Valerie L. Baker

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.).

Age-specific serum anti-Müllerian hormone values for 17,120 women presenting to fertility centers within the United States

OBJECTIVE To determine age-specific serum anti-Müllerian hormone (AMH) values for women presenting to U.S. fertility clinics. DESIGN Retrospective study. SETTING Single clinical reference laboratory. PATIENT(S) A total of 17,120 women of reproductive age ranging from 24 to 50 years old. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Determination of single-year median and mean AMH values with SDs. RESULT(S) Single-year-specific median, mean, and SD values are summarized in Table 1. Both median and mean AMH values decreased steadily in a manner highly correlated with advancing age. The average yearly decrease in the median serum AMH value was 0.2 ng/mL/year through age 35 and then diminished to 0.1 ng/mL/year after age 35. The rate of decline in mean AMH values was 0.2 ng/mL/year through age 40 and then diminished to 0.1 ng/mL/year thereafter. CONCLUSION(S) Median and mean AMH levels decreased steadily with increasing age from 24 to 50 years of age. Such data may be of value to physicians and their patients who are considering reproductive options.

Improving embryo selection using a computer-automated time-lapse image analysis test plus day 3 morphology: results from a prospective multicenter trial

OBJECTIVE To assess the first computer-automated platform for time-lapse image analysis and blastocyst prediction and to determine how the screening information may assist embryologists in day 3 (D3) embryo selection. DESIGN Prospective, multicenter, cohort study. SETTING Five IVF clinics in the United States. PATIENT(S) One hundred sixty women ≥ 18 years of age undergoing fresh IVF treatment with basal antral follicle count ≥ 8, basal FSH <10 IU/mL, and ≥ 8 normally fertilized oocytes. INTERVENTION(S) A noninvasive test combining time-lapse image analysis with the cell-tracking software, Eeva (Early Embryo Viability Assessment), was used to measure early embryo development and generate usable blastocyst predictions by D3. MAIN OUTCOME MEASURE(S) Improvement in the ability of experienced embryologists to select which embryos are likely to develop to usable blastocysts using D3 morphology alone, compared with morphology plus Eeva. RESULT(S) Experienced embryologists using Eeva in combination with D3 morphology significantly improved their ability to identify embryos that would reach the usable blastocyst stage (specificity for each of three embryologists using morphology vs. morphology plus Eeva: 59.7% vs. 86.3%, 41.9% vs. 84.0%, 79.5% vs. 86.6%). Adjunctive use of morphology plus Eeva improved embryo selection by enabling embryologists to better discriminate which embryos would be unlikely to develop to blastocyst and was particularly beneficial for improving selection among good-morphology embryos. Adjunctive use of morphology plus Eeva also reduced interindividual variability in embryo selection. CONCLUSION(S) Previous studies have shown improved implantation rates for blastocyst transfer compared with cleavage-stage transfer. Addition of Eeva to the current embryo grading process may improve the success rates of cleavage-stage ETs.

Subfertility: causes, treatment and outcome

Common causes of subfertility include ovulatory disorders, tubal disease, peritoneal adhesions, endometriosis, uterine abnormalities, abnormalities of sperm and advancing female age. Infertility is unexplained after thorough evaluation in about 5-10% of cases. Significant caveats must be attached to the interpretation of available data regarding infertility treatments. Successful ovulation induction in anovulatory women is possible for nearly all women except in cases of ovarian failure. Surgery is an option for some patients with tubal damage, adhesions, endometriosis and uterine abnormalities. Male factor infertility may be amenable to treatment of a specific cause, but is often empirical with the use of intra-uterine insemination (IUI) or in vitro fertilization (IVF). Egg donation is currently the most effective treatment available for age-related infertility when other treatments have not been successful. Couples with unexplained infertility may be effectively treated with ovulation induction plus IUI or IVF.

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.).

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.

