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.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。目的：评估克罗米芬柠檬酸氯酸酯和七叶唑对子宫内膜雌激素和孕激素受体表达的影响，妊娠率，妊娠损失率，活出生率，排卵率和后毛图后测试导致多囊性卵巢综合征的女性。研究计划：这项研究是一项随机，双盲，超过了18-39岁的女性对letrozole与柠檬酸克罗米芬柠檬酸盐的研究，并根据希望怀孕的NIH/NICHD标准诊断为PCOS。方法：将随机分配具有显性卵泡的超声检查证据的非妊娠患者。患者将通过随机数表随机分组，每天用50毫克的柠檬酸克罗米芬治疗5天，或每天letrozole 2.5 mg，持续5天。药物完成后四天，患者将返回骨盆超声。超声将每两天进行一次，直到：1）通过尿液LH检测或高于3 ng/ml的血清孕酮的尿液LH检测或塌陷记录排卵，或者2）在没有卵泡发育的情况下进行了五次超声波。当铅卵泡平均直径为16-18毫米时，将执行毛状后测试和子宫内膜活检（卵泡期）。尿液LH测试阳性或超声记录的卵泡塌陷后9-11天进行排卵的患者将进行血清妊娠试验。子宫内膜活检将对非妊娠患者（黄体期）进行。在超声（临床妊娠）或重复的血清妊娠试验中，孕妇（化学妊娠）将是临床上必要的，直到宫内妊娠囊为阴性为阴性为止。宫内妊娠的患者将被转诊为产科护理，并与妇产科医生结合。怀疑的异位妊娠的患者将被转诊为治疗。子宫内膜活检标本将被冷冻，并使用对人雌激素和孕酮受体的小鼠单克隆抗体进行免疫组织化学分析。在子宫内膜基质和上皮中，免疫组织化学染色将被记录为阴性，弱，中度或强烈。对活检的评估将对治疗视而不见。不受孕的排卵患者将以诱发排卵的最低剂量治疗多达三个周期。剂量增加的研究药物（克罗米芬50mg，100mg，150mg，150mg； letrozole 2.5mg，5mg，5mg，7.5mg），无排卵患者最多三个周期治疗。在三个周期之后，尚未想到怀孕的患者将在一个月的洗涤后与其他药物进行治疗。仅在每种治疗药物的第一个排卵周期中，才能在第一个排卵周期内进行毕业后测试和子宫内膜活检。临床相关性：多囊卵巢综合征（PCOS）是女性不育的最常见形式，影响了5-10％的普通人群和20％的不育群体。在继发于PCOS的不孕症的女性中，诱导排卵的一线治疗方法是抗雌激素，最常见的是CC。但是，20％-25％的女性对CC有抵抗力，并且不排卵。此外，临床数据表明，用柠檬酸氯芬氏酸酯疗法排卵的许多PCOS妇女没有受孕，而那些构思的女性表现出比预期的流产发生率高的女性。据认为，CC通过在下丘脑和垂体水平上阻止内源性雌激素的负反馈来启动或增强排卵，从而促进了黄体激素和卵泡刺激激素的脉冲释放的增加。大量实验证据表明，除了刺激促性腺激素分泌的瞬时增加的中心作用外，CC还对外围雌激素靶组织还具有其他意外且潜在的有害影响。这些观察结果归因于CC的抗雌激素作用机理，涉及持续的雌激素受体消耗。结果，CC可能会对雌激素依赖的生育因子产生负面影响，例如宫颈粘液和子宫内膜发育的质量和数量。我们假设在月经周期的早期，letrozole的给药将从雌激素负反馈中释放垂体/下丘脑轴，类似于柠檬酸氯菲尼的作用，但没有雌激素受体的下调。随后的促性腺激素分泌增加会刺激卵巢卵泡发育。我们进一步假设，letrozole对子宫内膜的任何直接抗源性作用可能会降低怀孕的PCOS女性的流产率。