Roselli Charles E, Amodei Rebecka, Gribbin Kyle P, Corder Keely, Stormshak Fred, Estill Charles T
Department of Physiology and Pharmacology (C.E.R., R.A., K.P.G.), Oregon Health and Science University, Portland, Oregon 97239-3098; and Department of Animal and Rangeland Sciences (K.C., F.S., C.T.E.) and College of Veterinary Medicine (C.T.E.), Oregon State University, Corvallis, Oregon 97331-4501.
Endocrinology. 2016 Nov;157(11):4234-4245. doi: 10.1210/en.2016-1411. Epub 2016 Sep 27.
Prenatal exposure to excess androgen may result in impaired adult fertility in a variety of mammalian species. However, little is known about what feedback mechanisms regulate gonadotropin secretion during early gestation and how they respond to excess T exposure. The objective of this study was to determine the effect of exogenous exposure to T on key genes that regulate gonadotropin and GnRH secretion in fetal male lambs as compared with female cohorts. We found that biweekly maternal testosterone propionate (100 mg) treatment administered from day 30 to day 58 of gestation acutely decreased (P < .05) serum LH concentrations and reduced the expression of gonadotropin subunit mRNA in both sexes and the levels of GnRH receptor mRNA in males. These results are consistent with enhanced negative feedback at the level of the pituitary and were accompanied by reduced mRNA levels for testicular steroidogenic enzymes, suggesting that Leydig cell function was also suppressed. The expression of kisspeptin 1 mRNA, a key regulator of GnRH neurons, was significantly greater (P < .01) in control females than in males and reduced (P < .001) in females by T exposure, indicating that hypothalamic regulation of gonadotropin secretion was also affected by androgen exposure. Although endocrine homeostasis was reestablished 2 weeks after maternal testosterone propionate treatment ceased, additional differences in the gene expression of GnRH, estrogen receptor-β, and kisspeptin receptor (G protein coupled receptor 54) emerged between the treatment cohorts. These changes suggest the normal trajectory of hypothalamic-pituitary axis development was disrupted, which may, in turn, contribute to negative effects on fertility later in life.
产前暴露于过量雄激素可能导致多种哺乳动物成年后生育能力受损。然而，对于早期妊娠期间调节促性腺激素分泌的反馈机制以及它们如何应对过量睾酮暴露，我们知之甚少。本研究的目的是确定与雌性羔羊相比，外源性睾酮暴露对调节雄性胎儿羔羊促性腺激素和促性腺激素释放激素（GnRH）分泌的关键基因的影响。我们发现，在妊娠第30天至第58天每两周给母羊注射丙酸睾酮（100毫克），会使血清促黄体生成素（LH）浓度急剧下降（P < 0.05），并降低两性促性腺激素亚基mRNA的表达以及雄性GnRH受体mRNA的水平。这些结果与垂体水平负反馈增强一致，同时睾丸类固醇生成酶的mRNA水平降低，表明睾丸间质细胞功能也受到抑制。GnRH神经元的关键调节因子亲吻素1 mRNA的表达在对照雌性中显著高于雄性（P < 0.01），而在雌性中因睾酮暴露而降低（P < 0.001），这表明雄激素暴露也影响了下丘脑对促性腺激素分泌的调节。尽管在母羊停止注射丙酸睾酮2周后内分泌稳态得以重建，但治疗组之间GnRH、雌激素受体-β和亲吻素受体（G蛋白偶联受体54）的基因表达出现了其他差异。这些变化表明下丘脑 - 垂体轴发育的正常轨迹被破坏，这反过来可能对后期的生育能力产生负面影响。
