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An ongoing interest in environmental exposures and female fertility has led to an increasing number of studies focusing on endocrine-disrupting chemicals (EDCs). Both natural and synthetic compounds have the ability to impact reproductive health by altering the structure and/or function of genes and proteins that facilitate normal ovarian and endometrial functions. This mini-review aims to summarize the effects of some of the most common EDCs on female fertility, including the effects of pesticides and plasticizer alternatives (phthalates, bisphenol A), based on available data in human studies. A literature search was performed using the key words "pesticides, fertility, reproduction, plasticizers, bisphenol A, phthalate, miscarriage, and in vitro fertilization." The data supporting EDCs' role in female infertility remain limited, but existing evidence suggests that exposure may have an adverse impact. Accumulating evidence in animal studies provides important insights into the mechanisms underlying EDC effects. As dose-response dynamics are better elucidated, understanding the effects of EDCs on female fertility will help in the development of guidelines for both industry and individuals.

Objective To investigate whether there is a difference in the ectopic/heterotopic pregnancy rate of blastocyst-stage frozen-thawed embryo transfers (FETs) compared with that of cleavage-stage FETs. Design A retrospective cohort study. Setting Not applicable. Patient(s) Women undergoing autologous FETs at either the blastocyst stage (n = 118,572) or the cleavage stage (n = 117,619), as reported to the Society for Assisted Reproductive Technology from 2004 to 2013. Intervention(s) None. Main Outcome Measure(s) Pregnancy outcomes, specifically ectopic pregnancy rates and heterotopic pregnancy rates. Result(s) Among those who became pregnant, there was a significantly lower incidence of ectopic/heterotopic pregnancies in blastocyst-stage FETs versus that in cleavage-stage FETs (0.8% vs. 1.1%). The differences in ectopic/heterotopic pregnancy rates remained statistically significant after controlling for confounders such as tubal factor infertility and number of embryos transferred. Conclusion(s) Blastocyst-stage FET was associated with a lower ectopic/heterotopic pregnancy rate compared with cleavage-stage FET.

Objective: To investigate whether there is a difference in live-birth gender rates in blastocyst-stage frozen-thawed embryo transfers (FETs) compared with those in cleavage-stage FETs. Design: Retrospective cohort study. Setting: Academic medical center. Patient(s): All women with recorded live births who underwent FET at either the blastocyst or cleavage stage, reported to the Society for Assisted Reproductive Technology during 2004–2013. Intervention(s): None. Main Outcome Measure(s): The primary outcome was live-birth gender rates. Demographic criteria were also collected. The chi-square analyses were used for bivariate associations, and multiple logistic regression models were used for adjusted associations, with all two-sided P

