G.W. Bates

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.).

Longterm management of Polycystic Ovarian Syndrome (PCOS)

Polycystic Ovarian Syndrome (PCOS) has been associated with numerous reproductive and metabolic abnormalities. Despite tremendous advances in the management of reproductive dysfunction, insight into the metabolic implications of PCOS is limited by the lack of uniform diagnostic criteria, the heterogeneity of the condition and the presence of confounders including obesity. Obesity clearly has a role in long term health and may best predict both reproductive and metabolic dysfunction as well as negatively affect the response to treatment in women with PCOS. Diabetes, cardiovascular disease and cancer are also at the forefront of any risk assessment or comprehensive treatment strategy for these women. Lifestyle modifications including dietary changes, increased exercise and weight loss are appropriate first line interventions for many women with PCOS. Pharmaceuticals including metformin, lipid lowering agents and oral contraceptives should be tailored to the individuals risk profile and treatment goals.

Adhesion prevention in patients with multiple cesarean deliveries

Adhesion formation is a well-known complication of abdominal surgery. Although one third of all deliveries in the United States are by cesarean delivery (CD), little is known about adhesions in the obstetric setting. Various surgical techniques for reducing adhesion formation following CD have been investigated. The relative benefits of peritoneal closure and single-layer uterine closure are areas of continued research and debate. Adhesion prevention products are also becoming more commonplace in gynecologic surgery. Two membrane/adhesion barriers have been approved in the United States. A barrier consisting of oxidized regenerated cellulose (Interceed absorbable adhesion barrier) has been shown to reduce adhesions during microsurgery. Its use may be limited following CD because complete hemostasis is crucial to its efficacy. Seprafilm adhesion barrier, composed of hyaluronic acid and carboxymethylcellulose, is approved for use in abdominal or pelvic laparotomy. Preliminary data suggest that it may be effective for reducing adhesions following CD. This article discusses what is currently known about adhesion prevention in the obstetric population and highlights the paucity of level I evidence available to clinicians in this setting.

Antral follicle count predicts natural menopause in a population-based sample: the Coronary Artery Risk Development in Young Adults Women's Study.

Objective The timing of menopause is associated with multiple chronic diseases. Tools that predict this milestone have relevance for clinical and research purposes. Among infertile women, a positive relationship exists between antral follicle count (AFC) and response to controlled ovarian hyperstimulation, a marker of ovarian reserve. However, an age-independent relationship between AFC and menopause has not been demonstrated. Thus, our objective was to evaluate the relationship between AFC measured in women aged 34 to 49 years and incident natural menopause during 7 years of follow-up. Methods The Coronary Artery Risk Development in Young Adults Study is a longitudinal community-based study (Chicago, IL; Birmingham, AL; Minneapolis, MN; and Oakland, CA) begun in 1985-1986. In 2002-2003, the Coronary Artery Risk Development in Young Adults Women’s Study measured follicle-stimulating hormone (FSH) levels and performed a transvaginal ultrasound protocol that included AFC (2-10 mm follicles on both ovaries). Incident natural menopause was assessed by surveys in 2005-2006 and 2009-2010. Results In our sample (n = 456), the median (interquartile range) AFC and FSH level were 5 (2-9) and 7.8 (5.6-11.0) mIU/mL, respectively, at a mean (range) age of 42 (34-49) years in 2002-2003. One hundred one women reported natural menopause by 2009-2010. In Cox models, current smoking, stable menses, FSH level higher than 13 mIU/mL, and AFC of 4 or less were independently associated with incident natural menopause. Compared with AFC higher than 4, those with an AFC of 4 or less were nearly twice as likely to have undergone menopause during 7 years of follow-up (hazard ratio, 1.89; 95% CI, 1.19-3.02) after adjustment for covariates. Conclusions AFC has been found to be independently associated with natural menopause during 7 years of follow-up after controlling for other markers of ovarian aging.

