Ruben Alvero

Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome

BACKGROUND Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. METHODS In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. RESULTS Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. CONCLUSIONS As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).

Letrozole, gonadotropin, or clomiphene for unexplained infertility

BACKGROUND The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).

Maternal vasoactive intestinal peptide and the regulation of embryonic growth in the rodent.

Vasoactive intestinal peptide (VIP) has been shown to regulate early postimplantation growth in rodents through central nervous system receptors. However, the source of VIP mediating these effects is unknown. Although VIP binding sites are present prenatally, VIP mRNA was not detected in the rat central nervous system before birth and was detected in the periphery only during the last third of pregnancy. In the present study, the embryonic day (E11) rat embryo/trophoblast was shown to have four times the VIP concentration of the E17 fetus and to have VIP receptors in the central nervous system. However, no VIP mRNA was detected in the E11 rat embryo or embryonic membranes by in situ hybridization or reverse transcriptase-PCR. RIA of rat maternal serum revealed a peak in VIP concentration at days E10-E12 of pregnancy, with VIP rising to levels 6-10-fold higher than during the final third of pregnancy. After intravenous administration of radiolabeled VIP to pregnant female mice, undegraded VIP was found in the E10 embryo. These results suggest that maternal tissues may provide neuroendocrine support for embryonic growth through a surge of VIP during early postimplantation development in the rodent.

Multivariate analysis of factors affecting probability of pregnancy and live birth with in vitro fertilization: an analysis of the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System

OBJECTIVE To evaluate factors predictive of clinical pregnancy and of pregnancy loss from assisted reproductive technology (ART) using data from the Society for Assisted Reproductive Technology database for 2004-2006. DESIGN Retrospective cohort. SETTING Clinic-based data. PATIENT(S) The study population included 225,889 fresh embryo transfer cycles using autologous oocytes and partner semen. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Clinical intrauterine gestation (presence of gestational sac) and live birth (>or=22 weeks gestation and >or=300 g birth weight). RESULT(S) Increasing maternal age was significantly associated with a reduced odds of conception and increased fetal loss until 19 weeks gestation, but not with later pregnancy loss. Intracytoplasmic sperm injection (ICSI), assisted hatching, and increasing number of embryos transferred had significant positive effects on the odds of conception and pregnancy continuation through the first trimester, but did not affect the risk of later loss. Blacks, Asians, and Hispanics had significantly lower odds of clinical pregnancy compared with whites. Also compared with whites, Hispanics and Asians had a significantly greater risk of pregnancy loss in the second and third trimesters, and blacks had a significantly greater risk of pregnancy loss in all trimesters. CONCLUSION(S) Certain demographic and ART treatment parameters influenced chance of conception and early pregnancy loss, whereas black race and Hispanic ethnicity were also significantly associated with late pregnancy loss in ART-conceived pregnancies.

Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome

PurposeTo determine if microRNAs are differentially expressed in the follicular fluid of women with PCOS compared to fertile oocyte donors and identify associated altered gene expression.MethodsWomen undergoing IVF who met Rotterdam criteria for PCOS or who were fertile oocyte donors were recruited from a private IVF center. Individual follicle fluid was collected at the time of oocyte retrieval. MicroRNA analysis was performed using microarray and validated using real-time PCR on additional samples. Potential gene targets were identified and their expression analyzed by real time PCR.ResultsMicroarray profiling of human follicular fluid revealed expression of 235 miRNAs, 29 were differentially expressed between the groups. Using PCR validation, 5 miRNAs (32, 34c, 135a, 18b, and 9) showed significantly increased expression in the PCOS group. Pathway analysis revealed genes involved in insulin regulation and inflammation. Three potential target genes were found to have significantly decreased expression in the PCOS group (interleukin 8, synaptogamin 1, and insulin receptor substrate 2).ConclusionsMicroRNAs are differentially expressed in the follicular fluid of women with PCOS when compared to fertile oocyte donors. There is also altered expression of potential target genes associated with the PCOS phenotype.

Do U.S. Medical Licensure Examination Step 1 Scores Correlate with Council on Resident Education in Obstetrics and Gynecology In-Training Examination Scores and American Board of Obstetrics and Gynecology Written Examination Performance?