STUDY QUESTION Can preimplantation genetic testing for aneuploidy (PGT-A) improve the live birth rate in patients with recurrent pregnancy loss (RPL)? SUMMARY ANSWER PGT-A use was associated with improved live birth rates in couples with recurrent pregnancy loss undergoing frozen embryo transfer (IVF-FET). WHAT IS KNOWN ALREADY Euploid embryo transfer is thought to optimize outcomes in some couples with infertility. There is insufficient evidence, however, supporting this approach to management of recurrent pregnancy loss. STUDY DESIGN, SIZE, DURATION This study included data collected by the Society of Assisted Reproductive Technologies Clinical Outcomes Reporting System (SART-CORS) for IVF-FET cycles between years 2010 through 2016. A total of 12 631 FET cycles in 10 060 couples were included in this analysis designed to assess the utility of PGT-A in couples with RPL undergoing FET, including 4287 cycles in couples with tubal disease who formed a control group. PARTICIPANTS/MATERIALS, SETTING, METHODS The experimental group included couples with RPL (strictly defined as a history of 3 or more pregnancy losses) undergoing FET with or without PGT-A. The primary outcome was live birth rate. Secondary outcomes included rates of clinical pregnancy, spontaneous abortion, and biochemical pregnancy loss. Differences were analyzed using generalized estimating equations logistic regression models to account for multiple cycles per patient. Covariates included in the model were age, gravidity, geographic region, race/ethnicity, smoking history, and indication for assisted reproductive technologies. Analyses were stratified for age groups as defined by SART: 42 years. MAIN RESULTS AND THE ROLE OF CHANCE In women with a diagnosis of RPL, the adjusted odds ratio (OR) comparing IVF-FET with PGT-A versus without PGT-A for live birth outcome was 1.31 (95% CI: 1.12, 1.52) for age 42 years. For clinical pregnancy, the OR was 1.26 (95% CI: 1.08, 1.48) for age 42 years. Finally, for spontaneous abortion, the OR was 0.95 (95% CI: 0.74, 1.21) for age 42 years. LIMITATIONS, REASONS FOR CAUTION The retrospective collection of data including only women with recurrent pregnancy loss undergoing FET presents a limitation of this study, and results may not be generalizable to all couples with recurrent pregnancy loss. Also, data regarding evaluation and treatment for RPL for the included women is unavailable. WIDER IMPLICATIONS OF THE FINDINGS This is the largest study to date assessing the utility of PGT-A in women with RPL. PGT-A was associated with improvement in live birth and clinical pregnancy in women with RPL, with the largest difference noted in the group of women with age greater than 42 years. Couples with RPL warrant counseling on all management options to reduce subsequent miscarriage, which may include IVF with PGT-A for euploid embryo selection. STUDY FUNDING/COMPETING INTEREST(S) There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

Background Postpartum women are at risk for unintended pregnancy. Access to immediate long-acting reversible contraception (LARC) may help decrease this risk, but it is unclear how many providers in the United States routinely offer this to their patients and what obstacles they face. Our primary objective was to determine the proportion of United States obstetric providers that offer immediate postpartum LARC to their obstetric patients. Methods We surveyed practicing Fellows and Junior Fellows of the American College of Obstetricians and Gynecologists (ACOG) about their use of immediate postpartum LARC. These members are demographically representative of ACOG members as a whole and represent all of the ACOG districts. Half of these Fellows were also part of the Collaborative Ambulatory Research Network (CARN), a group of ACOG members who voluntarily participate in research. We asked about their experience with and barriers to immediate placement of intrauterine devices and contraceptive implants after delivery. Results There were a total of 108 out of 600 responses (18%). Participants practiced in a total of 36 states and/or US territories and their median age was 52 years. Only 26.9% of providers surveyed offered their patients immediate postpartum LARC, and of these providers, 60.7% work in a university-based practice. There was a statistically significant association between offering immediate postpartum LARC and practice type, with the majority of providers working at a university-based practice (p

Research question: Does hemoglobin A1C (HbA1C) predict pre-diabetes (pre-DM) in a population of women with infertility and/or recurrent pregnancy loss (RPL), when considering the 75 g, 2-hour oral glucose tolerance test (2h GTT) as the gold standard? Design: Retrospective study of 242 patients with infertility or RPL presenting to a university-affiliated reproductive endocrinology and infertility clinic between January 2012 and December 2016 who underwent screening for disorders of glucose metabolism with a 2h GTT. The prevalence of pre-DM as defined by HbA1C 5.7% to 6.4% and 2h GTT values of 140-199 mg/dL, and predictive values of HbA1C for the identification of pre-DM when compared with 2h GTT, were calculated and compared. Results: Of 242 patients, 188 (77.7%) women had both HbA1C and 2h GTT performed. Of these, 89 (47.3%) tested positive for pre-DM by one or both methods. Of 89 patients, 14 (15.7%) had both an abnormal 2h GTT and an abnormal HbA1C. Only 6 out of 89 (6.7%) patients tested positive for pre-DM by an abnormal 2h GTT in the setting of a normal HbA1C result. Conversely, 69 of these 89 patients (77.5%) tested positive for pre-DM by an abnormal HbA1C in the setting of a normal 2h GTT. The prevalence of pre-DM, as defined by 2h GTT, was 10.6% (20/188) (95% CI, 6.6-16.0), compared with a prevalence of 44.1% (83/188) (95% CI, 36.9-51.6) when pre-DM was defined by HbA1C alone. When the 2h GTT was considered the gold standard for the identification of pre-DM, the negative predictive value (NPV) of HbA1C compared with 2h GTT was 94.3% (95% CI, 88.0-97.9), whereas the positive predictive value (PPV) of HbA1C compared with 2h GTT was only 16.9% (95% CI, 9.5-26.7). Conclusions: Although a normal HbA1C was highly predictive of a normal 2h GTT, the two tests demonstrate poor agreement in the identification of pre-DM in women with infertility and/or RPL. Hemoglobin A1C is superior to the 2h GTT as an initial screening test for pre-DM in this population, since it identified a substantial number of women who would otherwise remain undiagnosed in the setting for a normal 2h GTT alone. However, the long-term clinical relevance of an elevated HbA1C in this population needs to be better defined.

