Gossypol

Scientific Name(s):Gossypol is derived from members of the family Malvaceae. Cotton ( Gossypium spp.) represents the most common source.

Clinical Overview

Uses of Gossypol

Gossypol acts as a male and female contraceptive. It may be used to treat gynecological problems and viral infections.

Gossypol Dosing

Gossypol has been studied at an oral dose of 20 mg/day.

Contraindications

No longer considered safe.

Pregnancy/Lactation

Documented abortifacient effects. Avoid use.

Gossypol Interactions

None well documented.

Gossypol Adverse Reactions

Contraceptive effects may not be reversible.

Toxicology

Gossypol is potentially toxic.

History

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 exclusive use of crude cottonseed oil for cooking. Further investigation revealed that the antifertility component was gossypol, a potentially toxic phenolic pigment found in the seed, stem, and root of the cotton plant. 1

Chemistry

Gossypol is a natural product that can be made synthetically 2 or produced inexpensively on a very large scale by the extraction of cottonseed. Estimates have placed potential US gossypol production at more than 50,000 tons per year, all as a by-product of cottonseed oil production. 3 Cotton represents the most well-known source of this compound. The seeds of the Gossypium species vary widely in gossypol content, with levels ranging from 0.13% to 6.6%. 2

Gossypol Uses and Pharmacology

Gossypol is a nonsteroidal compound that inhibits sperm production and motility in a variety of male animals and in humans. It does not affect sex hormone levels or libido, and its mechanism is distinct from that of steroidal oral contraceptives used by women.

Gossypol exerts its contraceptive action by inhibiting an enzyme that plays a crucial role in energy metabolism in sperm and spermatogenic cells. The target enzyme, lactate dehydrogenase X, is found only in sperm and male gonadal cells. It is involved in glycolysis and plays a role in inducing mitochondria to produce energy. A variety of lactate dehydrogenases are found throughout the body and gossypol exerts a degree of inhibition on many of these. However, the drug exhibits its greatest inhibitory effect on lactate dehydrogenase X.

Gossypol has been shown to be an active antifertility agent in male hamsters and rats. 4 Sperm recovered from the epididymis of rats and hamsters treated with gossypol for as little as 6 weeks were immotile, with detached heads or tails. 5 Gossypol does not demonstrate estrogenic or androgenic activity but it can potentiate the androgenicity of methyltestosterone. 6

Large-scale clinical trials in men 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. The usual daily dose is 20 mg until the sperm count is reduced below 4 million/mL; this usually requires 2 to 3 months of treatment. Maintenance doses of 75 to 100 mg are subsequently taken twice a month. A proposed contraceptive dose is 3 g/man/year.

A comprehensive review of the clinical trials of gossypol has been published. 7 Clinical trials have found the drug's antifertility effect to be more than 99%. 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 20% 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.

Although gossypol is generally considered to be a male antifertility agent, it is also effective when given to female animals. The intramuscular injection of gossypol into female rats inhibited implantation and the maintenance of normal pregnancy, most likely by affecting luteinizing hormone levels. 8 Gossypol is also an inhibitor of platelet activating factor and leukotrienes. 9 In addition, gossypol has been evaluated as a topical spermicide. A gelatin coprecipitate of gossypol is an effective spermicide in monkeys. 10

Gossypol has shown effects that suggest some inhibition of ovarian function and cytotoxicity in endometrial cells. 11

Gossypol has been evaluated as a topical spermicide in humans. Solutions of gossypol or gossypol acetate do not decrease sperm motility. However, a solution of gossypol-PVP coprecipitate completely immobilized all spermatozoa within 3 minutes at a concentration of 5 mg/mL and within 20 seconds at 40 mg/mL. The spermicidal activity of gossypol was found to be equal to or greater than that of the commercially available creams Delfin and Preceptin , as well as Encare Oval vaginal suppositories. 12 A gossypol-containing gel decreased the number and rapidly immobilized sperm when tested in healthy women. 13 The topical use of gossypol has been recommended because it has low systemic toxicity, it acts in micromolar concentrations, and it is effective in the presence of cervical mucus. 14

Gossypol has been investigated for the treatment of uterine myoma, endometriosis, and dysfunctional uterine bleeding. Gossypol and its derivatives are active against the HIV virus 15 and the herpes simplex virus type 2. 16 A trial evaluated the therapeutic efficacy of gossypol for the treatment of metastatic carcinoma of the endometrium or ovary, and as an antiviral and interferon inducer in patients with AIDS. 7

Dosage

Gossypol has been studied at an oral dose of 20 mg/day. 17 , 18 , 19

Pregnancy/Lactation

Documented abortifacient effects. 20 Avoid use.

Interactions

None well documented.

Adverse Reactions

Commercial cotton seed oil is processed in order to remove its gossypol content.

A low incidence of side effects was originally reported in men treated with gossypol. Some men developed transient weakness during the first days of administration, which appears to be related to hypokalemia induced by gossypol. This may be caused by renal loss of potassium during therapy and can be managed effectively with oral potassium supplementation. Some men notice changes in appetite. At high doses (100 to 700 times the contraceptive dose) gossypol may cause diarrhea, hair discoloration, malnutrition, circulatory problems, and heart failure.

The results of more recent, well-controlled studies found that the incidence of adverse events was significant enough to warrant abandoning the development of gossypol as a male contraceptive. 21

Gossypol is found in 2 isomeric forms. Only (-) gossypol shows antispermatogenic effects in animals; the (+) form appears to be associated with hypokalemia. Therefore, administration of a purified (-) form may provide efficacy while reducing certain side effects.

Toxicology

Gossypol inhibits malate dehydrogenase in animals and glutathione-S-transferase in both animals and man. This latter enzyme is involved in the detoxification of potentially toxic and carcinogenic compounds.

The compound has not been found to be mutagenic when tested in the Ames salmonella microsome test, 22 but questions still remain about its genotoxic characteristics. 23

Gossypol toxicity is a potential veterinary problem, and as little as 200 parts per million of free gossypol could kill a calf. 23 Nonruminant animals are more sensitive to the toxic effects of gossypol than ruminants. 24

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