THE EFFECTS OF CLOMIPHENE CITRATE AND LETROZOLE IN WOMEN WITH PCOS

克罗米芬柠檬酸盐和来曲唑对多囊卵巢综合征女性的影响

• 批准号: 7627548
• 负责人: ROBERT G BRZYSKI
• 金额: $ 6.77万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627548
• 关键词: Affect; Age-Years; Biopsy; Biopsy Specimen; Birth Rate; Blinded; Caliber; Caring; Cervix Mucus; Chemicals; Clinical; Clinical Data; 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

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：评价克罗米芬和来曲唑对多囊卵巢综合征患者子宫内膜雌激素和孕激素受体表达、妊娠率、妊娠丢失率、活产率、排卵率和性交后检查结果的影响。 研究报告：本研究是一项随机、双盲、交叉研究，在年龄18-39岁、根据NIH/NICHD标准诊断为PCOS并希望怀孕的女性中比较来曲唑与克罗米芬。 方法：将无优势卵泡超声证据的非妊娠患者随机分组。 患者将通过随机数字表随机分配至接受枸橼酸氯米芬50 mg/天治疗5天或来曲唑2.5 mg/天治疗5天。 完成药物治疗后4天，患者将返回进行盆腔超声检查。 每两天进行一次超声检查，直至：1）通过尿LH检测记录排卵或血清孕酮大于3 ng/ml的优势卵泡塌陷，或2）进行了5次超声检查，无卵泡发育证据。 当主导卵泡平均直径为16-18 mm时，将进行性交后检测和子宫内膜活检（卵泡期）。 记录排卵的患者将在尿LH试验阳性或超声记录卵泡塌陷后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。 将根据临床需要对妊娠患者（化学妊娠）进行随访，直至超声检查发现宫内妊娠囊（临床妊娠）或重复血清妊娠试验结果为阴性。 宫内妊娠的患者将被转诊接受产科护理，并与产科医生一起随访。 疑似异位妊娠的患者将被转诊治疗。 将冷冻子宫内膜活检标本，并使用抗人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。 子宫内膜间质和上皮的免疫组织化学染色将记录为阴性、弱、中度或强。 活检的评价将对治疗设盲。 没有怀孕的排卵患者将以诱导排卵的最低剂量治疗最多三个周期。 无排卵患者将以递增剂量的研究药物（枸橼酸氯米芬50 mg、100 mg、150 mg;来曲唑2.5 mg、5 mg、7.5 mg）治疗最多3个周期。 三个周期后，未怀孕的患者将在一个月的洗脱期后交叉接受另一种药物治疗。 仅在每种治疗药物的第一个排卵周期内进行性交后检查和子宫内膜活检。 临床相关性：多囊卵巢综合征（PCOS）是女性不孕症的最常见形式，影响5-10%的一般人群和20%的不孕人群。 对于继发于PCOS的无排卵性不孕妇女，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，许多患有PCOS的女性在使用克罗米芬治疗排卵时没有怀孕，并且那些怀孕的女性显示出高于预期的流产发生率。 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，促进促黄体生成素和促卵泡激素的脉冲式释放的增加来启动或增强排卵。 大量的实验证据表明，除了刺激促性腺激素分泌短暂增加的理想中枢作用外，CC对外周雌激素靶组织具有其他非预期和潜在的有害作用。 这些观察结果归因于CC的抗雌激素作用机制，其涉及持久的雌激素受体耗竭。 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，来曲唑在月经周期的早期给药将释放垂体/下丘脑轴雌激素的负反馈，类似于克罗米芬的效果，但没有雌激素受体下调。 随后促性腺激素分泌增加可刺激卵泡发育。 我们进一步推测，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PCOS妊娠妇女的流产率。