Department of Integrated Traditional & Western Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Department of Integrated Traditional & Western Medicine, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
Front Endocrinol (Lausanne). 2022 Oct 19;13:951928. doi: 10.3389/fendo.2022.951928. eCollection 2022.
High concentrations of glucocorticoids caused by chronic stress are known to affect ovarian function and cause diminished ovarian reserve. Androgens are essential for early-stage ovarian follicle development, but the effects and mechanisms of androgens on follicle development under chronic stress remain unclear. In this study, we aim to investigate the effects of high concentrations of glucocorticoids on the function of cultured ovarian cells and mouse early-stage ovarian follicles and to validate the hypothesis that androgen-insulin-like growth factor 1 (IGF1)-follicle-stimulating hormone (FSH) synergistic signaling helps to ameliorate the damage caused by high concentrations of glucocorticoids. KGN cells (human granulosa cell line) and mouse primary cells were treated with different concentrations of glucocorticoids, and the cell proliferation, apoptosis, and sex hormone secretion were detected. The effects of glucocorticoid and androgens on IGF1 receptor (IGF1R) and FSH receptor (FSHR) expression in KGN cells were detected by Western blot. Steroidogenic synthase expressions under androgens and androgen-IGF1-FSH combination treatment were examined by qPCR after manipulation using low and high concentrations of glucocorticoids. The mechanism of androgen regulation of IGF1R and FSHR was explored by small interfering RNA (siRNA) and chromatin immunoprecipitation (ChIP)-qPCR. Damage of glucocorticoids and the treatment effects of androgens were further validated in mouse ovarian follicles cultured . The results demonstrated that prolonged treatment with high-dose glucocorticoids reduced cell viability of granulosa cells, inhibited their sex hormone secretion, and impaired their sensitivity to IGF1 and FSH signaling by affecting IGF1R and FSHR functions. Androgens at an appropriate dose range improved early-stage follicle development and their hormone secretion under high-dose glucocorticoid treatment, which was related to increased transcription of and . This work showed that excessive glucocorticoids impaired ovarian function and validated that balanced concentrations of androgens synergized with IGF1 and FSH to improve the function of early-stage ovarian follicles under conditions of chronic stress.
慢性应激导致的高浓度糖皮质激素已知会影响卵巢功能并导致卵巢储备减少。雄激素对于早期卵巢卵泡的发育至关重要，但雄激素在慢性应激下对卵泡发育的影响和机制尚不清楚。在这项研究中，我们旨在研究高浓度糖皮质激素对培养的卵巢细胞和小鼠早期卵巢卵泡功能的影响，并验证雄激素-胰岛素样生长因子 1（IGF1）-卵泡刺激素（FSH）协同信号有助于改善高浓度糖皮质激素引起的损伤的假说。用不同浓度的糖皮质激素处理 KGN 细胞（人颗粒细胞系）和小鼠原代细胞，检测细胞增殖、凋亡和性激素分泌。用 Western blot 检测糖皮质激素和雄激素对 KGN 细胞中 IGF1 受体（IGF1R）和 FSH 受体（FSHR）表达的影响。用 qPCR 检测在低浓度和高浓度糖皮质激素处理后，雄激素和雄激素-IGF1-FSH 联合处理对类固醇生成酶表达的影响。通过小干扰 RNA（siRNA）和染色质免疫沉淀（ChIP）-qPCR 探讨雄激素调节 IGF1R 和 FSHR 的机制。进一步在培养的小鼠卵巢卵泡中验证糖皮质激素的损伤作用和雄激素的治疗效果。结果表明，高剂量糖皮质激素延长处理会降低颗粒细胞的活力，抑制其性激素分泌，并通过影响 IGF1R 和 FSHR 的功能来损害其对 IGF1 和 FSH 信号的敏感性。在高剂量糖皮质激素处理下，适当剂量范围内的雄激素改善了早期卵泡的发育及其激素分泌，这与 和 的转录增加有关。这项工作表明，过量的糖皮质激素损害了卵巢功能，并验证了平衡浓度的雄激素与 IGF1 和 FSH 协同作用，改善了慢性应激条件下早期卵巢卵泡的功能。
