Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17 beta production by rat ovarian granulosa cells.
Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17 beta production by rat ovarian granulosa cells.
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DOI：
10.1210/en.138.2.847
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发表时间：
1997
期刊：
影响因子：
4.8
通讯作者：
R. Zachow;D. Magoffin
中科院分区：
文献类型：
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作者：
R. Zachow;D. Magoffin
Ob基因产物瘦素由脂肪细胞分泌，是小鼠生育所必需的。缺乏瘦素的小鼠肥胖且不育，症状让人联想到多囊卵巢综合征（PCOS）。先前的研究表明，血清瘦素水平升高，在一个显着的亚群无排卵妇女与PCOS，这表明，瘦素水平升高可能会对卵巢功能产生不利影响。由于瘦素受体mRNA已在卵巢中检测到，本研究旨在验证瘦素可能通过直接机制损害颗粒细胞（GC）雌二醇-17 β（E2）产生的假设。从26日龄Sprague-Dawley大鼠的卵巢中分离GC，并在存在和不存在绵羊FSH（0.001-100 ng/ml）和雄烯二酮（0.1 μ M）、存在和不存在重组鼠瘦素（0.1 - 100 ng/ml）的情况下，在96孔板中培养（60，000 GC/孔）48小时。单独的瘦素对E2的产生没有影响。FSH导致GC测定的E2产生量呈剂量相关性增加（ED 50 = 1.9 +/- 0.4 ng/ml）。添加瘦素并没有改变FSH刺激的B2水平。FSH和IGF-I（30 ng/ml）的联合治疗使最大FSH依赖性E2产生增加了5倍。瘦素对FSH刺激的E2产生的IGF-I增加产生剂量依赖性（IC 50 = 2.7 +/- 0.6 ng/ml）抑制（30-50%）。瘦素的抑制作用是特异性的E2生产，因为没有影响基础，FSH，或FSH+ IGF-I依赖的孕酮水平。本研究的结果表明，瘦素可以直接损害IGF-I介导的增强FSH刺激的E2合成的GC。这些数据提高了这样的可能性，即高瘦素水平可能通过抵消优势卵泡中IGF-I的致敏作用而导致某些PCOS妇女的不孕。
The Ob gene product, leptin, is secreted by adipocytes and is required for fertility in the mouse. Leptin-deficient mice are obese and infertile, symptoms reminiscent of polycystic ovary syndrome (PCOS). Prior studies have shown that serum leptin levels are elevated in a significant sub-population of anovulatory women with PCOS, suggesting that elevated leptin levels may adversely affect ovarian function. Since leptin receptor mRNA has been detected in the ovary, this study was designed to test the hypothesis that leptin may impair granulosa cell (GC) estradiol-17 beta (E2) production by a direct mechanism. GC were isolated from the ovaries of 26-day-old Sprague-Dawley rats, and were cultured (60,000 GC/well) in 96-well plates in the presence and absence of ovine FSH (0.001-100 ng/ml) and androstenedione (0.1 microM), with and without recombinant murine leptin (0.1-100 ng/ml) for 48 h. Leptin alone had no effect on E2 production. FSH caused a dose-related increase in E2 production by GC (ED50 = 1.9 +/- 0.4 ng/ml). Addition of leptin did not alter FSH-stimulated B2 levels. Concomitant treatment with FSH and IGF-I (30 ng/ml) augmented maximal FSH-dependent E2 production five-fold. Leptin caused a dose-dependent (IC50 = 2.7 +/- 0.6 ng/ml) inhibition (30-50%) of the IGF-I increase in FSH-stimulated E2 production. The inhibitory effect of leptin was specific for E2 production since there was no effect on basal, FSH-, or FSH+ IGF-I-dependent progesterone levels. The results of this study demonstrate that leptin can directly impair the IGF-I-mediated augmentation of FSH-stimulated E2 synthesis by GC. These data raise the possibility that high leptin levels may contribute to infertility in some women with PCOS by counteracting the sensitizing effects of IGF-I in dominant follicles.