Scientific Name(s): Gossypium spp. Family: Malvaceae (mallow)
Common Name(s): Gossypol , AT-101 , ApoG2
According to Chinese studies, gossypol is effective as a nonhormonal male contraceptive; however, it has been documented to have irreversible effects on male fertility. It is being studied for clinical applications in cancer therapy.
Antifertility : Trials have used 5 to 10 mg daily for 2 to 3 months to achieve azoospermia, with a lower maintenance dose for up to 2 years. Cancer : Maximum tolerated dosages appear to be 40 mg of gossypol (as AT-101) per day.
None well documented.
Documented abortifacient effects. Avoid use.
None well documented.
Nausea, emesis, anorexia, diarrhea, altered taste sensation, small intestine obstruction, and fatigue have been recorded in clinical trials. The irreversible effects of gossypol on male fertility have been well documented, as has the incidence of hypokalemia.
Gossypol is potentially toxic.
Gossypol is derived from members of the family Malvaceae. The stem, seed, and root of the cotton plant Gossypium hirsutum represent the most common source of gossypol. Gossypium are shrubs that grow to a height of 3 m, have broad lobed leaves, and contain seeds in a capsule or “boll” of fibers. These fibers are harvested and woven in the textile industry. The seeds of Gossypium species vary widely in gossypol content, with levels ranging from 0.13% to 6.6%. 1 , 2
Gossypol was first identified as an antifertility agent as a result of epidemiologic studies conducted in China during the 1950s. Investigators had been puzzled by the extremely low birth rates in a particular geographic region. The men had very low sperm counts and many women had amenorrhea. Eventually the phenomenon was attributed to the use of crude cottonseed oil for cooking and the consumption of cotton cake left over after the extraction of oil and fiber from the cotton plant. Further investigation revealed that the antifertility component was gossypol, and crystalline extracts were supplied to Chinese doctors for widespread use in the 1970s as the principle contraceptive method in China. Because gossypol's use had irreversible effects on fertility and caused hypokalemia in some people, this led to a reduced scientific interest in gossypol. 3
Gossypol is a polyphenolic compound that can be made synthetically or produced inexpensively on a very large scale by the extraction of cottonseed. In more recent years, different versions of the compound have been developed to improve efficacy and reduce the toxicity of the original chemical. Apogossypolone (ApoG2) and R-(-)-gossypol (AT-101) have been used in clinical trials. 2 , 4 , 5 , 6
Uses and PharmacologyAntifertility/Contraceptive
Gossypol is a nonsteroidal compound that inhibits sperm production and motility in a variety of male animals and in humans, but it does not affect sex hormone levels or libido. Gossypol exerts its contraceptive action by inhibiting enzyme systems that play a crucial role in energy metabolism in sperm and spermatogenic cells. 2 , 3Animal data
Gossypol is used as an active antifertility agent in a variety of male animals, including mice, rats, hamsters, monkeys, rabbits, and bulls. 2Clinical data
Large-scale clinical trials in men, conducted by Chinese investigators, have found gossypol to be orally active and relatively safe and effective. The clinical testing of gossypol began in the early 1970s in China, and to date the drug has been studied extensively in thousands of men. Reviews of the clinical trials of gossypol have been published. 7 , 8
Clinical trials focus on establishing lower dosages in an attempt to reduce the potential for hypokalemia and irreversibility. Trials have used 10, 12.5, and 15 mg daily for 2 to 3 months to achieve azoospermia, with maintenance dosages of 35 to 43.75 mg weekly and 7.5 to 10 mg daily tested for up to 2 years. 3 , 9
Sperm counts usually return to normal within 3 months after termination of therapy, and men treated with gossypol have fathered normal children. However, long-term follow-up studies indicate that inhibition of spermatogenesis may continue following discontinuation in up to 50% of men after 2 years. Spermatogenesis does not return to normal in some men. Concerns regarding the lack of predictable, reversible effects have delayed the further clinical development of gossypol in Western countries. 3 The use of gossypol as a nonhormonal alternative to high-dose estrogen in transsexual patients has been suggested. 10Cancer
Gossypol inhibits the growth of various cancer cell lines in vitro, including breast, colon, prostate, and leukemia. Inhibition of cytoplasmic and mitochondrial enzymes (including key enzymes for DNA replication and repair), uncoupling of oxidative phosphorylation, and depletion of cellular ATP are proposed mechanisms of action. 2 , 4 , 6 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18Animal data
Phase 1 and 2 clinical trials are being conducted using gossypol enantiomer AT-101 in non-Hodgkin lymphomas and breast and prostate cancer. 4 , 15 , 17 Limited efficacy has been demonstrated, with effects on surrogate outcomes such as Rb protein and cyclin D1 expression in the breast cancer study and decreased prostate-specific antigen in the prostate cancer study. Maximum tolerated dosages appear to be 40 mg/day. 15Other uses
Although gossypol is generally considered to be a male antifertility agent, it is also effective when given to female animals. In addition, gossypol has been evaluated as a topical spermicide; however, this line of study appears to have not been pursued. 19 , 20
Gossypol and its derivatives have demonstrated antiviral, antibacterial, and antiprotozoal activity. An effect on plasma cholesterol has also been demonstrated in animals. 2
Maximum tolerated dosages appear to be 40 mg of gossypol (as AT-101) per day. 15
Documented abortifacient effects. Avoid use.
The intramuscular injection of gossypol into female rats inhibited implantation and the maintenance of normal pregnancy, most likely by affecting luteinizing hormone levels. 21
None well documented.
The irreversible effects of gossypol on male fertility have been well documented, as has the incidence of hypokalemia. 2
Dose-dependent acute, subchronic, and chronic toxicity has been demonstrated in animals.
Circulatory failure and pulmonary edema are consequent to the cardiotoxicity of gossypol, thought to be due to the prevention of oxygen release from oxyhemoglobin and interference in enzymatic processes. Hepatotoxicity has been observed in some animal studies. 2 , 22 , 23 , 24
Cottonseed oil was nontoxic in short-term oral studies in rats because the gossypol content is generally low and extraction processes may influence the amount of gossypol obtained. However, an increase in the incidence of mammary tumors was observed in some studies. Apogossypol is suggested to have a lower toxicity profile. 2 , 22
The compound was not mutagenic when tested in the Ames Salmonella microsome test, but questions remain about its genotoxic characteristics. 22 Teratogenicity studies found no adverse effect on the fetus or pregnancy in rats at 40 mg/kg body weight. 3
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