Gossypol: a potential antifertility agent for males.

Abstract

The discussion provides a general review of gossypol as a potential male contraceptive, focusing on the pharmacological features not discussed in previous review articles. Attention is directed to the chemistry of gossypol, the antifertility effect of gossypol, its metabolism and toxicity, the genetic and endocrine effects of gossypol; clinical trails of gossypol; hypokalemic paralysis; and the site and mechanism of action. Gossypol is a yellowish phenolic compound ocurring naturally in certain species of cotton plants of the family Malvaciae, mostly in the seeds and root bark. The Hubei Provincial group documented the antispermatogenic effects of crude cottonseed oil in rats and monkeys, and since then a number of workers have investigated the active principle(s) in cottonseed and cotton root bark. The work on gossypol as an antifertility agent, initiated by Liu (1957) and pursued actively, has stimulated nationwide attention. After publication of a review article by the National Coordinating Group, it attracted universal interest. 3 forms of gossypol -- gossypol, gossypol acetic acid, and gossypol formic acid -- have been used in laboratory investigations and clinical trials. They are very much the same in their biological activities and are discussed as a whole under the generic name gossypol. Unless psecified otherwise, the term refers to the racemate administered orally. There are pronounced differences among animal species in their sensitivity to the antifertility action of gossypol. Gossypol is absorbed through the intestine as well as through the epithelial lining of the stomach. In an attempt to mitigate the gastric side effects of gossypol, 1 group of clinicians adopted enteric-coated tablets for the clinical trial. They found that both the antifertiltiy effect and the systemic side effects of these tablets were much less than those of ordinary tablets. Gossypol is an effective antispermatogenic agent for certain susceptible animals and humans and represents the only approach which has a reasonable chance to reach the stage of large scale clinical testing before the end of this decade. Much work must be done, particularly in regard to its toxicology, before it (or 1 of its analogues) can be developed into a practical male antifertility drug. The following points suggest the main directions for future research in the scope of pharmacology and toxicology: hypokalemia -- exploration of the contributing factor(s), means to prevent its occurrence, mechanism(s) of development, production of animal model; irreversibility; general toxicological assessment; and studies on the mechanism of action, which also may be helpful in the development of gossypol analogue(s) exhibiting satisfactory antifertility and minimal toxic effects.