Objective This study aims to determine whether myometrial artery calcifications increase with age and whether uterine sections are an appropriate model for studying vascular aging. Methods An observational study of 172 women (aged 45 y or older) who underwent hysterectomy for benign indications at the University Hospital (Newark, NJ) between July 1, 2009 and June 1, 2012 was performed. Women with a history of malignancy, undocumented last menstrual period, or unavailable uterine tissue slides were excluded. H&E-stained uterine sections were evaluated for myometrial artery calcifications (defined as the presence of acellular densely basophilic material within the media of vessels) by a single pathologist in a blinded manner. Results Between July 1, 2009 and June 1, 2012, hysterectomies were performed on 441 women, 172 of whom met inclusion criteria. Seventeen women (9.9%) had myometrial artery calcifications detectable on H&E-stained tissue sections. None of 84 women aged 45 to 49 years, 2 of 51 women (3.9%) aged 50 to 59 years (aged 56 and 58 y), 10 of 27 women (37%) aged 60 to 69 years, and 5 of 10 women (50%) aged 70 to 81 years had myometrial artery calcifications. The prevalence of myometrial artery calcifications significantly increased with advancing age (P = 0.022). Conclusions Myometrial artery calcifications increase with advancing age. Histological sections of uterine tissue from hysterectomy specimens seem to be a useful model for evaluating vascular aging markers.

Objective To investigate whether there is a difference in obstetrical and perinatal outcomes in blastocyst frozen-thawed embryo transfers (FETs) compared with cleavage-stage FET. Design A retrospective cohort study. Setting Not applicable. Patient(s) Women undergoing autologous FETs at either the blastocyst stage (n = 118,572) or the cleavage stage (n = 117,619) reported to the Society for Assisted Reproductive Technology in the years 2004–2013. Intervention(s) None. Main Outcome Measure(s) Live birth, gestational age, birth weight, miscarriage. Result(s) After controlling for confounders, there were a 49% increased odds of live birth after blastocyst-stage FET compared with cleavage-stage FET (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.44, 1.54). Additionally, blastocyst FET was associated with a 68% (OR = 1.68; 95% CI, 1.63, 1.74) increased odds of clinical pregnancy and an 7% (OR = 0.93; 95% CI, 0.88, 0.92) decreased odds of miscarriage. There was also a 16% increased odds of preterm delivery (OR = 1.16; 95% CI, 1.06, 1.27) after blastocyst FET but no difference in birth weights. Conclusion(s) In patients undergoing FET, blastocyst-stage transfer is associated with higher live-birth rates when compared with cleavage-stage transfers. Furthermore, perinatal outcomes are similar between the groups.

