Cyclic Treatment With WIN 18,446, a Potential Male Contraceptive, is as Effective as Continuous Treatment for Suppression of Spermatogenesis in Mice.

BACKGROUND

Retinoic acid plays a critical role in spermatogenesis during both spermatogonial differentiation and spermiation. Mice lacking enzymes that synthesize retinoic acid, Aldh1a1/1a2, in the testes are infertile. WIN 18,446 reversibly inhibits spermatogenesis by inhibiting ALDH1A1/1A2 and is a promising approach to male contraception. Previously, we demonstrated the kinetics, efficacy, and reversibility of continuous treatment with WIN18,446 as a male contraceptive.

OBJECTIVE

We sought to investigate whether cyclic administration of WIN 18,446 could be as effective at inhibiting spermatogenesis as continuous treatment with WIN 18,446 while reducing the risk of potential testicular damage from continuous treatment. We studied testicular histology and sperm counts in response to continuous vs. cyclic treatment of WIN 18,446 and assessed recovery from the two treatment regimens.

MATERIALS AND

METHODS

Male mice were fed a diet containing WIN 18,446 for 15 weeks, followed by a diet without the drug for up to 16 weeks. For cyclic treatment, male mice were fed the WIN 18,446-containing diet for 4 weeks, followed by three cycles of 2-weeks of control diet, followed by 2-weeks of WIN 18,446 diet for 12 additional weeks. After the last cyclic treatment, drug treatment was discontinued, and animals were allowed to recover for 8 weeks. Mice were euthanized at predetermined time points to assess recovery of spermatogenesis by testicular histology and sperm counts.

RESULTS

Testis weights and sperm counts were similar between cyclically treated mice and mice treated with WIN 18,446 continuously for 15 weeks. Testes of mice under cyclic treatment contained spermatocytes/spermatids, but not mature, normal spermatozoa, while those from the mice under continuous treatment had only spermatogonia. Importantly, spermatogenesis recovered more quickly when mice were treated cyclically compared to those receiving continuous treatment based on testes weight and histology.

CONCLUSIONS

Cyclic treatment of mice with the ALDH1A inhibitor WIN 18,446 is as efficacious as continuous treatment in suppressing spermatogenesis and may allow for faster recovery of spermatogenesis after the cessation of drug treatment, and reduce the chance of injury to the testes from continuous treatment.