青春期前不同时长脱氢表雄酮暴露对成年雌鼠生殖力的影响

Prepubal hyperandrogen exposure induces reproductive changes in adult female rats

目的雄激素是体内合成雌激素的重要前体,参与女性生殖功能的调控。文中探讨了青春期前接受不同时长的高雄激素刺激,对成年雌鼠生殖能力的影响。方法 23日龄离乳雌性大鼠25只随机分为5组,即油剂对照组和脱氢表雄酮(DHEA)2、4、6、8周组,每日注射DHEA,分别持续2、4、6、8周,80日龄交配,检测血清总睾酮(T)、雌二醇、促卵泡生成素(FSH)、促黄体生成素(LH)浓度,观察雌鼠阴门开启时间及动情周期的改变,统计交配率、受孕率、产子数与离乳存活数。结果 1DHEA注射2周总睾酮浓度升高,停止注射后DHEA 2、4周组总睾酮随时间下降至正常,DHEA6周组仍维持在高水平,与同时间油剂对照组比较,差异有统计学意义(P<0.05);2DHEA注射2周、4周雌二醇浓度显著升高,延长注射至6周、8周雌二醇呈下降趋势,与同时间油剂对照组比较,差异有统计学意义(P<0.05);3DHEA注射FSH水平无显著改变,LH水平随总睾酮浓度增加而显著上升;4DHEA注射2周阴门开启时间提前[(26.60±0.89)d vs(35.20±2.49)d,P<0.01];5DHEA注射4周动情周期紊乱比例较油剂对照组明显增加[(86.67%vs 20.00%),P<0.05],停止注射后DHEA2、4周组动情周期逐渐复常,DHEA6、8周组持续紊乱;6DHEA 6、8周组产仔数低于油剂对照组[(6.40±1.14)只vs(10.2±1.48)只;(6.60±1.52)只vs(10.20±1.48)只]、离乳存活数低于油剂对照组[(5.60±0.55)只vs(9.40±1.67)只;(5.40±1.67)只vs(9.40±1.67)只],差异有统计学意义(P<0.05)。各组交配率、受孕率、离乳存活率差异无统计学意义(P>0.05)。结论青春期前持续高雄激素暴露可促使雌鼠肾上腺功能初现提前,并影响随后的性腺功能启动,长期高雄刺激可显著降低育龄期生育力,应及时干预青春期早期高雄激素水平。

Objective Androgen is an important precursor for the synthesis of estrogen in vivo and is involved in the regulation of female reproductive function. In this study,we explored the influence of different lengths of prepubertal exposure to hyperandrogen on the reproductive function of adult female rats. Methods Twenty-five 23-day-old female rats were equally randomized into five groups：oil control,2-wk dehydroepiandrosterone（ DHEA）,4-wk DHEA,6-wk DHEA,and 8-wk DHEA,injected with oil or DHEA daily for 2,4,6,and 8 weeks respectively,and mated at 80 days old. We detected serum concentrations of total testosterone（ t T）,estradiol（ E2）,follicle-stimulating hormone（ FSH） and luteinizing hormone（ LH） by ELISA,observed the time of vaginal opening and changes of the estrous cycle,and recorded the rates of mating and pregnancy,the number of the offspring and their survival rate. Results The t T level was elevated after 2 weeks of DHEA injection,fell to normal after drug withdrawal in the 2-wk and 4-wk DHEA groups,and remained at a high level in the 6-wk group. The E2 level was markedly increased in at 2 and 4 weeks but showed a falling trend at 6 and 8 weeks.DHEA injection did not change the level of FSH significantly but remarkably lifted that of LH with the increased concentration of t T. The vaginal opening time was significantly advanced in the 2-wk DHEA group as compared with the controls（ [26. 60 ± 0. 89] d vs [35. 20 ±2. 49] d,P 0. 01）. The estrous cycle exhibited no significant change until the 4th week（ 20. 00% vs 86. 67%,P 0. 05） and returned to normal with drug withdrawal in the 2-wk and 4-wk groups,but not in 6-wk and 8-wk groups. Compared with the oil controls,the rats in the 6-wk and 8-wk groups showed a dramatically lower number of offspring（ 10. 20 ± 1. 48 vs 6. 40 ± 1. 14 and 6. 60 ± 1. 52,P 0. 01）as well as a lower survival rate of the offspring（ 9. 40 ± 1. 67 vs 5. 60 ± 0. 55 and 5. 40 ± 1. 67,P 0. 05）. However,no statistically significant differences were found in the rates of mating and pregnancy among the five groups（ P 0. 05）. Conclusion Prepubertal exposure to hyperandrogen may advance adrenarche and gonadarche and affect the initiation of the sexual gland function in female rats. Improving the hyperandrogen status in the early pubertal stage can reverse the disorder of the estrous cycle,while long-term exposure to DHEA may significantly reduce the fecundity at the childbearing age.