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Published on: February 6, 2018
Cyclic Treatment With WIN 18,446, a Potential Male Contraceptive, is as Effective as Continuous Treatment for
Jisun Paik1, Jessica M Snyder1, Haley A Martin1
1Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.
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.
Insights
Cyclic administration of WIN 18,446 effectively inhibits spermatogenesis, similar to continuous treatment. This cyclic approach may offer faster recovery and reduce testicular damage, advancing male contraceptive development.
Area of Science:
- Reproductive biology
- Pharmacology
- Male contraception
Background:
- Retinoic acid is essential for spermatogenesis.
- Aldehyde dehydrogenase 1A (ALDH1A) enzymes are critical for retinoic acid synthesis in testes.
- WIN 18,446 inhibits ALDH1A1/1A2, showing potential as a reversible male contraceptive.
Purpose of the Study:
- To compare the efficacy of cyclic vs. continuous WIN 18,446 treatment on spermatogenesis.
- To assess potential testicular damage and recovery rates between the two treatment regimens.
- To determine if cyclic WIN 18,446 offers advantages over continuous administration for male contraception.
Main Methods:
- Male mice received either continuous or cyclic WIN 18,446 treatment for spermatogenesis inhibition.
- Cyclic treatment involved alternating periods of drug administration and control diet.
- Testicular histology and sperm counts were analyzed to evaluate efficacy and recovery post-treatment.
Main Results:
- Both cyclic and continuous WIN 18,446 treatments similarly inhibited spermatogenesis, with cyclic treatment showing fewer mature spermatozoa.
- Continuous treatment resulted in only spermatogonia in testes, while cyclic treatment retained spermatocytes/spermatids.
- Spermatogenesis recovery was faster in mice that received cyclic WIN 18,446 compared to continuous treatment.
Conclusions:
- Cyclic WIN 18,446 administration is as effective as continuous treatment in suppressing spermatogenesis.
- Cyclic treatment may lead to quicker recovery of fertility and potentially reduce testicular injury.
- This regimen presents a promising strategy for reversible male contraception with improved safety profile.
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