While simulation training has been established as an effective method for improving laparoscopic surgical performance in surgical residents, few studies have focused on its use for attending surgeons, particularly in obstetrics and gynecology. Surgical simulation may have a role in improving and maintaining proficiency in the operating room for practicing obstetrician gynecologists.We sought to determine if parameters of performance for validated laparoscopic virtual simulation tasks correlate with surgical volume and characteristics of practicing obstetricians and gynecologists.All gynecologists with laparoscopic privileges (n = 347) from 5 academic medical centers in New York City were required to complete a laparoscopic surgery simulation assessment. The physicians took a presimulation survey gathering physician self-reported characteristics and then performed 3 basic skills tasks (enforced peg transfer, lifting/grasping, and cutting) on the LapSim virtual reality laparoscopic simulator (Surgical Science Ltd, Gothenburg, Sweden). The association between simulation outcome scores (time, efficiency, and errors) and self-rated clinical skills measures (self-rated laparoscopic skill score or surgical volume category) were examined with regression models.The average number of laparoscopic procedures per month was a significant predictor of total time on all 3 tasks (P = .001 for peg transfer; P = .041 for lifting and grasping; P.001 for cutting). Average monthly laparoscopic surgical volume was a significant predictor of 2 efficiency scores in peg transfer, and all 4 efficiency scores in cutting (P = .001 to P = .015). Surgical volume was a significant predictor of errors in lifting/grasping and cutting (P.001 for both). Self-rated laparoscopic skill level was a significant predictor of total time in all 3 tasks (P.0001 for peg transfer; P = .009 for lifting and grasping; P .001 for cutting) and a significant predictor of nearly all efficiency scores and errors scores in all 3 tasks.In addition to total time, there was at least 1 other objective performance measure that significantly correlated with surgical volume for each of the 3 tasks. Higher-volume physicians and those with fellowship training were more confident in their laparoscopic skills. By determining simulation performance as it correlates to active physician practice, further studies may help assess skill and individualize training to maintain skill levels as case volumes fluctuate.

STUDY QUESTION Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking? SUMMARY ANSWER Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment. WHAT IS KNOWN ALREADY Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction. STUDY DESIGN, SIZE, DURATION Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case-control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with PCOS, age 18-40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA. MAIN RESULTS AND THE ROLE OF CHANCE Overall, self-report of smoking in the nested case-control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels

Women with polycystic ovary syndrome have substantially higher rates of insulin resistance, impaired glucose tolerance, type 2 diabetes, dyslipidemia, and metabolic syndrome when compared with women without the disease. Given the high prevalence of these comorbidities, guidelines issued by the American College of Obstetricians and Gynecologists and the Endocrine Society recommend that all women with polycystic ovary syndrome undergo screening for impaired glucose tolerance and dyslipidemia with a 2 hour 75 g oral glucose tolerance test and fasting lipid profile upon diagnosis and also undergo repeat screening every 2-5 years and every 2 years, respectively. Although a hemoglobin A1C and/or fasting glucose are widely used screening tests for diabetes, both the American College of Obstetricians and Gynecologists and the Endocrine Society preferentially recommend the 2 hour oral glucose tolerance test in women with polycystic ovary syndrome as a superior indicator of impaired glucose tolerance/diabetes mellitus. However, we found that gynecologists underutilize current recommendations for metabolic screening in women with polycystic ovary syndrome. In an online survey study targeting American College of Obstetricians and Gynecologists fellows and junior fellows, 22.3% of respondents would not order any screening test at the initial visit for at least 50% of their patients with polycystic ovary syndrome. The most common tests used to screen for impaired glucose tolerance in women with polycystic ovary syndrome were hemoglobin A1C (51.0%) and fasting glucose (42.7%). Whereas 54.1% would order a fasting lipid profile in at least 50% of their polycystic ovary syndrome patients, only 7% of respondents order a 2 hour oral glucose tolerance test. We therefore call for increased efforts to encourage obstetrician-gynecologists to address metabolic abnormalities in their patients with polycystic ovary syndrome. Such efforts should include education of physicians early in their careers, at the medical student and resident level. Efforts should also include implementation of continuing medical education activities, both locally and at the national level, to improve understanding of the metabolic implications of polycystic ovary syndrome. Electronic medical record systems should be utilized to generate prompts for appropriate screening tests in patients with a diagnosis of polycystic ovary syndrome. Because obstetrician-gynecologists may be the only physicians seen by many polycystic ovary syndrome patients, particularly those in their young reproductive years, such interventions could effectively promote optimal preventative health care and early diagnosis of metabolic comorbidities in these at-risk women.

