Alterations in the estrogen environment of the testis contribute to declining sperm production in aging rats

Abstract

Testicular function, specifically, production of testosterone by Leydig cells, diminishes during aging. Estradiol is also produced by the testis and potentially acts in an autocrine or paracrine manner to help regulate spermatogenesis. However, changes in estradiol concentration or receptor expression within the testis during aging remain unclear. This study was designed to test the hypothesis that the estrogen environment of the testis is altered during aging and that these changes are associated with declining sperm production. Sprague Dawley rats were examined at three, 15, 18, and 21 months of age to detail changes in sperm production and testicular concentration of testosterone and estradiol; five rats were used at three and 21 months and three rats were used at 15 and 18 months. Daily sperm production declined 49% from 15 to 21 months of age. Testicular concentrations of estradiol declined 53% from 15 to 21 months of age; testosterone concentrations were not significantly different. These results suggest that declines in intra-testicular estradiol may contribute to declining sperm production. We further tested our hypothesis by treating rats once every third day with a subcutaneous injection of estradiol valerate (1 µg/kg) from 15 to 18 months of age. Estradiol was increased 54% in treated animals while testosterone was unaffected. Estrogen receptor alpha (ESR1) expression was significantly reduced from 15 to 18 months and expression in estrogen-treated animals was significantly higher than age-matched controls. Additionally, ESR1 expression in 18 month treated animals was not different from 15 months of age. Importantly, daily sperm production in 18 month treated animals was 22% higher than age-matched controls; thus, treatment prevented approximately half of the decline observed in control animals. Collectively, our results suggest that estrogen is involved in maintaining optimum spermatogenesis in adult rats and that estrogen treatment may attenuate the age-associated loss in sperm production.

High butter-fat diet and bisphenol A additively impair male rat spermatogenesis

“…To address this question, one male offspring per litter exposed in utero to the above diets, without any secondary exposures, was sacrificed at ~18 months of age (equivalent to 45 human years, middle age [36]). It has been previously shown that sperm count and quality begins to decline around age 40 in humans [37,38] and at 18 months of age in rats [20]. We found that while 100% of offspring exposed to the control AIN diet showed normal spermatogenesis (presence of spermatozoa in >20% of STs), only 17% (1 in 6 rats) of offspring exposed to HFB + BPA had significantly normal spermatogenesis (Table 3).…”

“…1), a hormonal milieu previously reported to mimic aging [20,35]. We found that while 100% of the offspring exposed to the control AIN diet showed normal spermatogenesis (presence of spermatozoa in >14% of STs), only 37–43% of offspring exposed to 25 μg/kg bw-d BPA and/or HFB had spermatozoa in STs (Table 2).…”

“…Adult rats are sacrificed at 18 months (PND 540), when E2:T ratio was previously been shown to be highest [20]. However, some pups (2 each for HFB + BPA and HFO group and 1 for HFO + BPA group) either died before PND500 (16.6 months) of unknown causes, or were sacrificed early due to distress, as advised by the veterinarians.…”

“…In Sprague-Dawley (SD) rats, the testicular E2 to T ratio is highest at 18 months of age [20], coinciding with declining sperm production. Other contributors to reduced spermatogenesis include exposure to xeno/phyto-estrogens, obesity, inflammatory cytokines, poor dietary choices, and reactive toxins [21–24], all of which contribute to stress, and also increase E2 levels.…”

Effect of estrogen receptor-subtype-specific ligands on fertility in adult male rats

“…Results of studies have revealed a correlation between decreasing E 2 levels in the testis and decreasing sperm production during ageing and indicated that E 2 can attenuate the age-related decline in spermatogenesis (Hamden et al 2008, Clarke & Pearl 2014. On the other hand, overexposure to E 2 , synthetic estrogens, like DES, and SERMs, like tamoxifen and BPA, cause deleterious effects on the male reproductive tract and fertility.…”