Recent research conducted by the Programme to find safe and effective contraceptive methods for men shows that hormones can be used to reduce men's sperm to levels that render them virtually infertile. This effect is completely reversible.
Research results published in 1990 clearly showed almost complete contraceptive efficacy in men whose sperm concentrations in the ejaculate were reduced to undetectable levels (azoospermia) by weekly injections of the hormone testosterone enanthate (TE). Although the hormone reduced sperm counts in all men in the study, not all of them became azoospermic. The question remained: could these men with very low but still detectable sperm counts also be infertile?
In a multicentre study completed last year a total of 399 men in nine countries were given regular injections of TE to assess the contraceptive effect of low sperm counts. Results showed high contraceptive effectiveness among men whose sperm concentrations were reduced to 3 million or less per ml (oligozoo-spermia). The failure rate of 1.4 pregnancies per 100 person-years was similar to that of hormonal methods of fertility regulation for women, such as the oral contraceptive pill. The average time taken to reach oligozoospermic or azoospermic sperm counts was 68 and 100 days, respectively, after the first injection; return to normal fertile levels or to baseline values of sperm production after the last injection took an average of 112 days in oligozoospermic men and 203 days in azoospemic men.
Since TE is short-acting and therefore has to be given once a week to have a contraceptive effect, the Programme has also conducted research into longer-acting androgen esters that could be administered less frequently. One of the most promising such compounds is testosterone buciclate (TB) and research has been carried out in Germany to assess its effect in suppressing the secretion of gonadotrophin, and thereby reducing sperm counts to contraceptive levels of oligozoospermia. Azoospermia was achieved in some men given a single dose of 1200 mg of TB but men given half that dose did not reach oligozoospermia. Further studies are planned that will involve single and repeated administration of different doses of testosterone buciclate.
As the work on longer-acting androgen esters continues, there is also emphasis on research into the male contraceptive effect of progestogen-androgen combinations. These may have an advantage over androgen-only preparations for several reasons. Progestogen, which suppresses the secretion of gonadotrophins, prevents the production of sperm at much lower doses than androgen; the androgen, which is given to replace the testosterone that is inhibited as a result of the suppression of gonadotrophin, is needed less frequently and at lower doses than when it is used alone to suppress gonadotrophin; and the combined preparation seems to suppress the production of sperm more quickly than androgen does alone. The national authorities in China, India and Indonesia are proposing to carry out large-scale efficacy studies with a variety of progestogen-androgen combinations.
One drawback to use of the combined regimen as a contraceptive method is that the currently available progestogen and androgen have to be injected at different intervals, which may make the administration too complex for large-scale use. This may be overcome by combining TB with a progestogen with the same duration of action and giving both hormones at the same time. In all its research, the Programme is aware of the need for the highest standards of safety, and this is a particular concern in the case of long-acting injectable agents that cannot be removed once they have been administered and whose effects cannot easily be reversed.
In addition to this pioneering research on the development of hormonal contraceptives for men, the Programme is also looking at ways of improving the acceptability of an already established male method - vasectomy. While some 41.5 million men are estimated to have undergone vasectomy, two main factors seem to limit its wider acceptability: the surgical nature of the procedure and the uncertainty of reversibility. The development of "no-scalpel" vasectomy has greatly alleviated the first problem and is proving increasingly popular in many parts of the world. The second problem is being tackled by developing a means of vas occlusion, in particular by a silicone rubber plug that could subsequently be removed. Pilot studies are planned in Indonesia and the Netherlands to compare occlusion rates, perhaps using silicone of different viscosities and volumes.
Another area in which efforts are being made to follow leads that may result in new male contraceptives is the evaluation of drugs that would render sperm incapable of fertilizing an ovum. The aim is to develop drugs that do not interfere with the hormonal mechanisms or tissues involved in sperm production, but instead impair the function of the spermatozoa stored in the epididymis; such an effect should be completely reversible. Evaluation has followed two lines of investigation: the extent to which a drug may by itself impair the function of sperm, and the extent to which a drug may impair the function of the small numbers of sperm that continue to be produced in men made oligozoo-spermic by other drugs. Research has looked particularly at the effects of compounds isolated from Tripterygium wilfordii, a plant used in traditional Chinese medicine to treat inflammation. The antifertility properties of this plant were first reported in China following clinical observation of its effect on sperm stored in the epididymis. Animal studies indicate that an extract of the plant's root may have an action late in the process of sperm production. Studies to isolate the compound that was having this effect identified triptolide as the most active agent. Current efforts are being directed towards isolating sufficient quantities of triptolide for preclinical safety studies. The first need is to determine the size of the gap between the minimum dose at which triptolide is effective and the dose at which it is toxic.