Experimental evidence supports a relevance of vitamin D (VitD) for reproduction; however, data in humans are sparse and inconsistent.To assess the relationship of VitD status with ovulation induction (OI) outcomes in women with polycystic ovary syndrome (PCOS).A retrospective cohort.Secondary analysis of randomized controlled trial data.Participants in the Pregnancy in PCOS I (PPCOS I) randomized controlled trial (n = 540) met the National Institutes of Health diagnostic criteria for PCOS.Serum 25OHD levels were measured in stored sera.Primary, live birth (LB); secondary, ovulation and pregnancy loss after OI.Likelihood for LB was reduced by 44% for women if the 25OHD level was30 ng/mL (75 nmol/L; odds ratio [OR], 0.58 [0.35-0.92]). Progressive improvement in the odds for LB was noted at thresholds of ≥38 ng/mL (≥95 nmol/L; OR, 1.42 [1.08-1.8]), ≥40 ng/mL (≥100 nmol/L; OR, 1.51 [1.05-2.17]), and ≥45 ng/mL (≥112.5 nmol/L; OR, 4.46 [1.27-15.72]). On adjusted analyses, VitD status was an independent predictor of LB and ovulation after OI.In women with PCOS, serum 25OHD was an independent predictor of measures of reproductive success after OI. Our data identify reproductive thresholds for serum 25OHD that are higher than recommended for the nonpregnant population.

Many women with polycystic ovary syndrome (PCOS) experience infertility and hirsutism and often seek treatment for both concurrently. We investigated whether women who ovulate in response to treatment with clomiphene citrate, metformin, or both would have greater improvement in hirsutism compared with those who did not ovulate.This is a secondary analysis evaluating the change in Ferriman-Gallwey score for the hirsute women (n=505 [80.7%]) from the Pregnancy in Polycystic Ovary Syndrome I study. This was a prospective, randomized, doubled-blind trial of 626 women with PCOS and infertility recruited from 12 university sites. They were treated with clomiphene citrate, metformin, or both (combination) for up to six cycles, and hirsutism evaluators were blinded to group assignment.There was a significant decrease in the Ferriman-Gallwey score between baseline and completion of the study in each of the three individual groups (clomiphene citrate, P=.024; metformin, P=.005; combination, P.001). There was no significant difference in the degree to which the hirsutism score changed when comparing the three groups (P=.44). The change in hirsutism was not associated with the duration of treatment or with the presence or absence of ovulation.In infertile hirsute women with PCOS, treatment with clomiphene citrate, metformin, or both for up to six cycles does not alter hirsutism.ClinicalTrials.gov, www.clinicaltrials.gov, NCT00068861.II.

Since the first description of successful human in vitro fertilization in 1978, researchers and clinicians have been striving to improve the efficacy and safety of the technique. Advances in technology and in our understanding of human reproduction have contributed to increased success rates and decreased rates of higher order multiple births. However, there is still room for improvement as 'unexplained infertility' still affects many couples, and the incidence of twin pregnancies remains elevated. This review will discuss some of the recent advances in the fields of molecular genetics, proteomics and oocyte culture that will ultimately enhance the clinical practice of preimplantation genetic diagnosis, embryo selection and in vitro maturation. It will also discuss the potential for these advances to improve both the safety and efficacy of in vitro fertilization in the near future.

Objective To describe fertility patients' preferences for disposition of cryopreserved embryos and determine factors important to these preferences. Design Cross-sectional survey conducted between June 2006 and July 2007. Setting Nine geographically diverse U.S. fertility clinics. Patient(s) 1020 fertility patients with cryopreserved embryos. Intervention(s) Self-administered questionnaire. Main Outcome Measure(s) Likelihood of selecting each of five conventional embryo disposition options: store for reproduction, thaw and discard, donate to another couple, freeze indefinitely, and donate for research; likelihood of selecting each of two alternative options identified in previous research: placement of embryos in the woman's body at an infertile time, or a disposal ceremony; importance of each of 26 considerations to disposition decisions; and views on the embryo's moral status. Result(s) We found that 54% of respondents with cryopreserved embryos were very likely to use them for reproduction, 21% were very likely to donate for research, 7% or fewer were very likely to choose any other option. Respondents who ascribed high importance to concerns about the health or well-being of the embryo, fetus, or future child were more likely to thaw and discard embryos or freeze them indefinitely. Conclusion(s) Fertility patients frequently prefer disposition options that are not available to them or find the available options unacceptable. Restructuring and standardizing the informed consent process and ensuring availability of all disposition options may benefit patients, facilitate disposition decisions, and address problems of long-term storage.

