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

临床试验：克罗米芬柠檬酸盐和来曲唑对患有 PC 的女性的影响

基本信息

批准号：
7718738
负责人：
ROBERT G BRZYSKI
金额：
$ 0.03万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7718738
关键词：
Affect Age-Years Biopsy Biopsy Specimen Birth Rate Blinded Caliber Caring Cervix Mucus Chemicals Clinical Clinical Data Clinical Trials Clomiphene Citrate Computer Retrieval of Information on Scientific Projects Database Cross-Over Studies Detection Development Diagnosis Discipline of obstetrics Dose Double-Blind Method Down-Regulation Endometrial Endometrium Epithelium Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptors Estrogens Evaluation F Factor Feedback Female infertility Follicle Stimulating Hormone Freezing Funding General Population Genetic Crossing Over Gonadotropins Grant Human Hypothalamic structure Incidence Infertility Institution Lead Letrozole Live Birth Luteal Phase Luteinizing Hormone Menstrual cycle Monoclonal Antibodies Mus Numbers Ovarian Follicle Ovulation Ovulation Induction Patient currently pregnant Patients Pelvis Peripheral Pharmaceutical Preparations Pituitary Gland Polycystic Ovary Syndrome Population Pregnancy Pregnancy Rate Pregnancy Tests Pregnancy loss Progesterone Progesterone Receptors Randomized Rate Research Research Personnel Resistance Resources Secondary to Serum Source Spontaneous abortion Staining method Stains Test Result Testing Tissues Ultrasonography United States National Institutes of Health Urine Woman base clinically relevant day desire endometrial stroma hypothalamic pituitary axis proliferative phase Menstrual cycle receptor expression

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。目的：评价克罗米芬和来曲唑对多囊卵巢综合征女性子宫内膜雌激素和孕激素受体表达、妊娠率、流产率、活产率、排卵率和性交后检查结果的影响。研究计划：本研究是一项随机、双盲、交叉研究，针对根据 NIH/NICHD 标准诊断为 PCOS 并希望怀孕的 18-39 岁女性，对来曲唑与克罗米芬进行比较。方法：没有优势卵泡超声检查证据的非妊娠患者将被随机分组。患者将通过随机数字表被随机分配接受克罗米芬柠檬酸盐治疗，每天 50 毫克，持续 5 天，或来曲唑每天 2.5 毫克，持续 5 天。服药四天后，患者将返回进行盆腔超声检查。每两天进行一次超声检查，直到：1) 通过尿液 LH 检测记录排卵或血清黄体酮大于 3 ng/ml 的优势卵泡塌陷，或 2) 已进行五次超声检查但没有卵泡发育的证据。当卵泡平均直径为 16-18 毫米时，将进行性交后测试和子宫内膜活检（卵泡期）。有排卵记录的患者将在尿液 LH 检测呈阳性或超声记录的卵泡塌陷后 9-11 天进行血清妊娠试验。将对非妊娠患者（黄体期）进行子宫内膜活检。怀孕患者（生化妊娠）将根据临床需要进行随访，直至超声检查发现宫内孕囊（临床妊娠）或重复血清妊娠试验呈阴性。宫内妊娠患者将被转诊至产科护理，并与产科医生一起进行随访。疑似宫外孕的患者将被转诊接受治疗。子宫内膜活检标本将被冷冻，并使用针对人类雌激素和孕激素受体的小鼠单克隆抗体进行免疫组织化学分析。子宫内膜基质和上皮细胞的免疫组织化学染色将记录为阴性、弱、中度或强。活组织检查的评估对于治疗将是盲法的。未受孕的排卵患者将以诱导排卵的最低剂量接受最多三个周期的治疗。无排卵患者将以递增剂量的研究药物（克罗米芬柠檬酸盐 50mg、100mg、150mg；来曲唑 2.5mg、5mg、7.5mg）接受最多三个周期的治疗。三个周期后，未怀孕的患者将在一个月的清洗后交叉接受另一种药物的治疗。仅在每种治疗药物的第一个排卵周期期间进行性交后测试和子宫内膜活检。临床相关性：多囊卵巢综合征 (PCOS) 是女性不孕症最常见的形式，影响 5-10% 的普通人群和 20% 的不孕人群。对于继发于 PCOS 的无排卵不孕症的女性，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有抵抗力并且不排卵。此外，临床数据显示，许多患有多囊卵巢综合症的女性在接受克罗米芬柠檬酸盐治疗后排卵后却没有怀孕，而那些怀孕的女性流产率也高于预期。据信，CC通过阻断下丘脑和垂体水平的内源性雌激素的负反馈来启动或增强排卵，促进黄体生成素和卵泡刺激素的脉冲式释放的增加。大量实验证据表明，除了刺激促性腺激素分泌短暂增加的理想中枢作用外，CC 对周围雌激素靶组织还有其他意想不到的潜在有害影响。这些观察结果归因于 CC 的抗雌激素作用机制，涉及长期雌激素受体耗竭。因此，CC 可能会对雌激素依赖性生育因素（如宫颈粘液的质量和数量以及子宫内膜发育）产生负面影响。我们假设在月经周期早期给予来曲唑会释放垂体/下丘脑轴的雌激素负反馈，类似于克罗米芬柠檬酸盐的作用，但不会下调雌激素受体。随后促性腺激素分泌的增加可以刺激卵泡发育。我们进一步假设，来曲唑对子宫内膜没有任何直接的抗雌激素作用，可能会降低怀孕的 PCOS 女性的流产率。