Threshold intrauterine perfusion pressures for intraperitoneal spill during hydrotubation and correlation with tubal adhesive disease

OBJECTIVE To determine the minimum intrauterine perfusion pressure that will produce spill from the fallopian tubes into the peritoneal cavity and to correlate this pressure with the extent of tubal adhesive disease. DESIGN Hydrotubation was performed at laparoscopy and intrauterine perfusion pressure was measured. The extent of peritubal and fimbrial adhesions was graded at laparoscopy. SETTING Ambulatory surgery suites. PATIENTS Ten patients with infertility and/or pelvic pain were enrolled in the study. Data from nine patients were analyzed. INTERVENTIONS Measurement of intrauterine perfusion pressures. MAIN OUTCOME MEASURES The minimum pressure that produced spill of dye from each fallopian tube and the correlation between extent of external tubal pathology and this threshold pressure. RESULTS The median threshold pressure at which dye spilled from at least one fallopian tube was 100 mm Hg, and no spill occurred at pressures < 70 mm Hg. The threshold pressure was correlated negatively with the extent of tubal disease. CONCLUSIONS Fluid with the same viscosity as hydrotubation dye will not spill into the peritoneal cavity through normal fallopian tubes until the intrauterine perfusion pressure exceeds 70 mm Hg. The threshold pressure is higher when tubal adhesive disease that can be visualized by laparoscopy is present.

The time is now for a new approach to primary ovarian insufficiency

OBJECTIVE To articulate the need for a new approach to primary ovarian insufficiency. The condition, also known as premature menopause or premature ovarian failure, is defined by the presence of menopausal-level serum gonadotropins in association with irregular menses in adolescent girls or women younger than 40 years. It can be iatrogenic as related to cancer therapy or may arise spontaneously, either alone or as part of a host of ultrarare syndromes. In a large percentage of spontaneous cases no pathogenic mechanism can be identified. DESIGN Literature review and consensus building at a multidisciplinary scientific workshop. CONCLUSION(S) There are major gaps in knowledge regarding the etiologic mechanisms, psychosocial effects, natural history, and medical and psychosocial management of primary ovarian insufficiency. An international research consortium and disease registry formed under the guidance of an umbrella organization would provide a pathway to comprehensively increase basic and clinical knowledge about the condition. Such a consortium and patient registry also would provide clinical samples and clinical data with a goal toward defining the specific pathogenic mechanisms. An international collaborative approach that combines the structure of a patient registry with the principles of integrative care and community-based participatory research is needed to advance the field of primary ovarian insufficiency.

Race matters: a systematic review of racial/ethnic disparity in Society for Assisted Reproductive Technology reported outcomes.

OBJECTIVE To systematically review the reporting of race/ethnicity in Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System (CORS) publications. DESIGN Systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology of literature published in PubMed on race/ethnicity that includes data from SART CORS. SETTING Not applicable. PATIENT(S) Not applicable. INTERVENTION(S) In vitro fertilization cycles reported to SART. MAIN OUTCOME MEASURE(S) Any outcomes reported in SART CORS. RESULT(S) Seven publications were identified that assessed racial/ethnic disparities in IVF outcomes using SART data. All reported a racial/ethnic disparity. However, more than 35% of cycles were excluded from analysis because of missing race/ethnicity data. CONCLUSION(S) Review of current publications of SART data suggests significant racial/ethnic disparities in IVF outcomes. However, the potential for selection bias limits confidence in these findings, given that fewer than 65% of SART reported cycles include race/ethnicity. Our understanding of how race/ethnicity influences ART outcome could be greatly improved if information on race/ethnicity was available for all reported cycles.

Selective estrogen receptor modulators in reproductive medicine and biology.

Estrogen replacement therapy has significant potential benefits for postmenopausal women, such as improvement of menopausal symptoms and protection from osteoporosis, but it may also increase a womans risk of breast cancer. Also, some women do not take hormone replacement therapy because of such undesirable side effects as breast tenderness and uterine bleeding. Therefore, there is much interest in the development of compounds that provide the benefits of estrogen replacement therapy without the risks and side effects. The selective estrogen receptor modulators make up one class of compounds with both estrogen agonist and antagonist activity. This review discusses the clinical indications, risks, benefits, and mechanisms of action of selective estrogen receptor modulators and related compounds.