INDUCTION OF OVULATION IN PCOS

多囊卵巢综合征(PCOS)是美国女性因素不孕的主要原因。这在一定程度上与慢性无排卵有关，并可能因其他因素而进一步加剧，这些因素导致早期(即早期三个月)妊娠丢失(EPL)的比率增加。现在人们认识到胰岛素抵抗是PCOS的一个显著特征，它导致PCOS无排卵，应用二甲双胍后排卵频率显著增加就是明证。在多囊卵巢综合征中，二甲双胍I)增加自发排卵的频率，II)增加诱导排卵的成功率，III)增加临床妊娠率。研究表明，胰岛素抵抗还通过产生不利的子宫内膜环境而导致多囊卵巢综合征患者的不孕不育，而在怀孕期间对多囊卵巢综合征患者服用二甲双胍与EPL发生率降低79%有关。这个U54子项目的重点是胰岛素抵抗在多囊卵巢综合征不孕症中的作用。现在 申请书提出了两项临床研究。第一项研究是生殖医学网络的一项合作试验，目的是确定哪些药物代表了最初诱导PCOS排卵的最佳药物干预措施：二甲双胍单一疗法、克罗米芬单一疗法，还是同时给予二甲双胍和克罗米芬。第二项研究探讨了二甲双胍对健康妇女和PCOS妇女生殖系统的影响，评估了二甲双胍对以下方面的影响：1)垂体促性腺激素分泌的动态，2)黄体期孕酮和其他循环性类固醇的充分性， 解剖子宫内膜成熟以及性激素和整合素受体在子宫内膜的表达。获得这一信息是至关重要的，因为医生们越来越多地给患有多囊卵巢综合征的女性使用二甲双胍以促进排卵和怀孕。 综上所述，拟议的研究将提供重要的翻译和机械信息。他们承诺加强我们对胰岛素抵抗与多囊卵巢综合征不孕的关系的理解，并提供有用的信息，可以直接转化为多囊卵巢综合征妇女的临床护理。

The polycystic ovary syndrome (PCOS) is the major cause of female factor infertility in the United States. This is in part related to chronic anovulation, and is likely further aggravated by other factors which produce an increased rate of early (i.e., first trimester) pregnancy loss (EPL). It is now recognized that insulin resistance is a prominent feature of PCOS and that it contributes to the anovulation of PCOS, as evidenced by a marked increase in frequency of ovulation with the administration of metformin. In PCOS metformin i) increases frequency of spontaneous ovulation, ii) increases success of induction of ovulation, and iii) increases rate of clinical pregnancy. Studies suggest that insulin resistance also contributes to infertility in PCOS by producing an unfavorable endometrial milieu, and administration of metformin to women with PCOS throughout pregnancy is associated with a 79% reduction in the rate of EPL. The focus of this U54 Subproject is the role of insulin resistance in the infertility of PCOS. The present application proposes two clinical research studies. The first study is a collaborative trial the Reproductive Medicine Network to determine what represents the optimal pharmacologic intervention for initial induction of ovulation in PCOS: metformin monotherapy, clomiphene monotherapy, or simultaneous administration of both metformin and clomiphene. The second study explores the effects of metformin on the reproductive system of both healthy women and women with PCOS, assessing the effects of metformin on i) dynamics of pituitary gonadotropin secretion, ii) adequacy of luteal phase progesterone and other circulating sex steroids, and iii) anatomic endometrial maturation as well as endometrial expression of receptors for sex steroids and integrins. Obtaining this information is critical since physicians are increasingly administering metformin to women with PCOS to facilitate ovulation and pregnancy. In summary, the proposed studies will provide both important translational and mechanistic information. They promise to enhance our understanding of the relationship of insulin resistance to the infertility of PCOS, and to provide useful information that can be directly translated into the clinical care of women with PCOS.