The fragile X syndrome is the most common cause of genetic-based mental retardation. Mutations of the fragile X gene occur as a spectrum of genetic changes. Both premutations and full mutations are associated with a variety of clinical syndromes including mental retardation, autism, premature ovarian aging and failure, and fragile X-associated tremor and ataxia. The mechanisms of inheritance of fragile X gene mutations are complex in that the mutation can change during transmission from one generation to the next. Womens’ healthcare providers should be aware of the association of fragile X premutations with early ovarian aging and premature ovarian failure. Women with the fragile X premutation are at increased risk of having offspring with fragile X syndrome. The American College of Obstetrics and Gynecology recommends that women with an elevated level of follicle-stimulating hormone before the age of 40 years without a known cause; any child with a developmental delay, mental retardation, autism or autis...

When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS).Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS.A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed.Study volunteers at multiple academic medical centers were included.Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study.Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy.Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1-2 wk.The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups.Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS.

Ovarian reserve tests are an indirect measurement of a woman's remaining follicular pool and give an estimate of her sensitivity to ovarian stimulation and her prognosis for success with fertility treatments. They cannot be used to predict future fertility or the exact timing of the decline or cessation of fertility. It is important to become familiar with these tests and understand their correct performance and interpretation, including their limitations. We review the correct timing and interpretation of the most commonly accepted tests of ovarian reserve, and suggest which patient populations will benefit most from screening. Discussed in detail are the natural age-related decline in fecundity, basal follicle stimulating hormone and estradiol levels, the clomiphene citrate challenge test, and use of transvaginal ultrasound for antral follicle counts. Other tests, such as for ovarian volume, anti-Müllerian hormone, gonadotropin-releasing hormone agonist and exogenous follicle-stimulating hormone, are discussed briefly.

Kallmann syndrome is a genetic disorder with the hallmarks of anosmia and hypogonadotrophic hypogonadism. It has a male preponderance. With the elucidation of the genetic pathways involved, affected females and inheritance patterns are becoming more clearly identified. It is an eminently treatable disorder, but it must first be recognized by the physician. With treatment, favorable reproductive outcomes can be attained in addition to maturation of secondary sex characteristics.

Context: Clomiphene and insulin sensitizers such as metformin are used to induce ovulation in polycystic ovary syndrome (PCOS), but the ovulatory response is variable, and the causes of this variation are poorly understood. Objective: Our objective was to identify predictive genetic polymorphisms and other determinants of ovulatory response. Design: This was a substudy of a multicenter randomized clinical trial. Setting: This study was performed at academic medical centers and their affiliates. Participants: A total of 312 women with PCOS were included in the study. Main Outcome Measures: Historical, biometric, biochemical, and genetic parameters were performed. Results: We found that the C allele of a single nucleotide polymorphism in the STK11 gene (expressed in liver; also known as LKB1) was associated with a significantly decreased chance of ovulation in PCOS women treated with metformin. In an analysis of ovulation per cycle, the adjusted odds ratio (OR) comparing the C/C genotype to the G/G genotype was 0.30 [95% confidence interval (CI) 0.14, 0.66], and the OR for the C/G genotype vs. the G/G genotype was also 0.30 (95% CI 0.14, 0.66). In an analysis of metformin-treated subjects, we found that the percentage of women who ovulated increased with the number of G alleles present: 48% (10 of 21) of C/C women, 67% (32 of 48) of C/G women, and 79% (15 of 19) of G/G women ovulated. We also found that increased frequency of ovulation was associated with lower body mass index (BMI) [adjusted OR of 2.36 (95% CI 1.65, 3.36) and 2.05 (95% CI 1.46, 2.88), respectively, for comparisons of BMI less than 30 vs. BMI equal to or more than 35, BMI 30–34 vs. BMI equal to or more than 35, in the analysis of ovulation per cycle], a lower free androgen index (FAI) [adjusted OR of 1.59 (95% CI 1.17, 2.18) for FAI < 10 vs. FAI ≥ 10], and a shorter duration of attempting conception [adjusted OR of 1.63 (95% CI 1.20, 2.21) for < 1.5 vs. ≥ 1.5 yr]. Conclusions: We have demonstrated that a polymorphism in STK11, a kinase gene expressed in liver and implicated in metformin action, is associated with ovulatory response to treatment with metformin alone in a prospective randomized trial. The interaction with the effects of changes in modifiable factors (e.g. BMI or FAI) requires further study.

