Rosiglitazone and Clomiphene for Ovulation Induction

这项建议将评估一种新的药物组合罗格列酮和克罗米芬在多囊卵巢综合征(PCOS)无排卵妇女中诱导排卵的有效性。多囊卵巢综合征是一种影响约5%育龄妇女的疾病，其特征是无排卵，失去月经周期，并伴有高雄激素血症，经常导致多毛症或粉刺。无排卵会导致自发性不孕，如果不进行治疗，还会有患子宫内膜癌的风险。大多数患有多囊卵巢综合征的女性都有外周胰岛素抵抗和代偿性高胰岛素血症。这些异常可能导致2型糖尿病、高血压和加速动脉粥样硬化的长期风险增加。诱导排卵对于恢复多囊卵巢综合征患者的生育能力是必要的。标准的初始治疗是口服克罗米芬，这是一种选择性雌激素受体调节剂，可以增加内源性FSH的分泌。克罗米芬仅在大约70%的多囊卵巢综合征患者中成功诱导排卵，失败与高胰岛素血症有关。克罗米芬诱导排卵失败的妇女通常接受肠外促卵泡刺激素治疗，但这与多胎妊娠和卵巢过度刺激综合征的克罗米芬相比风险更大，后者在严重情况下可能危及生命。这项研究将研究克罗米芬与罗格列酮联合使用是否能更有效地诱导多囊卵巢综合征妇女排卵，罗格列酮是一种胰岛素增敏剂，可降低循环胰岛素水平。被选为克罗米芬诱导排卵抵抗的多囊卵巢综合征患者将随机接受罗格列酮或安慰剂双结合治疗6周，然后接受克罗米芬诱导排卵。如果不成功，将在随后的两个周期中以标准方式增加克罗米芬的剂量，以努力实现排卵。罗格列酮组和安慰剂组将通过血清孕酮水平评估自发和克罗米芬诱导的排卵结果，并与高胰岛素血症的变化、口服葡萄糖耐量试验(OGTT)的评估以及基线促黄体生成激素、总和游离睾酮、性激素结合球蛋白(SHBG)和胰岛素样生长因子结合蛋白-1(IGFBP-1)水平的变化相关联。罗格列酮对OGTT中胰岛素分泌的影响可能与其对上述激素和结合蛋白水平的影响有关。

This proposal will evaluate the effectiveness of a new drug combination, rosiglitazone and clomiphene, for the induction of ovulation in anovulatory women with polycystic ovary syndrome (PCOS). PCOS is a disorder affecting about 5% of women of reproductive age, characterized by anovulation with loss of menstrual cyclicity and hyperandrogenism, often resulting in hirsutism or acne. Anovulation leads to spontaneous infertility and poses a risk of endometrial carcinoma if untreated. A majority of women with PCOS have peripheral insulin resistance and compensatory hyperinsulinemia. These abnormalities may lead to a long-term increased rish of Type 2 diabetes mellitus, hypertension, and accelerated atherosclerosis. Induction of ovulation is necessary to restore fertility to women with PCOS. The standard initial treatment is oral clomiphene citrate, a selective estrogen-receptor modulator which increases endogenous FSH secretion. Clomiphene is successful in inducing ovulation in only about 70% of women with PCOS, and failure is associated with hyperinsulinemia. Women who fail clomiphene ovulation induction are usually treated with parenteral FSH, but this is associated with a greater risk than clomiphene of both multiple gestation and ovarian hyperstimulation syndrome, which in its severe form can be life- threatening. This study will examine whether clomiphene can be more effective in inducing ovulation in women with PCOS when given concomitantly with rosiglitazone, an insulin sensitizer which lowers circulating insulin levels. Women with PCOS selected for previous resistance to clomiphene ovulation induction will be randomized to receive either rosiglitazone or placebo in double-bind fashion for 6 weeks, and then will undergo attempted ovulation induction with clomiphene. If unsuccessful, the clomiphene dose will be increased in up to 2 subsequent cycles in standard fashion in an effort to achieve ovulation. Spontaneous and clomiphene-induced ovulatory outcomes, assessed by serum progesterone levels, will be compared between rosiglitazone and placebo groups and correlated with changes in hyperinsulinemia, assessed on oral glucose tolerance testing (OGTT), and with changes in baseline LH, total and free testosterone, sex hormone binding globulin (SHBG), and insulin-like growth factor binding protein-1 (IGFBP-1) levels. The effects of rosiglitazone on insulin secretion on OGTT will be correlated with its effects on the levels of the above hormones and binding proteins.