CLINICAL TRIAL: THE EFFECTS OF CLOMIPHENE CITRATE AND LETROZOLE IN WOMEN WITH PC

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：探讨克罗米芬和来曲唑对多囊卵巢综合征患者子宫内膜雌、孕激素受体表达、妊娠率、妊娠丢失率、活产率、排卵率及性交后检测结果的影响。 研究计划：这项研究是一项随机、双盲、交叉研究，研究对象为18-39岁、根据NIH/NICHD标准诊断为多囊卵巢综合征并希望怀孕的妇女，研究对象为来曲唑和克罗米芬。 方法：将无优势卵泡超声证据的非妊娠患者随机分为两组。患者将通过随机数字表分成两组，每天服用克罗米芬50毫克，疗程5天，或服用来曲唑，每天2.5毫克，疗程5天。药物完成四天后，患者将回来进行盆腔超声波检查。 每隔两天进行一次超声检查，直到：1)尿液中检测到黄体生成素或优势卵泡塌陷，血孕酮高于3 ng/ml；或2)进行了5次超声检查，但没有发现卵泡发育的迹象。 当铅卵泡的平均直径为16-18 mm时，将进行性交后检测和子宫内膜活检(卵泡期)。 有排卵记录的患者将在尿液黄体生成素试验阳性或超声记录的卵泡塌陷后9-11天进行血清妊娠试验。对非妊娠患者(黄体期)进行子宫内膜活检。 将根据临床需要对怀孕患者(化学妊娠)进行跟踪，直到超声检查发现宫内妊娠囊(临床妊娠)或重复的血清妊娠试验呈阴性。宫内妊娠的患者将被转介到产科护理，并与产科医生一起接受治疗。疑似异位妊娠的患者将被转介接受治疗。 子宫内膜活检标本将被冷冻，并使用鼠抗人雌激素和孕激素受体的单抗进行免疫组织化学分析。免疫组织化学染色在子宫内膜间质和上皮均记录为阴性、弱、中度或强阳性。对活检的评估将被视作盲目的治疗。 未怀孕的排卵患者将接受最低剂量的促排卵治疗，最长可达三个周期。无排卵症患者将接受最多三个周期的治疗，剂量增加(克罗米芬50 mg、100 mg、150 mg；来曲唑2.5 mg、5 mg、7.5 mg)。在三个周期之后，没有怀孕的患者将在一个月的洗涤后交叉使用另一种药物进行治疗。 性交后测试和子宫内膜活检将仅在每种治疗药物的第一个排卵周期进行。 临床意义：多囊卵巢综合征(PCOS)是最常见的女性不孕症，影响5-10%的普通人群和20%的不孕不育人群。 在继发于多囊卵巢综合征的无排卵性不孕的妇女中，诱导排卵的一线治疗是抗雌激素，最常见的是CC。然而，20%-25%的女性对CC有抵抗力，不排卵。此外，临床数据显示，一些使用克罗米芬治疗排卵的多囊卵巢综合征患者不会怀孕，而怀孕的妇女流产率高于预期。 据认为，CC通过在下丘脑和垂体水平阻断内源性雌激素的负反馈，促进黄体生成素和卵泡刺激素的脉动性释放，从而启动或促进排卵。大量实验证据表明，CC除了具有刺激促性腺激素分泌短暂增加的中枢性作用外，还对外周雌激素靶向组织有其他意想不到的和潜在的有害影响。这些观察结果被归因于CC的抗雌激素作用机制，这涉及到长时间的雌激素受体耗竭。因此，CC可能对宫颈粘液的质量和数量以及子宫内膜发育等雌激素依赖性生育因素产生负面影响。 我们假设，在月经周期的早期给予来曲唑将使垂体/下丘脑轴从雌激素负反馈中释放出来，类似于克罗米芬的作用，但不会下调雌激素受体。随后促性腺激素分泌的增加可能会刺激卵泡的发育。我们进一步假设，来曲唑在子宫内膜上没有任何直接的抗雌激素作用，可能会降低怀孕的多囊卵巢综合征妇女的流产率。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: To evaluate the effect of clomiphene citrate and letrozole on endometrial estrogen and progesterone receptor expression, pregnancy rates, pregnancy loss rate, live-birth rate, ovulation rate, and post-coital test result in women with polycystic ovary syndrome. RESEARCH PLAN: This study is a randomized, double blind, cross over study of letrozole versus clomiphene citrate in women 18-39 years of age with the diagnosis of PCOS based on the NIH/NICHD criteria who desire pregnancy. METHODS: Non-pregnant patients without sonographic evidence of a dominant follicle will be randomized. Patients will be randomized via random number table to treatment with clomiphene citrate 50 mg per day for 5 days or letrozole 2.5 mg per day for 5 days. Four days following completion of the drug the patient will return for a pelvic ultrasound. Ultrasounds will be performed every two days until: 1) ovulation is documented by urine LH detection or collapse of the dominant follicle with serum progesterone greater than 3 ng/ml, or 2) five ultrasounds have been performed without evidence of follicular development. Post-coital testing and endometrial biopsy (follicular phase) will be performed when the lead follicle is 16-18 mm average diameter. Patients with documented ovulation will have a serum pregnancy test performed 9-11 days following either the positive urine LH test or sonographically documented follicular collapse. Endometrial biopsy will be performed on non-pregnant patients (luteal phase). Pregnant patients (chemical pregnancy) will be followed as clinically necessary until an intrauterine gestational sac is seen on ultrasound (clinical