In this article we review the existing fertility preservation options for women diagnosed with Turner syndrome and provide practical guidelines for the practitioner. Turner syndrome is the most common sex chromosome abnormality in women, occurring in approximately 1 in 2500 live births. Women with Turner syndrome are at extremely high risk for primary ovarian insufficiency and infertility. Although approximately 70%-80% have no spontaneous pubertal development and 90% experience primary amenorrhea, the remainder might possess a small residual of ovarian follicles at birth or early childhood. The present challenge is to identify these women as early in life as is possible, to allow them to benefit from a variety of existing fertility preservation options. To maximize the benefits of fertility preservation, all women with Turner syndrome should be evaluated by an expert as soon as possible in childhood because the vast majority will have their ovarian reserve depleted before adulthood. Cryopreservation of mature oocytes and embryos is a proven fertility preservation approach, and cryopreservation of ovarian tissue is a promising technique with a growing number of live births, but remains investigational. Oocyte cryopreservation has been performed in children with Turner syndrome as young as 13 years of age and ovarian tissue cryopreservation in affected prepubertal children. However, current efficacy of these approaches is unknown in this cohort. For those who have already lost their ovarian reserve, oocyte or embryo donation and adoption are strategies that allow fulfillment of the desire for parenting. For those with Turner syndrome-related cardiac contraindications to pregnancy, use of gestational surrogacy allows the possibility of biological parenting using their own oocytes. Alternatively, gestational surrogacy can serve to carry pregnancy resulting from the use of donor oocytes or embryos, if needed.

OBJECTIVE: To estimate the effects of estrogen plus progestin (E+P) therapy on menopausal symptoms, vaginal bleeding, gynecologic surgery rates, and treatment-related adverse effects in postmenopausal women. METHODS: Randomized, double-blind, placebo-controlled trial of 16,608 postmenopausal women, ages 50-79 (mean +/- standard deviation 63.3 +/- 7.1) years, with intact uterus, randomized to one tablet per day containing 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or placebo (n = 8,102), and followed for a mean of 5.6 years. Change in symptoms and treatment-related effects were analyzed at year 1 in all participants. Bleeding and gynecologic surgery rates were analyzed through study close-out. RESULTS: Baseline symptoms did not differ between the treatment groups. More women assigned to E+P than placebo reported relief of hot flushes (85.7% versus 57.7%, respectively; odds ratio 4.40; 95% confidence interval 3.40-5.71), night sweats (77.6% versus 57.4%; 2.58; 2.04-3.26), vaginal or genital dryness (74.1% versus 54.6%; 2.40; 1.90-3.02), joint pain or stiffness (47.1% versus 38.4%; 1.43; 1.24-1.64), and general aches or pains (49.3% versus 43.7%; 1.25; 1.08-1.44). Women asymptomatic at baseline who were assigned to E+P more often developed breast tenderness (9.3% versus 2.4%, respectively; 4.26; 3.59-5.04), vaginal or genital discharge (4.1% versus 1.0%; 4.47; 3.44-5.81), vaginal or genital irritation (4.2% versus 2.8%; 1.52; 1.27-1.81), and headaches (5.8% versus 4.7%; 1.26; 1.08-1.46) than women on placebo. Estrogen plus progestin treatment prevented the onset of new musculoskeletal symptoms. Vaginal bleeding was reported by 51% of women on E+P and 5% of women on placebo at 6 months; most bleeding was reported as spotting. Gynecologic surgeries (hysterectomy and dilation and curettage) were performed more frequently in women assigned to E+P (3.1% versus 2.5% for hysterectomy, hazard ratio = 1.23, P = .026; 5.4% versus 2.4% for dilation and curettage, hazard ratio = 2.23, P < .001). CONCLUSION: Estrogen plus progestin relieved some menopausal symptoms, such as vasomotor symptoms and vaginal or genital dryness, but contributed to treatment-related effects, such as bleeding, breast tenderness, and an increased likelihood of gynecologic surgery.

