New compounds eyed for male contraception
The push is on to develop an effective male contraceptive, with almost $8 million from the National Institutes of Health (NIH) going to researchers at the University of Kansas in Lawrence and the University of Kansas Medical Center in Kansas City toward identifying potential chemical compounds for such use.
Several compounds to be studied
The five-year contract, issued through the Contraceptive and Reproductive Health Branch of the NIH’s National Institutes of Child Health and Human Development, will allow the Kansas scientists to pursue research and testing started in partnership with the NIH four years ago. The research team headed by Gunda Georg, PhD, distinguished professor of medicinal chemistry at University of Kansas, includes Ernst Schonbrunn, PhD, assistant professor and X-ray crystallographer, and Qizhuang Ye, PhD, director of the High Throughput Screening facility, both at the University of Kansas, and Joseph Tash, PhD, associate professor and a reproductive biologist at the University of Kansas Medical Center. The team will be look at several compounds and targeting those that temporarily deactivate key enzymes to inhibit sperm development or motility.
During their previous work with the NIH, the Kansas researchers identified a chemical compound, now known as Gamendazole, which caused temporary infertility in male rats by affecting sperm production. Designed through structure activity studies based on the lead compound, lonidamine, Gamendazole was the most promising analog in terms of potency and lack of side effects, says Tash, the lead reproductive biologist on the contract effort for the contraceptive work. Investigators are planning to publish research on the compound soon, he states.
The Kansas researchers hope to conduct detailed preclinical studies of Gamendazole’s toxicology, dosing, and stability, reports Tash. Upon completion of such studies, clinical trials of the compound could begin in three to five years, he notes.
Other research in works
Research stemming from lonidamine is offering potential results in the male contraceptive field for scientists at the Population Council, a New York City-based research organization. C. Yan Cheng, PhD, a biochemist and molecular biologist, and other council investigators began looking at candidate compounds from lonidamine, an anticancer drug, when research indicated that one side effect of the drug was a temporary disruption of spermatogenesis. While lonidamine itself could not be used as a contraceptive due to its toxic side effects, Cheng’s team began looking at nontoxic analogues of lonidamine with an eye toward their use in male contraception.1-6
With funding from the NIH, the Population Council scientists have identified one compound, AF-2364 or Adjudin, as a promising candidate for male contraception. Early research in male rats indicates that it does not affect the hypothalamic-pituitary-testicular axis.7,8 Researchers are developing a testis-specific delivery system to target Adjudin to the testis so that the action of Adjudin can be limited to the cells behind the blood-testis barrier in the seminiferous epithelium. Why?
"First, a very low dose of Adjudin will be needed for its administration since it is being targeted to cells in the seminiferous epithelium to perturb cell adhesion function there; as such, the mild toxicity issue associated with this compound can be overcome," observes Cheng. "Second, this delivery system can be developed into a therapeutic approach to treat disease behind the blood-testis barrier, such as testicular cancer."
Will it work in a pill?
Will Adjudin be effective in oral administration when it comes to male contraception? Cheng says so; he notes that it does not interfere with the hypothalamic-pituitary-testicular axis, so the physiological events that are dependent on androgens are not affected. Furthermore, it does not interfere with the serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in addition to testosterone.
This finding is significant because it illustrates this compound does not interfere with the male hormones, Cheng points out.
Adjudin apparently exerts its effects largely on the Sertoli-germ cell adhesion function, thereby inducing premature loss of germ cells from the seminiferous epithelium, he observes. Since this effect occurs locally in the testis, general toxicity, if any, is minimal, Cheng notes. This lack of toxicity is crucial for a successful male pill, since men likely will take such a pill over a long period of time for contraceptive benefits, states Cheng.
If a potent agent such as Adjudin can be targeted specifically to the site of action, this will likely reduce its toxicity to a minimum, he says. "At present, we’re using Adjudin to develop an in vivo model to study cell adhesion function in the testis," Cheng explains. "We have identified several signaling pathways that are being activated to regulate junction restructuring, and recently published findings from our laboratory have shown that their inactivation can indeed affect cell adhesion function in the testis."9
References
- Chung SS, Zhu LJ, Mo MY, et al. Evidence for cross-talk between Sertoli and germ cells using selected cathepsins as markers. J Androl 1998; 19:686-703.
- Grima J, Wong CC, Zhu LJ, et al. Testin secreted by Sertoli cells is associated with the cell surface, and its expression correlates with the disruption of Sertoli-germ cell junctions but not the inter-Sertoli tight junction. J Biol Chem 1998; 273:21,040-21,053.
- Grima J, Zhu L, Cheng CY. Testin is tightly associated with testicular cell membrane upon its secretion by Sertoli cells whose steady-state mRNA level in the testis correlates with the turnover and integrity of inter-testicular cell junctions. J Biol Chem 1997; 272:6,499-6,509.
- Mruk DD, Cheng CY. Sertolin is a novel gene marker of cell-cell interactions in the rat testis. J Biol Chem 1999; 274: 27,056-27,068.
- Mruk D, Zhu LJ, Silvestrini B, et al. Interactions of proteases and protease inhibitors in Sertoli-germ cell cocultures preceding the formation of specialized Sertoli-germ cell junctions in vitro. J Androl 1997; 18:612-622.
- Mruk DD, Cheng CY. Cell-cell interactions at the ectoplasmic specialization in the testis. Trends Endocrinol Metab 2004; 15:439-447.
- Cheng CY, Silvestrini B, Grima J, et al. Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis. Biol Reprod 2001; 65:449-461.
- Grima J, Silvestrini B, Cheng CY. Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4 -dichlorobenzyl)-indazole-3-carbohydrazide. Biol Reprod 2001; 64:1,500-1,508.
- Cheng CY, Mo M, Grima J, et al. Indazole carboxylic acids in male contraception. Contraception 2002; 65:265-268.
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