pregnancy) or a repeat serum pregnancy test is negative. Patients with an intrauterine pregnancy will be referred for obstetric care and followed in conjunction with the obstetrician. Patients with suspected ectopic gestations will be referred for treatment. Endometrial biopsy specimens will be frozen and immunohistochemical analysis performed using mouse monoclonal antibodies to human estrogen and progesterone receptors. Immunohistochemical staining will be recorded as negative, weak, moderate or strong in both the endometrial stroma and epithelium. The evaluation of the biopsies will be blinded as to treatment. Ovulatory patients who do not conceive will be treated for up to three cycles at the lowest dose that induced ovulation. Anovulatory patients will be treated for up to three cycles at increasing doses of the study drug (clomiphene citrate 50mg, 100mg, 150mg; letrozole 2.5mg, 5mg, 7.5mg). Following three cycles, patients who have not conceived a pregnancy will be crossed-over to treatment with the other drug following a one-month washout. The post-coital test and endometrial biopsies will be performed only during the first ovulatory cycle on each treatment medication. CLINICAL RELEVANCE: Polycystic ovary syndrome (PCOS) is the most common form of female infertility, affecting 5-10% of the general population and 20% of the infertile population. In women with anovulatory infertility secondary to PCOS, the first-line treatment for the induction of ovulation is an antiestrogen, most commonly CC. However, 20%-25% of women are resistant to CC and do not ovulate. In addition, clinical data have revealed that a number of women with PCOS that ovulate with clomiphene citrate therapy do not conceive, and those that conceive demonstrate a higher than expected incidence of miscarriage. It is believed that CC initiates or augments ovulation by blocking negative feedback of endogenous estrogen at the level of the hypothalamus and pituitary, promoting an increase in the pulsatile release of luteinizing hormone and follicle stimulating hormone. A considerable body of experimental evidence suggests that, in addition to its desirable central action of stimulating a transient increase in gonadotropin secretion, CC has other unintended and potentially detrimental effects on peripheral estrogen target tissues. These observations have been attributed to the antiestrogenic mechanism of action of CC, which involves long-lasting estrogen receptor depletion. As a result, CC may negatively effect such estrogen dependent fertility factors as the quality and quantity of cervical mucus and endometrial development. We hypothesized that letrozole administration in the early part of the menstrual cycle would release the pituitary/hypothalamic axis from estrogenic negative feedback, similar to the effect of clomiphene citrate but without estrogen receptor down-regulation. The subsequent increase in gonadotropin secretion could stimulate ovarian follicle development. We further hypothesize that the absence of any direct antiestrogenic effects of letrozole on the endometrium may decrease the miscarriage rate in women with PCOS who become pregnant.