Body mass index–associated differences in response to ovulation induction with letrozole

OBJECTIVE To compare occurrence of pregnancy among obese (body mass index [BMI] ≥30) and nonobese (BMI <30), infertile women undergoing ovulation induction with the aromatase inhibitor letrozole followed by intrauterine insemination (IUI). DESIGN Retrospective cohort study. SETTING Academic reproductive endocrinology and infertility clinic. PATIENT(S) Ninety women with a variety of infertility diagnoses. INTERVENTION(S) Letrozole (5 mg) on menstrual cycle days 3-7, followed by intrauterine insemination (IUI). MAIN OUTCOME MEASURE(S) Occurrence of pregnancy and pregnancy outcomes. RESULT(S) Ninety women underwent 180 letrozole-IUI cycles. Conception of pregnancy occurred in 10.4% and 18.2% of the BMI <30 and BMI ≥30 groups, respectively. Using BMI as a continuous variable showed a pregnancy odds ratio of 1.093 (confidence interval 1.008-1.184) for each unit increase in BMI. Incidence of miscarriage, multiple births, number of mature follicles, and presence of LH surge were similar between groups. CONCLUSION(S) Our study of 90 women undergoing letrozole-IUI treatment showed greater likelihood of pregnancy in higher-BMI women, although the difference was not significant. Letrozole is an effective ovulation induction agent in higher-BMI women.

Antral Follicle Count Predicts Natural Menopause in a Population-Based Sample: The CARDIA Women’s Study

Objective The timing of menopause is associated with multiple chronic diseases. Tools that predict this milestone have relevance for clinical and research purposes. Among infertile women, a positive relationship exists between antral follicle count (AFC) and response to controlled ovarian hyperstimulation, a marker of ovarian reserve. However, an age-independent relationship between AFC and menopause has not been demonstrated. Thus, our objective was to evaluate the relationship between AFC measured in women aged 34 to 49 years and incident natural menopause during 7 years of follow-up. Methods The Coronary Artery Risk Development in Young Adults Study is a longitudinal community-based study (Chicago, IL; Birmingham, AL; Minneapolis, MN; and Oakland, CA) begun in 1985-1986. In 2002-2003, the Coronary Artery Risk Development in Young Adults Women’s Study measured follicle-stimulating hormone (FSH) levels and performed a transvaginal ultrasound protocol that included AFC (2-10 mm follicles on both ovaries). Incident natural menopause was assessed by surveys in 2005-2006 and 2009-2010. Results In our sample (n = 456), the median (interquartile range) AFC and FSH level were 5 (2-9) and 7.8 (5.6-11.0) mIU/mL, respectively, at a mean (range) age of 42 (34-49) years in 2002-2003. One hundred one women reported natural menopause by 2009-2010. In Cox models, current smoking, stable menses, FSH level higher than 13 mIU/mL, and AFC of 4 or less were independently associated with incident natural menopause. Compared with AFC higher than 4, those with an AFC of 4 or less were nearly twice as likely to have undergone menopause during 7 years of follow-up (hazard ratio, 1.89; 95% CI, 1.19-3.02) after adjustment for covariates. Conclusions AFC has been found to be independently associated with natural menopause during 7 years of follow-up after controlling for other markers of ovarian aging.

Antral follicle count predicts natural menopause in a population-based sample

Objective The timing of menopause is associated with multiple chronic diseases. Tools that predict this milestone have relevance for clinical and research purposes. Among infertile women, a positive relationship exists between antral follicle count (AFC) and response to controlled ovarian hyperstimulation, a marker of ovarian reserve. However, an age-independent relationship between AFC and menopause has not been demonstrated. Thus, our objective was to evaluate the relationship between AFC measured in women aged 34 to 49 years and incident natural menopause during 7 years of follow-up. Methods The Coronary Artery Risk Development in Young Adults Study is a longitudinal community-based study (Chicago, IL; Birmingham, AL; Minneapolis, MN; and Oakland, CA) begun in 1985-1986. In 2002-2003, the Coronary Artery Risk Development in Young Adults Women’s Study measured follicle-stimulating hormone (FSH) levels and performed a transvaginal ultrasound protocol that included AFC (2-10 mm follicles on both ovaries). Incident natural menopause was assessed by surveys in 2005-2006 and 2009-2010. Results In our sample (n = 456), the median (interquartile range) AFC and FSH level were 5 (2-9) and 7.8 (5.6-11.0) mIU/mL, respectively, at a mean (range) age of 42 (34-49) years in 2002-2003. One hundred one women reported natural menopause by 2009-2010. In Cox models, current smoking, stable menses, FSH level higher than 13 mIU/mL, and AFC of 4 or less were independently associated with incident natural menopause. Compared with AFC higher than 4, those with an AFC of 4 or less were nearly twice as likely to have undergone menopause during 7 years of follow-up (hazard ratio, 1.89; 95% CI, 1.19-3.02) after adjustment for covariates. Conclusions AFC has been found to be independently associated with natural menopause during 7 years of follow-up after controlling for other markers of ovarian aging.