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
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.
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