Nonhormonal drugs for contraception in men: a systematic review.

UNLABELLED: Nonhormonal drugs for contraception in men may have advantages over hormonal methods. The nonhormonal methods can have more rapid onset and less interference with androgen-dependent functions. This systematic review summarizes the clinical studies evaluating nonhormonal drugs administered to men for contraception. Relevant clinical results were found for gossypol, which is derived from the cotton plant, and for extracts of Tripterygium, a plant used in Chinese traditional medicine. Randomized, controlled trials were available on the efficacy of gossypol and on the effect of gossypol on potassium levels. Gossypol had problems with low efficacy and toxicity. For Tripterygium, 2 observational studies described men who were treated for rheumatoid arthritis. Although sperm density was lower among those taking Tripterygium, later reports indicated some toxicity. Nonclinical research continues on isolates of Tripterygium. No clinical studies for contraception in men were found for nonhormonal vaccines or neem, which is also a plant used for medicinal purposes. Clinical trials studied injecting styrene maleic anhydride into the vas deferens, but no comparative data were provided. At this time, no safe and effective nonhormonal drug is available for contraception in men. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to state that the number of studies concerning the use of nonhormonal drugs for male contraception are very limited, point out that the two nonhormonal drugs used to a small degree have varying results and serious side effects, and recall that there are limited clinical studies on use of vas deferens injections and vaccines in humans.

A combined regimen of gossypol plus methyltestosterone and ethinylestradiol as a contraceptive induces germ cell apoptosis and expression of its related genes in rats.

Attempts to develop gossypol and steroidal hormones alone as a male contraceptive have been tested for many years; however, both caused undesirable side effects that have prevented their acceptance. In this study, we formulated a regimen of combined gossypol at a low dose of 12 mg/kg or a high dose of 50 mg/kg plus methyltestosterone 20 mg/kg and ethinylestradiol 100 g/kg daily (12 mg G+H and 50 mg G+H) administered for 6 weeks in adult rats. The possible roles of germ cell apoptosis and related genes expression were studied by techniques of TdT-mediated dUTP nick end-labeling (TUNEL), agarose gel electrophoresis of low-molecular-weight DNA, in situ hybridization and reverse transcription-polymerase chain reaction detection. Results showed that germ cell apoptosis and related genes expression were significantly induced after combined drug administration. The apoptosis index increased 3.86- and 9.65-fold in the 12-mg and 50-mg G+H-treated groups, respectively, as compared to the control group. DNA ladder formation on the agarose gel further validated the findings of TUNEL-stained apoptotic cells. The apoptosis-related genes fas mRNA expression levels increased 0.44- and 1.39-fold, bax mRNA 0.74- and 2.56-fold, caspase-3 mRNA 0.60- and 1.29-fold, and caspase-9 mRNA 2.50- and 4.08-fold, respectively, in the 12-mg and 50-mg G+H-treated groups vs. the control group. These results indicated that our drug regimen applied as a contraceptive could induce rat germ cell apoptosis. The apoptotic process involved fas system, bax and caspase family genes and the apoptotic extent and cell types were gossypol dose-dependent.

Effects of K salt or a potassium blocker on gossypol-related hypokalemia.

Gossypol was found to be an effective male contraceptive. The most serious side effect of gossypol contraception was the presumed lowering of serum potassium levels. The purpose of this present randomized and controlled study was to evaluate the merit of ingesting K salt or a potassium blocker while using gossypol. Results indicated that supplementation of K salt does not cause a reversal of the effect of gossypol on serum potassium levels and the blocker triamterene does not prevent loss of serum potassium.

Experiences with gossypol as a male pill.

In 1981 to 1983 we performed a clinical study with gossypol involving 152 participants, and in 1983 to 1985 we conducted another study of 120 participants. The first study was aimed at confirming gossypol's antifertility efficacy and determining the existence of side effects. The objective of the latter study was to find out whether the addition of a potassium salt supplement or a potassium-sparing agent could alleviate the side effect of hypokalemia. In both studies, the participants took a gossypol pill, 20 mg/day for 60 to 75 days for loading, and 50 mg/wk for maintenance. All participants were followed up for a year. The antifertility efficacy was found to be more than 90%, and the chief side effect was lowered serum potassium. In our 1983 to 1985 study, we concluded that since neither potassium supplementation nor triamterene solved the problem, it is very likely that gossypol is a nephrotoxic agent. With 1 year of gossypol treatment, serum testosterone and serum luteinizing hormone showed no change, whereas serum follicle-stimulating hormone showed some elevation after 6 months. The Shanghai researchers found that in their gossypol users, plasma and urinary beta 2-microglobulin levels were elevated to a certain extent. However, 25 subjects in our 1983 to 1985 study showed no appreciable change. Our volunteers had stopped taking gossypol for more than 1 year. In 1986 we started a third study, which was aimed at finding the lowest antifertility dose to minimize possible renal toxicity.

PIP: In 1981 to 1983 we performed a clinical study with gossypol involving 152 participants, and in 1983 to 1985 we conducted another study of 120 participants. The 1st study was aimed at confirming gossypol's antifertility efficacy and determining the existence of side effects. The objective of the latter study was to find out whether the addition of a potassium salt supplement or a potassium-sparing agent could alleviate the side effect of hypokalemia. In both studies, the participants took a gossypol pill, 20 mg/ day for 60-75 days for loading, and 50 mg/wk for maintenance. All participants were followed up for a year. The antifertility efficacy was found to be more than 90%, and the chief side effect was lowered serum potassium. In our 2nd study, we concluded that since neither potassium supplementation nor triamterene solved the problem, it is very likely that gossypol is a nephrotoxic agent. With 1 year of gossypol treatment, serum testosterone and serum luteinizing hormone showed no change, whereas serum follicle-stimulating hormone showed some elevation after 6 months. The Shanghai researchers found that in their gossypol users, plasma and urinary beta-2 microglobulin levels were elevated to a certain extent. However 25 subjects in our 2nd study showed no appreciable change. Our volunteers had stopped taking gossypol for more than 1 year. In 1986 we started a 3rd study, which was aimed at finding the lowest antifertility dose to minimize possible renal toxicity.