Forsdike Rachel A, Hardy Kate, Bull Lauren, Stark Jaroslav, Webber Lisa J, Stubbs Sharron, Robinson Jane E, Franks Stephen
Department of Mathematics, Imperial College London, London, UK.
J Endocrinol. 2007 Feb;192(2):421-8. doi: 10.1677/joe.1.07097.
Exposure to excess androgens in utero induces irreversible changes in gonadotrophin secretion and results in disrupted reproductive endocrine and ovarian function in adulthood, in a manner reminiscent of the common clinical endocrinopathy of polycystic ovary syndrome (PCOS). We have recently identified an abnormality in early follicle development in PCOS which we suggested might be an androgenic effect. We propose that altered ovarian function in androgenized ewes is due to prenatal androgens not only causing an abnormality of gonadotrophin secretion, but also exerting a direct effect on the early stages of folliculogenesis. Therefore, in this study, we explored the possible differences between small preantral follicles in the ovarian cortex of androgenized female lambs with those of normal lambs. At 8 months of age, small ovarian cortical biopsies (approximately 5 mm3) were obtained at laparotomy from nine female lambs that had been exposed to androgens in utero from embryonic days 30 to 90 of a 147-day pregnancy, and 11 control female lambs. Further, ovarian tissue was obtained at 20 months of age from ten androgenized and nine control animals. Tissue was either fixed immediately for histology or cultured for up to 15 days prior to fixing. The number of follicles in haematoxylin and eosin-stained sections was counted and recorded along with the stage of development. Before culture, the total follicle density (follicles/mm3 tissue) was not statistically significantly different between the two types of ovary at either 8 or 20 months of age. Furthermore, there were no statistically significant differences in the density of follicles at each stage of development. However, there was a lower percentage of primordial follicles, but a higher percentage of primary follicles, in biopsies taken at 8 months from androgenized lambs when compared with controls. At 20 months, the proportions of follicles at the primordial and primary stages were not significantly different between the two groups, but this was mainly attributable to an increase in the proportion of growing follicles in biopsies from control animals. Culture of ovarian cortex from 8-month-old lambs resulted in a progressive increase in the proportion of growing follicles when compared with tissue fixed on the day of surgery. However, there was no difference between androgenized and control tissue in the percentage of growing follicles. The increase in the proportion of growing follicles in the cortex of androgenized animals is reminiscent of similar observations in human polycystic ovaries and suggests that excess exposure to androgen in early life plays a part in the accelerated progression of follicle development from the primordial to the primary stage in polycystic ovaries.
子宫内暴露于过量雄激素会导致促性腺激素分泌发生不可逆变化,并在成年后导致生殖内分泌和卵巢功能紊乱,其方式类似于多囊卵巢综合征(PCOS)这种常见的临床内分泌疾病。我们最近发现PCOS早期卵泡发育存在异常,我们认为这可能是雄激素的作用。我们提出,雄激素化母羊卵巢功能改变是由于产前雄激素不仅导致促性腺激素分泌异常,还对卵泡发生的早期阶段产生直接影响。因此,在本研究中,我们探讨了雄激素化雌性羔羊与正常羔羊卵巢皮质中小窦前卵泡之间可能存在的差异。在8月龄时,通过剖腹手术从9只在147天妊娠期的胚胎第30天至90天期间子宫内暴露于雄激素的雌性羔羊以及11只对照雌性羔羊身上获取小块卵巢皮质活检组织(约5立方毫米)。此外,在20月龄时从10只雄激素化动物和9只对照动物身上获取卵巢组织。组织要么立即固定用于组织学检查,要么在固定前培养长达15天。对苏木精和伊红染色切片中的卵泡数量进行计数并记录,同时记录发育阶段。在培养前,两种类型的卵巢在8月龄或20月龄时的总卵泡密度(卵泡数/立方毫米组织)在统计学上没有显著差异。此外,在每个发育阶段的卵泡密度也没有统计学上的显著差异。然而,与对照组相比,8月龄时从雄激素化羔羊获取的活检组织中原始卵泡的百分比更低,但初级卵泡的百分比更高。在20月龄时,两组之间原始卵泡和初级卵泡阶段的卵泡比例没有显著差异,但这主要归因于对照动物活检组织中生长卵泡比例的增加。与手术当天固定的组织相比,8月龄羔羊卵巢皮质的培养导致生长卵泡的比例逐渐增加。然而,雄激素化组织和对照组织在生长卵泡的百分比上没有差异。雄激素化动物皮质中生长卵泡比例的增加类似于在人类多囊卵巢中的类似观察结果,表明生命早期过量暴露于雄激素在多囊卵巢中卵泡从原始阶段加速发育到初级阶段中起作用。