Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, KY, USA.
Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA.
Hum Reprod. 2023 Apr 3;38(4):671-685. doi: 10.1093/humrep/dead017.
Do cortisol/glucocorticoid receptors play an active role in the human ovary during ovulation and early luteinization?
The ovulatory hCG stimulation-induced glucocorticoid receptor signaling plays a crucial role in regulating steroidogenesis and ovulatory cascade in human periovulatory follicles.
Previous studies reported an increase in cortisol levels in the human follicular fluid after the LH surge or ovulatory hCG administration. However, little is known about the role of cortisol/glucocorticoid receptors in the ovulatory process and luteinization in humans.
STUDY DESIGN, SIZE, DURATION: This study was an experimental prospective clinical and laboratory-based study. An in vivo experimental study was accomplished utilizing the dominant ovarian follicles from 38 premenopausal women undergoing laparoscopic sterilization. An in vitro experimental study was completed using the primary human granulosa/lutein cells (hGLC) from 26 premenopausal women undergoing IVF.
PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted in a private fertility clinic and academic medical centers. Dominant ovarian follicles were collected before the LH surge and at defined times after hCG administration from women undergoing laparoscopic sterilization. Primary hGLC were collected from women undergoing IVF. hGLC were treated without or with hCG in the absence or presence of RU486 (20 µM; dual antagonist for progesterone receptor and glucocorticoid receptor) or CORT125281 (50 µM; selective glucocorticoid receptor antagonist) for 12 or 36 h. The expression of genes involved in glucocorticoid receptor signaling, steroidogenesis, and ovulatory cascade was studied with RT-quantitative PCR and western blotting. The production of cortisol, corticosterone, and progesterone was assessed by hormone assay kits.
hCG administration upregulated the expression of hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1), nuclear receptor subfamily 3 group C member 1 (NR3C1), FKBP prolyl isomerase 5 (FKBP5), and FKBP prolyl isomerase 4 (FKBP4) in human ovulatory follicles and in hGLC (P < 0.05). RU486 and CORT125281 reduced hCG-induced increases in progesterone and cortisol production in hGLC. The expression of genes involved in glucocorticoid receptor signaling, steroidogenesis, and the key ovulatory process was reduced by RU486 and/or CORT125281 in hGLC.
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LIMITATIONS, REASONS FOR CAUTION: The role of cortisol/glucocorticoid receptors demonstrated using the hGLC model may not fully reflect their physiological roles in vivo.
Successful ovulation and luteinization are essential for female fertility. Women with dysregulated cortisol levels often suffer from anovulatory infertility. Deciphering the functional role of glucocorticoid receptor signaling in human periovulatory follicles enhances our knowledge of basic ovarian physiology and may provide therapeutic insights into treating infertility in women.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by P01HD71875 (to M.J., T.E.C., and M.B.) and R01HD096077 (to M.J.) from the Foundation for the National Institutes of Health and the BTPSRF of the University of Kentucky Markey Cancer Center (P30CA177558). The authors report no competing interests.
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皮质醇/糖皮质激素受体在人类排卵和早期黄体化过程中是否发挥积极作用？
促黄体生成素刺激诱导的糖皮质激素受体信号在调节人促排卵卵泡中的类固醇生成和排卵级联反应中起着至关重要的作用。
先前的研究报道，在 LH 激增或排卵 hCG 给药后，人卵泡液中的皮质醇水平增加。然而，关于皮质醇/糖皮质激素受体在人类排卵过程和黄体化中的作用知之甚少。
研究设计、大小和持续时间：这是一项实验性的前瞻性临床和基于实验室的研究。利用 38 名接受腹腔镜绝育术的绝经前妇女的优势卵泡进行了体内实验研究。利用 26 名接受体外受精的绝经前妇女的原代人颗粒细胞/黄体细胞（hGLC）完成了体外实验研究。
参与者/材料、设置、方法：本研究在一家私人生育诊所和学术医疗中心进行。在接受腹腔镜绝育术的妇女中，在 LH 激增前和 hCG 给药后定义的时间采集优势卵泡。从接受 IVF 的妇女中采集原代 hGLC。hGLC 未经处理或用 hCG 处理，同时存在或不存在 RU486（20 μM；孕激素受体和糖皮质激素受体双重拮抗剂）或 CORT125281（50 μM；选择性糖皮质激素受体拮抗剂）12 或 36 小时。使用 RT-定量 PCR 和 Western blot 研究参与糖皮质激素受体信号、类固醇生成和排卵级联的基因表达。通过激素测定试剂盒评估皮质醇、皮质酮和孕酮的产生。
hCG 给药上调了人促排卵卵泡和 hGLC 中羟甾类 11-β 脱氢酶 1（HSD11B1）、核受体亚家族 3 组 C 成员 1（NR3C1）、FKBP 脯氨酰异构酶 5（FKBP5）和 FKBP 脯氨酰异构酶 4（FKBP4）的表达（P<0.05）。RU486 和 CORT125281 降低了 hGLC 中 hCG 诱导的孕酮和皮质醇产生增加。RU486 和/或 CORT125281 降低了 hGLC 中参与糖皮质激素受体信号、类固醇生成和关键排卵过程的基因表达。
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局限性、谨慎的原因：使用 hGLC 模型显示的皮质醇/糖皮质激素受体的作用可能无法完全反映其在体内的生理作用。
成功的排卵和黄体化是女性生育能力的关键。皮质醇水平失调的女性常患有排卵性不孕。阐明糖皮质激素受体信号在人促排卵卵泡中的功能作用，增强了我们对卵巢基本生理学的认识，并可能为治疗女性不孕提供治疗思路。
研究资金/竞争利益：本研究由 P01HD71875（M.J.、T.E.C. 和 M.B.）和 R01HD096077（M.J.）从国立卫生研究院基金会以及肯塔基大学 Markey 癌症中心的 BTPSRF（P30CA177558）资助。作者没有报告任何竞争利益。
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