OBJECTIVE The purpose of this study was to assess the possible association between scores of >200 on U.S. Medical Licensure Examination (USMLE) step 1 and the Council on Resident Education in Obstetrics and Gynecology (CREOG) in-training examinations and the pass rate on the American Board of Obstetrics and Gynecology (ABOG) written examination. METHODS The USMLE step 1 and postgraduate year 1 to 4 CREOG in-training examination scores for the graduating chief residents in eight accredited obstetrics and gynecology residency programs were obtained. Performance on USMLE step 1 was correlated with ABOG examination performance and CREOG in-training examination scores. The correlations between USMLE step 1 and CREOG in-training examination scores and ABOG examination performance were analyzed by using the Spearman correlation coefficient. RESULTS USMLE step 1 scores were significantly correlated with CREOG in-training examination scores (p < 0.000). None of the residents who scored >200 on USMLE step 1 and a mean of >200 on the CREOG in-training examinations failed the ABOG written examination. CONCLUSION Program directors have used USMLE step 1 to identify trainees who are likely to perform well on the CREOG in-training examination. The CREOG in-training examination has been used to identify residents who are likely to pass the ABOG written examination. The results of this study document the strength of these associations.

The Pregnancy in Polycystic Ovary Syndrome II study: baseline characteristics and effects of obesity from a multicenter randomized clinical trial

OBJECTIVE To summarize baseline characteristics from a large multicenter infertility clinical trial. DESIGN Cross-sectional baseline data from a double-blind randomized trial of two treatment regimens (letrozole vs. clomiphene). SETTING Academic Health Centers throughout the United States. PATIENT(S) Seven hundred fifty women with polycystic ovary syndrome (PCOS) and their male partners took part in the study. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Historic, biometric, biochemical, and questionnaire parameters. RESULT(S) Females averaged 30 years and were obese (body mass index [BMI] 35) with ∼20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). Most of the women had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH-to-FSH ratio (∼2), and antimüllerian hormone levels (8.0 ng/mL). In addition, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH-to-FSH levels, antimüllerian hormone levels, and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Men were obese (BMI 30) and had normal mean semen parameters. CONCLUSION(S) The treatment groups were well matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators. CLINICAL TRIAL REGISTRATION NUMBER NCT00719186.

Racial and ethnic differences in physiology and clinical symptoms of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders and affects approximately 5 to 10% of women of reproductive age. There exists substantial variation of physical stigmata and clinical symptoms among women, but PCOS has been known to be associated with irregular periods, infertility, increased pregnancy complications, as well as nonreproductive health problems arising from its association with the metabolic syndrome. Over the years, there have been various consensus statements regarding the diagnostic criteria, but the varying pronouncements suggest that the underlying cause is still not well understood and may be multifaceted. Importantly, the interaction of genetic predisposition and local environment is possibly responsible for the heterogeneity of phenotypes seen; it has been demonstrated that there is substantial ethnic and racial variation in the clinical presentations among PCOS patients and related individuals may vary in appearance based on nutritional and other aspects of locale. The differences in phenotype and clinical symptoms of PCOS related to the clinical, hormonal, and metabolic characteristics among various ethnic backgrounds, including Hispanics, African Americans, Asians, and Indians, need to be considered when assessing and treating these individuals. Future research must address the importance of interactions between genotype and the environment.

Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics

OBJECTIVE To identify baseline characteristics of women with unexplained infertility to determine whether treatment with an aromatase inhibitor will result in a lower rate of multiple gestations than current standard ovulation induction medications. DESIGN Randomized, prospective clinical trial. SETTING Multicenter university-based clinical practices. PATIENT(S) A total of 900 couples with unexplained infertility. INTERVENTION(S) Collection of baseline demographics, blood samples, and ultrasonographic assessments. MAIN OUTCOME MEASURE(S) Demographic, laboratory, imaging, and survey characteristics. RESULT(S) Demographic characteristics of women receiving clomiphene citrate (CC), letrozole, or gonadotropins for ovarian stimulation were very consistent. Their mean age was 32.2 ± 4.4 years and infertility duration was 34.7 ± 25.7 months, with 59% primary infertility. More than one-third of the women were current or past smokers. The mean body mass index (BMI) was 27 and mean antimüllerian hormone level was 2.6; only 11 women (1.3%) had antral follicle counts of <5. Similar observations were identified for hormonal profiles, ultrasound characterization of the ovaries, semen parameters, and quality of life assessments in both male and female partners. CONCLUSION(S) The cause of infertility in the couples recruited to this treatment trial is elusive, as the women were regularly ovulating and had evidence of good ovarian reserve both by basal FSH, antimüllerian hormone levels, and antral follicle counts; the male partners had normal semen parameters. The three treatment groups have common baseline characteristics, thereby providing comparable patient populations for testing the hypothesis that use of letrozole for ovarian stimulation can reduce the rates of multiples from that observed with gonadotropin and CC treatment. CLINICAL TRIAL REGISTRATION NUMBER NCT 01044862.

Physicians' perspectives and practices regarding the fertility management of obese patients

To assess the practice patterns and personal beliefs of fertility physicians who care for obese patients seeking assisted reproduction, we conducted a national survey of fertility program directors from both private and academic practices and discovered that although few practices have firm guidelines regarding the management of obese patients, the overwhelming majority of providers believe that body mass index guidelines or cutoffs should exist.