Objective To assess the ability of histological dating to discriminate between women of fertile and infertile couples. The utility of histological dating of endometrium in the evaluation of infertile couples is uncertain. Design Prospective multicenter study, with subjects randomly assigned to biopsy timing. Criterion standard for infertility was 12 months of unprotected, regular intercourse without conception and for fertility at least one live birth within 2 years. Setting University-based infertility practices. Patient(s) Volunteer subjects (847) recruited at 12 clinical sites participating in the National Institutes of Health-funded Reproductive Medicine Network. Inclusion criteria included ages 20–39 years, regular menstrual cycles, and no hormonal treatment or contraceptive use for 1 month before the study. Fertile controls were excluded if they had a history of infertility, recurrent pregnancy loss, or recent breastfeeding. Intervention(s) Subjects underwent daily urinary LH testing. After detection of the LH surge, subjects were randomized to biopsy in the mid (days 21–22) or the late (days 26–27) luteal phase. Pathologists at each site estimated the cycle day based on standard criteria. For the primary analysis, an out-of-phase biopsy was defined as a greater than 2-day delay in the histological maturation of the endometrium. Main outcome measure(s) The proportion of out-of-phase biopsies in fertile and infertile women was compared using logistic regression models with age at randomization as a covariate. Comparisons were also made between fertile vs. infertile at the midluteal or late luteal phase time points. Result(s) Biopsies were evaluated (301 mid and 318 late; N=619). Out-of-phase biopsy results poorly discriminated between women from fertile and infertile couples in either the midluteal (fertile: 49.4%, infertile: 43.2%) or late luteal phase (fertile: 35.3%, infertile 23.0%). Results did not substantially differ using alternative definitions of "out-of-phase" or standardized cycle day. Conclusion(s) Histological dating of the endometrium does not discriminate between women of fertile and infertile couples and should not be used in the routine evaluation of infertility.

The association of hysterectomy with increased coronary risk is controversial, and previous studies have reached differing conclusions as to whether the excess risk is confined to women who have also undergone bilateral oophorectomy. This analysis uses the Framingham algorithm to evaluate the hypothesis that hysterectomy with or without ovarian preservation is associated with increased coronary risk, using a cross-sectional analysis of baseline data from 1,501 participants of the Women's Health Initiative. Framingham risk scores, derived from the algorithm in the National Cholesterol Education Program Adult Treatment Panel III guidelines, which include age, smoking, systolic blood pressure, total and high-density lipoprotein cholesterol, were determined in a subgroup of Women's Health Initiative participants with measured plasma lipids and known ovariectomy status. Women with hysterectomy had fewer years of education than those without hysterectomy (30% with college degree vs 41%, p0.0001) and higher body mass index (29 vs 28 kg/m(2), p0.0001), consumed less alcohol, exercised less, and had a higher Framingham risk of myocardial infarction or coronary death (46% vs 41% with 10-year risk/=4%, p = 0.04). In multivariate analysis, hysterectomy with bilateral oophorectomy was an independent predictor of Framingham risk (p = 0.04), whereas hysterectomy with ovarian preservation was not.