Abstract
17 alpha-estradiol (17 alpha-E2) is referred to as a nonfeminizing estrogen that was recently found to extend healthspan and lifespan in male, but not female, mice. Despite an abundance of data indicating that 17 alpha-E2 attenuates several hallmarks of aging in male rodents, very little is known with regard to its effects on feminization and fertility. In these studies, we evaluated the effects of 17 alpha-E2 on several markers of male reproductive health in two independent cohorts of mice. In alignment with our previous reports, chronic 17 alpha-E2 treatment prevented gains in body mass, but did not adversely affect testes mass or seminiferous tubule morphology. We subsequently determined that chronic 17 alpha-E2 treatment also did not alter plasma 17 beta-estradiol or estrone concentrations, while mildly increasing plasma testosterone levels. We also determined that chronic 17 alpha-E2 treatment did not alter plasma follicle-stimulating hormone or luteinizing hormone concentrations, which suggests 17 alpha-E2 treatment does not alter gonadotropin-releasing hormone neuronal function. Sperm quantity, morphology, membrane integrity, and various motility measures were also unaffected by chronic 17 alpha-E2 treatment in our studies. Lastly, two different approaches were used to evaluate male fertility in these studies. We found that chronic 17 alpha-E2 treatment did not diminish the ability of male mice to impregnate female mice, or to generate successfully implanted embryos in the uterus. We conclude that chronic treatment with 17 alpha-E2 at the dose most commonly employed in aging research does not adversely affect reproductive fitness in male mice, which suggests 17 alpha-E2 does not extend lifespan or curtail disease parameters through tradeoff effects with reproduction.