In addition to the work previously described on the development of hormonal male contraceptives, there has been great interest in attempts to develop new non-hormonal male contraceptives. Nonhormonal male contraception can be defined as an approach to male contraception that does not use the administration of T or compounds that block T secretion. Nonhormonal contraception may have some advantages over hormonal male contraceptives because they likely avoid any effect on T concentrations and therefore do not affect sexual function, sex drive, or body composition.


The first widely clinically studied non-hormonal male contraceptive was gossypol. Gossypol is a large molecule purified from cotton seeds grown in China. Gosipol was studied extensively in the 1980s in 2 large phase III trials in China involving >8000 men. In these studies, gosipol reduced both sperm production and sperm motility, and induced abnormal sperm morphology through an unknown mechanism. Most men developed azoospermia, and gossypol was 90% effective in preventing pregnancy. Unfortunately, side effects including hypokalemia and hypokalemic periodic paralysis occurred in approximately 1% of men treated. In addition, spermatogenesis did not fully recover in almost 20% of men.


The second natural male contraceptive compound studied in China was the herb Tripterygium wilfordii, the active ingredient of which was called tryptolide. Tripterygium has been used in traditional Chinese medicine for centuries to treat arthritis. A clinical study of patients treated with this compound showed that administration of Tripterygium impaired sperm motility and reduced sperm count.

The compound ajudine was studied as a non-hormonal male contraceptive in animal studies in the early 2000s. When administered to rodents, ajudin interfered with the ability of sperm to adhere to Sertoli cells. Because of this, the spermatids underwent premature spermatization, resulting in the production of non-functional sperm that were incapable of fertilization. In rats, administration of ajudin (50 mg/kg) twice a week caused 100% infertility after 5 weeks of treatment. It is noteworthy that the administration of ajudin did not lead to changes in serum gonadotropin or T concentrations. Unfortunately, several animals experienced liver inflammation in the 29-day study.


H2-gamendazole is an ajudin derivative that interferes with the normal functioning of apical ectoplasmic specialization. In one in vivo experiment, all rats treated with a single dose of gamendazole (6 mg/kg) became infertile; unfortunately, only half recovered fertility after treatment. In addition, H2-gamendazole had serious toxicity. For example, in 1 study of H2-gamendazole, 3 out of 5 rats treated with a dose of 200 mg/kg died due to the low therapeutic index of this agent.