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methods - pharmaceuticals - gossypol
Gossypol is a non-hormonal fertility-inhibiting molecule which occurs naturally in unrefined cottonseed oil. An investigation of Jiangxi Province in China, conducted in 1929 (but not published until 1957), showed a correlation between low fertility rates for couples and use of crude cottonseed oil for cooking. Continued research showed that cottonseed oil was specifically affecting only male fertility. Eventually researchers isolated the compound causing the contraceptive effect, gossypol, from the oil.
In the 1970's, the Chinese government began large-scale research on the possible use of gossypol as a contraceptive. These studies involved over 10,000 subjects, and continued for over a decade. The researchers found that gossypol provided reliable contraception, could be taken orally as a tablet, and did not upset men's balance of hormones. At the conclusion of the trials, gossypol seemed a promising male contraceptive, but it also had serious flaws.
Some men in the Chinese studies remained azoospermic after prolonged use of gossypol. The longer the men had taken the drug, and the higher their overall dosage, the more likely the men were to lose part or all of their fertility. Various studies reported between 5 and 25 percent of the men remained infertile up to a year after stopping treatment.
The Chinese studies also reported an abnormally high rate of hypokalemia among subjects, varying between 1 and 10 percent. Hypokalemia is characterized by low blood potassium levels. Symptoms include fatigue, muscle weakness, and at its most extreme, paralysis. Hypokalemia is usually the result of kidney malfunction, although exactly how gossypol affects renal function is unknown. The Chinese researchers found that most subjects recovered after stopping gossypol treatment and taking potassium supplements. A later study showed that taking potassium supplements during gossypol treatment did not prevent hypokalemia in primates.
In 1986, the Chinese research program was called to a halt due to concerns about these side effects. Since then, gossypol's prospects have been unclear. The scientific community agrees that the rates of permanent infertility in the Chinese studies were unacceptably high. However, some researchers have argued that the data on hypokalemia were misinterpreted, and that diet and genetic predisposition are responsible for this side effect. Some researchers propose that lower doses of gossypol might still provide reliable contraception without such serious side effects.
Researchers in Brazil have undertaken trials of low dose gossypol. These researchers had promising results, but also had concerns about reversibility. In the mid 1990s, the Brazilian pharmaceutical company Hebron announced plans to market a low dose gossypol pill called Nofertil, but the pill never came to market. Its release to the public has been indefinitely postponed due to unacceptably high rates of infertility. Despite this controversy, the Brazilian public's interest in the drug is high. According to a Brazilian women's magazine, over 10,000 men have volunteered for clinical studies of Nofertil.
In 1998, the World Health Organization's Research Group on Methods for the Regulation of Male Fertility reviewed the research on gossypol and concluded that contraceptive research should be abandoned. In addition to the side effects mentioned above, the WHO researchers have major concerns about gossypol's toxicity. The toxic dose in primates is less than 10 times the contraceptive dose. This report will effectively halt further research into this method in the developed world.
South to South, an alliance of 16 developing countries researching reproductive health, is looking into gossypol as an alternative to vasectomy. Phase II clinical trials of this method of sterilization are taking place in Austria, Brazil, Chile, China, the Dominican Republic and Nigeria with over 300 men. Chinese researchers are still pursuing gossypol as a contraceptive. One study on rats combined the contraceptive effects of gossypol and Tripterygium wilfordii. They found that the drugs have additive effects when taken together, and that it may be possible to avoid the side effects of both drugs by taking them in combination at much lower doses.
effectiveness We have not been able to obtain specific efficacy rates for the Chinese trials of gossypol. However, it seems to be generally accepted, even by those who argue against continued research, that reliability is not an issue. Some articles describe the efficacy rate as 96-98%, or comparable to the female birth control pill.
convenience Gossypol is taken in a tablet form. In the most recently published low-dose study, pills were taken every other day. The amount of time it takes to become effective has varied greatly in different studies, but is consistently a minimum of two months.
ease of reversibility Reversibility is the single biggest issue with gossypol. In the published low-dose trial, which lasted 16-18 months, no permanent loss of fertility occurred. However, trials involving multiple years of use have consistently reported sterility rates of 10 to 20%.
safety Toxic dose is less than 10 times the contraceptive dose. In the Chinese trials, about 7% of subjects reported effects on their digestive system, and about 12% increased fatigue. At some trial sites, as many as 10% of subjects developed hypokalemia. The researchers reported that these effects vary based on factors such as diet and body weight.
research to date
Researchers Year # Studied % Effectiveness Reference
Gu et al 2000 77 n/a Asian Journal of Andrology 2000; vol 2(4), pp 283-287
The researchers report on side effects of gossypol during a low-dose study. Subjects took 10 or 12.5 milligrams of gossypol for 16 to 18 months. The men took the pill daily for the first 2 months until they became azoospermic. They then switched to a maintenance dose, taking the pill every other day for the duration of the study. After stopping treatment, all men returned to pre-treatment sperm counts. None of the subjects suffered from hypokalemia or muscle fatigue during this study.
Waites et al 1998 n/a n/a Internat'l Journal of Andrology 1998; vol 21(1), PP 8-12
Reports the WHO's review of gossypol research. The authors conclude that gossypol is not an acceptable male contraceptive. They cite concerns about hypokalemia, high toxicity and the risk of permanent sterility. They also cite the failure of gossypol-related compounds and gossypol enantiomers to provide a safer of more effective alternative.
Yu et al 1998 n/a n/a Internat'l Journal of Andrology 1998; vol 21(1), PP 2-7
The authors argue for the continuation of studies on gossypol as a male contraceptive. They stress the large regional variations in the occurrence of hypokalemia in the Chinese trials, with "0 of 1825 subjects (0%) in Shangdong Province [developing hypokalemia], but 25 of 255 (9.41%) in a Shanghai hospital alone." They cite the large variation in onset of contraceptive efficacy as a problem.
Lohiya et al 1990 ? primates n/a Contraception 1990; vol 41, PP 519-532
Reports a test of gossypol taken in combination with a potassium supplement for 120 days. The researchers observed "severe oligospermia" and "extensive renal potassium loss." Both sperm count and blood potassium levels returned to pretreatment levels within 105 days of the cessation of treatment.
Meng et al 1988 46 87% Internat'l Journal of Andrology 1988; vol 11(1), PP 1-11
A study of the reversibility of gossypol's contraceptive effect. Sixty-one percent of the subjects regained normal fertility with "a median recovery time of 1.1 years." Twenty-two percent remained azoospermic after 1.9 years. "The failure of recovery was strongly associated with longer treatment, greater total dose of gossypol, smaller testicular volume, elevated FSH [follicle stimulating hormone] concentrations and, to a lesser extent, with greater body weight."
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