Rosiglitazone and Clomiphene for Ovulation Induction

罗格列酮和克罗米芬用于诱导排卵

• 批准号: 6399073
• 负责人: NICHOLAS A CATALDO
• 金额: $ 6.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6399073
• 关键词: assistive reproductive technique; blood glucose; clomiphene; combination chemotherapy; fertility promoting drug; glucose tolerance test; hormone binding protein; human subject; human therapy evaluation; hyperinsulinism; hypoglycemic agents; immunologic assay /test; insulin; insulinlike growth factor; luteinizing hormone; ovulation; patient oriented research; polycystic ovary syndrome; reproductive system disorder chemotherapy; serology /serodiagnosis; testosterone; thiazoles; ultrasound; urinalysis; women's health

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.

该提案将评估罗格列酮和克罗米芬的新药物组合对于患有多囊卵巢综合征（PCOS）的无排卵女性诱导排卵的有效性。 PCOS 是一种影响约 5% 育龄女性的疾病，其特征是无排卵、月经周期丧失和雄激素过多症，通常导致多毛症或痤疮。无排卵会导致自发性不孕，如果不治疗，还会有患子宫内膜癌的风险。 大多数患有 PCOS 的女性患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风险长期增加。诱导排卵对于恢复患有多囊卵巢综合症的女性的生育能力是必要的。 标准的初始治疗是口服克罗米芬柠檬酸盐，这是一种选择性雌激素受体调节剂，可增加内源性 FSH 分泌。 克罗米芬仅对约 70% 的 PCOS 女性成功诱导排卵，失败与高胰岛素血症有关。 克罗米芬诱导排卵失败的女性通常会接受肠外 FSH 治疗，但与克罗米芬相比，这与多胎妊娠和卵巢过度刺激综合征的风险更大，严重时可能危及生命。这项研究将检验克罗米芬与罗格列酮（一种降低循环胰岛素水平的胰岛素增敏剂）同时服用时是否可以更有效地诱导多囊卵巢综合征女性排卵。 因先前对克罗米芬促排卵抵抗而选择的 PCOS 女性将随机接受罗格列酮或安慰剂双联治疗 6 周，然后尝试克罗米芬促排卵。 如果不成功，克罗米芬剂量将以标准方式在最多 2 个后续周期中增加，以努力实现排卵。将通过血清黄体酮水平评估自发和克罗米芬诱导的排卵结果，在罗格列酮组和安慰剂组之间进行比较，并与高胰岛素血症的变化相关，通过口服葡萄糖耐量试验（OGTT）进行评估，并与基线 LH、总睾酮和游离睾酮的变化相关、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。 罗格列酮对OGTT中胰岛素分泌的影响将与其对上述激素和结合蛋白水平的影响相关。