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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