Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Japan.
Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Aging Cell. 2017 Dec;16(6):1288-1299. doi: 10.1111/acel.12662. Epub 2017 Aug 31.
Irregular menstrual cycles, reduced responses to exogenous hormonal treatments, and altered endocrine profiles (high FSH/high LH/low AMH) are observed in women with increasing age before menopause. In this study, because the granulosa cell-specific Nrg1 knockout mice (gcNrg1KO) presented ovarian and endocrine phenotypes similar to older women, we sought to understand the mechanisms of ovarian aging and to develop a new strategy for improving fertility in older women prior to menopause. In the ovary of 6-month-old gcNrg1KO mice, follicular development was blocked in bilayer secondary follicles and heterogeneous cells accumulated in ovarian stroma. The heterogeneous cells in ovarian stroma were distinguished as two different types: (i) the LH receptor-positive endocrine cells and (ii) actin-rich fibrotic cells expressing collagen. Both the endocrine and fibrotic cells disappeared following long-term treatment with a GnRH antagonist, indicating that the high levels of serum LH induced the survival of both cell types and the abnormal endocrine profile to reduce fertility. Moreover, follicular development to the antral stages was observed with reduced LH and the disappearance of the abnormal stromal cells. Mice treated with the GnRH antagonist regained normal, recurrent estrous cycles and continuously delivered pups for at least for 3 months. We conclude that endocrine and matrix alternations occur within the ovarian stroma with increasing age and that abolishing these alternations resets the cyclical release of LH. Thus, GnRH antagonist treatments might provide a new, noninvasive strategy for improving fertility in a subset of aging women before menopause.
在绝经前，女性随着年龄的增长会出现月经周期不规律、对外源性激素治疗的反应减弱以及内分泌谱改变（高 FSH/高 LH/低 AMH）。在这项研究中，由于颗粒细胞特异性 Nrg1 敲除小鼠（gcNrg1KO）表现出与老年女性相似的卵巢和内分泌表型，我们试图了解卵巢衰老的机制，并为绝经前老年女性制定一种提高生育能力的新策略。在 6 月龄 gcNrg1KO 小鼠的卵巢中，双层次级卵泡中的卵泡发育受阻，并且在卵巢基质中积累了异质细胞。卵巢基质中的异质细胞可分为两种不同类型：（i）表达 LH 受体的内分泌细胞和（ii）富含肌动蛋白的纤维细胞，表达胶原。长期用 GnRH 拮抗剂治疗后，两种内分泌细胞和纤维细胞均消失，表明血清 LH 水平升高诱导了这两种细胞类型的存活和异常内分泌谱，从而降低了生育能力。此外，用 GnRH 拮抗剂治疗后观察到卵泡发育到腔前阶段，LH 减少，异常基质细胞消失。用 GnRH 拮抗剂治疗的小鼠恢复了正常、复发性动情周期，并至少连续产仔 3 个月。我们得出结论，随着年龄的增长，卵巢基质中会发生内分泌和基质改变，而消除这些改变会重置 LH 的周期性释放。因此， GnRH 拮抗剂治疗可能为绝经前部分老年女性提供一种新的、非侵入性的改善生育能力的策略。
