Agarwal S K, Judd H L, Magoffin D A
Department of Obstetrics and Gynecology, Cedars-Sinai Research Institute/ University of California, School of Medicine, Los Angeles 90048, USA.
J Clin Endocrinol Metab. 1996 Oct;81(10):3686-91. doi: 10.1210/jcem.81.10.8855823.
In polycystic ovary syndrome (PCOS), follicle development arrests in the early antral stage when aromatase expression in the granulosa cells (GC) would normally occur. Despite high intrafollicular concentrations of androstenedione and bioactive FSH, in vivo estrogen biosynthesis remains low. When GC from PCOS follicles are stimulated with FSH in vitro, a marked stimulation of estrogen production occurs, suggesting that PCOS follicles contain an endogenous inhibitor of estrogen production. To test this hypothesis, GC from hyperstimulated women were cultured with increasing concentrations of follicular fluid (FF) from PCOS and normally cycling control women in the presence of androstenedione (10(-5) mol/L). FF from control women caused a small decrease (20%) in estradiol production. PCOS FF caused a dose-related inhibition of estradiol production (60%), indicating that there was significantly more inhibitory activity in PCOS FF. To determine whether abnormal androgen metabolism could play a role in inhibiting estradiol production in PCOS, we measured 5 alpha-androstane-3, 17-dione, a competitive inhibitor of aromatase activity, in serum and FF of control and PCOS women. 5 alpha-Androstane-3, 17-dione levels in serum were significantly elevated in PCOS. 5 alpha-Androstane-3, 17-dione levels were 1000-fold higher in PCOS FF than serum. Moreover, FF levels were markedly higher in PCOS follicles (P < 0.0001) than in normal dominant and cohort follicles. Dose-response studies revealed that the concentration of 5 alpha-androstane-3, 17-dione present in FF form normal dominant follicles (79.4 +/- 14.6 nmol/L) had little effect on estradiol production. In contrast, 5 alpha-androstane-3, 17-dione levels in PCOS FF (581.6 +/- 62.9 nmol/L) inhibited estradiol production by 75%. These data support the hypothesis that PCOS FF contains one or more endogenous inhibitors of aromatase activity and suggest that abnormally high 5 alpha-androstane-3, 17-dione levels in PCOS FF may be an important inhibitor of estradiol production.
在多囊卵巢综合征（PCOS）中，卵泡发育在早期窦状卵泡阶段停滞，而此时颗粒细胞（GC）中的芳香化酶通常会表达。尽管卵泡内雄烯二酮和生物活性促卵泡激素（FSH）浓度很高，但体内雌激素的生物合成仍然很低。当体外使用FSH刺激PCOS卵泡的颗粒细胞时，雌激素生成会受到显著刺激，这表明PCOS卵泡中含有一种内源性雌激素生成抑制剂。为了验证这一假设，将超刺激妇女的颗粒细胞与来自PCOS和正常月经周期对照妇女的卵泡液（FF）在雄烯二酮（10⁻⁵mol/L）存在的情况下进行培养，且卵泡液浓度逐渐增加。来自对照妇女的卵泡液使雌二醇生成量略有下降（20%）。PCOS卵泡液导致雌二醇生成受到剂量相关的抑制（60%），这表明PCOS卵泡液中的抑制活性明显更高。为了确定异常的雄激素代谢是否在抑制PCOS中雌二醇生成方面发挥作用，我们测量了对照妇女和PCOS妇女血清及卵泡液中芳香化酶活性的竞争性抑制剂5α-雄烷-3,17-二酮。PCOS患者血清中5α-雄烷-3,17-二酮水平显著升高。PCOS卵泡液中5α-雄烷-3,17-二酮水平比血清中高1000倍。此外，PCOS卵泡中的卵泡液水平明显高于正常优势卵泡和同期卵泡（P < 0.0001）。剂量反应研究表明，正常优势卵泡的卵泡液中存在的5α-雄烷-3,17-二酮浓度（79.4±14.6 nmol/L）对雌二醇生成影响很小。相比之下，PCOS卵泡液中的5α-雄烷-3,17-二酮水平（581.6±62.9 nmol/L）使雌二醇生成受到75%的抑制。这些数据支持了PCOS卵泡液含有一种或多种芳香化酶活性内源性抑制剂的假设，并表明PCOS卵泡液中异常高的5α-雄烷-3,17-二酮水平可能是雌二醇生成的重要抑制剂。
