffin, and an acceptability study is being financed by WHO.
Hormonal contraceptive methods are most likely to become available first as injectables or implants, but more attractive delivery systems, such as pills or skin patches, may be possible. The Population Council is in the early stages of developing a patch.
Non-hormonal suppression
While hormonal methods of sperm suppression have tended to dominate male contraceptive research, some scientists are intrigued by a non-hormonal substance that does not affect androgen levels, and therefore does not influence libido or sexual characteristics. Called gossypol, an extract from natural cottonseed oil, it has achieved reliable contraception in Chinese men. In the doses given during early studies, however, gossypol depleted potassium levels, a condition that sometime led to dangerous heartbeat irregularities. Also, some men appeared to become permanently sterile.
More recent studies by South-to-South Cooperation in Reproductive Health have focused on smaller doses that may be safer. "A pilot study in a small group of five Brazilian men of a pill called Nofertil that contains low-dose gossypol has demonstrated its efficacy in suppressing spermatogenesis within two to three months of treatment without depleting potassium levels," says Dr. Sheldon Segal of the Population Council, a leading expert on gossypol. If approved by the Brazilian Ministry of Health and funding is obtained, South-to-South plans to conduct a trial of Nofertil in 320 Brazilian men at 10 centers beginning this year.
The low-dose gossypol pill is produced by the Brazilian pharmaceutical company Hebron, which Dr. Segal credits with improving the feasibility of gossypol as a male contraceptive by developing a highly purified form of gossypol and devising a means to coat tablets to prevent oxidation by light or heat.
Disrupting sperm function
A few researchers are seeking ways to impede the ability of sperm to fertilize eggs. Two well-known pharmaceutical agents have been shown to cripple sperm.
Nifedipine, routinely used to treat high blood pressure and migraine headaches, appears to stop the discharge of enzymes from the sperm cell that are needed to penetrate an egg's protein coating. Thus, sperm are unable to fertilize an egg. Leading a team investigating nifedipine's contraceptive potential is Dr. Susan Benoff, associate professor of obstetrics and gynecology and cell biology at North Shore University Hospital, New York University School of Medicine. Her interest was inspired by the observation that many men taking nifedipine for migraine headaches or high blood pressure became sterile. A major obstacle to development of this male method, she says, has been a concern that nifedipine could cause dangerously low blood pressure and heart rates.
Over the last two years, however, Dr. Benoff says her team has taken a research approach that may ultimately lead to new drugs that target sperm cells exclusively, thus reducing the possibility of circulatory system side effects. Dr. Benoff notes that this form of male contraception is at least 10 to 15 years from general use.
Mifepristone, the French drug formerly called RU 486, has been shown to disable sperm by acting on the sperm membrane. Dr. Etienne-Emile Beaulieu of the French Institut National de la Santé et de la Recherche Médicale reports that mifepristone prevents sperm from using calcium. Lacking calcium, sperm cannot move normally or fertilize eggs. Unfortunately, mifepristone interferes with certain hormonal functions. "However, we have tested and found a number of compounds that are different from RU 486, yet related chemically, that act specifically on sperm and not on these other [hormonal function] receptors. So, though RU 486 may never be fully developed as a male contraceptive, I believe it may prove to be the inspiration for a successful male contraceptive compound," he says.
Meanwhile, a vaccine that uses sperm surface proteins as agents to provoke an immune response that causes infertility is being investigated in rodents. Development of such a contraceptive vaccine for men is considered to be many years away. Research that aims to block fertilization by attaching antibodies to a sperm surface protein essential to fertilization is being directed by Dr. Paul Primakoff, professor in the Department of Cell Biology and Human Anatomy at the University of California at Davis.
With funding from the National Institute of Child Health and Human Development, Dr. Primakoff and his colleagues have found that immunization of male guinea pigs with the sperm surface protein PH-20 renders the animals reversibly infertile. Most of the infertile males have shown some testicular inflammation, and the researchers are investigating strategies to eliminate this inflammation, Dr. Primakoff says. The research group also has identified a number of other sperm surface proteins that might inhibit fertilization.
Another research approach involves an extract, triptolide, from the herb Tripterygium wilfordii, which comes from the root of a vine found in southern China. In WHO-sponsored work on triptolide, no genetic mutations or toxicity were seen in bacteria or mice. "A non-WHO funded study of the effectiveness of triptolide to inhibit fertilization in marmoset monkeys is in the late planning stages and may begin later this year," says Griffin of WHO.
-- Kim Best
References
- World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril 1996;65(4):821-29.
- Wu FCW, Farley TMM, Peregoudov A, et al. Effects of testosterone enanthate in normal men: experience from a multicenter efficacy study. Fertil Steril 1996;65(3):626-36; WHO; Meriggiola MC, Marcovina S, Paulsen CA, et al. Testosterone enanthate at a dose of 200 mg/week decreases HDL-cholesterol levels in healthy men. Int J Andrology 1995;18(5):237-42.
- Wu, 626.
- Progress in research into new methods of fertility regulation for men. Progr Human Reprod Res 1995;33:2.
- Griffin PD. Methods for the regulation of male fertility. Annual Technical Report 1995. Ed. Van Look PFA. Geneva: World Health Organization, 1996.
- Bebb RA, Anawalt BD, Christensen RB, et al. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab 1996;81(2):757-62.
- Meriggiola MC, Bremner WJ, Paulsen CA, et al. Testosterone enanthate (TE) and low doses of cyproterone acetate (CPA) for contraception in men. 10th International Congress of Endocrinology. Program and Abstracts 1996;2:734.
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