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OBJECTIVE: To study the presence of several maternal and neonatal complications in a cohort of women with hyperandrogenic as well as normoandrogenic polycystic ovary syndrome (PCOS) and women with PCOS who received different fertility treatments.DESIGN: Prospective multicenter cohort study.SETTING: Hospitals and midwifery practices.PATIENT(S): One hundred and eighty-eight women with PCOS and singleton pregnancies (study group) and 2,889 women with a naturally conceived singleton pregnancy (reference group).INTERVENTION(S): Observational study.MAIN OUTCOME MEASURE(S): Maternal and neonatal pregnancy complications.RESULT(S): Women with PCOS had a statistically significantly increased risk of developing gestational diabetes (adjusted odds ratio [AOR] 4.15; 95% confidence interval [CI], 2.07-8.33) compared with the reference group, and their infants were more often born small for gestational age (AOR 3.76; 95% CI, 1.69-8.35). In a subgroup analysis, maternal complications were statistically significantly more often present in women with hyperandrogenic (defined as a free androgen index >4.5) PCOS (n = 76; 40% of all PCOS women) compared with those with normoandrogenic PCOS (n = 97; 52% of all PCOS women) (45% vs. 24%; P=.003); no statistically significant differences were observed between these groups regarding neonatal complications.CONCLUSION(S): Women with PCOS have an increased risk of maternal and neonatal pregnancy complications, especially women with the hyperandrogenic phenotype.CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379.

Alongside the debate around clinical, scientific, and ethical aspects of assisted reproductive technology (ART), there exists a parallel debate around the economics of ART treatment and what is the most appropriate funding framework for providing safe, equitable, and cost-effective treatment. The cost of ART treatment from a patient perspective exhibits striking differences worldwide due to the costliness of underlying health care systems and the level of public and third-party subsidization. These relative cost differences affect not only who can afford to access ART treatment but how ART is practiced in terms of embryo transfer practices; in turn significantly impacting the health outcomes and costs of caring for ART conceived children. Although empirical evidence indicates that ART treatment is "good value money" from a societal and patient perspective, the challenge remains to communicate this to policy makers, primarily because fertility treatments are not easily accommodated by traditional health economic methods. Furthermore, with global demand for ART treatment likely to increase, it is important that future funding decisions are informed by what has been learned about how costs and economic incentives influence equity of access and clinical practice. In this review we provide an international perspective on the costs and consequences of ART and summarize key economic considerations from the perspective of ART patients, providers, and society as a whole in the coming decade.

Objective To compare the endocrine and cardiometabolic cord blood characteristics of offspring of mothers with polycystic ovary syndrome (PCOS) with those of healthy controls. Design Cross-sectional case control study. Setting University medical centers. Patient(s) Offspring from mothers with PCOS (n = 61) and healthy controls (n = 82). Intervention(s) Cord blood withdrawal from neonates. Main Outcome Measure(s) Cord blood estradiol, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone, sex hormone-binding globulin, free androgen index (FAI), insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, c-reactive protein, adiponectin, and leptin. Result(s) Androstenedione and leptin concentrations were increased in the offspring of women with PCOS compared with the controls: androstenedione median 2.9 (interquartile range [IQR] 2.3–3.9) nmol/L vs. 2.2 [IQR 1.6–2.7] nmol/L; and leptin median 13.6 [IQR 8.3–22.9] μg/L vs. 9.8 [IQR 6.0–16.5] μg/L. After adjusting for maternal and pregnancy-related confounders (such as maternal age, gestational age, birth weight), androstenedione appeared associated with PCOS in both male (relative change 1.36 [1.04; 1.78]) and female offspring (relative change 1.40 [1.08; 1.82]). Similarly, in male offspring the leptin concentrations appeared associated with PCOS after correction for confounders (relative change 1.55 [1.12; 2.14]). After correction for multiple testing, these associations attenuated. Conclusion(s) Observed results suggest that androstenedione concentrations are increased in the cord blood of male and female offspring of women with PCOS, although this requires confirmation. This finding would support the hypothesis that a maternal hyperandrogenic environment during pregnancy in women with PCOS may predispose their offspring to fetal hyperandrogenism. The potential associations between fetal hyperandrogenism and long-term health effects remain to be elucidated. Clinical Trial Registration Number NCT00821379.

Objective To evaluate the association between estrogen (E) exposure and deficiency and cardiovascular disease (CVD) risk among women with primary ovarian insufficiency (POI). Design Cross-sectional study conducted between 1996 and 2016. Setting Tertiary referral centers. Patient(s) A total of 385 women with POI, defined by amenorrhea and FSH levels ≥40 IU/L before 40 years of age, were recruited. Intervention(s) None. Main Outcome Measure(s) Women underwent a standardized intake questionnaire including data on menstrual cyclicity. Lifetime E exposure and E-free period were assessed. Serum was analyzed for endocrine and CVD profiles. The Framingham 30-year risk of CVD was calculated. Result(s) Lifetime E exposure (mean ± SD) was 19.3 ± 7.0 years, E-free period was 3.1 ± 4.1 years, and age at screening was 34.8 ± 7.4 years. In multivariate models E-free interval associated positively with estimated risk of hard and general CVD events (β 0.18 [95% confidence interval 0.08, 0.29]; 0.20 [0.05, 0.35], respectively), and lifetime E exposure associated negatively with estimated risk of hard and general CVD events (−0.15 [−0.24, −0.05]; −0.16 [−0.29, −0.03], respectively), as well as low density lipoprotein cholesterol (−0.03 [−0.06, 0.00]) and non–high density lipoprotein cholesterol (−0.04 [−0.07, 0.00]). Conclusion(s) Prolonged E deprivation is associated with an increased estimated risk of CVD, whereas prolonged E exposure is associated with a reduced estimated risk. These results support the policy of early and continued use of E replacement therapy in women with POI. Clinical Trial Registration Number NCT0230904.

Objective: To elucidate the impact of ovarian stimulation on the intrauterine milieu represented by the cytokine, chemokine, and growth factor profile in endometrial secretions aspirated before embryo transfer. Design: Prospective cohort study. Setting: Fertility center in tertiary referral university hospital. Patient(s): Forty-two patients undergoing ovarian stimulation with GnRH analogues were recruited. They participated in both a natural and an ovarian-stimulated cycle for within patient comparisons. Intervention(s): Endometrial secretion aspiration was performed immediately before embryo transfer. Main Outcome Measure(s): The concentrations of 17 mediators known to be involved in human embryo implantation were assessed by multiplex immunoassay. Result(s): After correction for multiple testing, significantly higher concentrations of interleukin (IL)-1 beta, IL-5, IL-10, IL-12, IL-17, tumor necrosis factor (TNF)-alpha, heparin-binding epidermal growth factor (HbEGF), eotaxin, and dickkopf homologue-1 were present in endometrial secretions obtained in stimulated compared with natural cycles. Conclusion(s): Endometrial secretion analysis provides a novel means of investigating the effect of ovarian stimulation on the intrauterine milieu. The in vivo milieu encountered by the embryo after transfer is significantly altered by ovarian stimulation. (Fertil Steril (R) 2010;94:1764-8. (C)2010 by American Society for Reproductive Medicine.)

Objective To develop a prognostic model for the prediction of ongoing pregnancy after single-embryo transfer (SET) following mild stimulation for IVF in women less than 38 years of age. Design Prospective cohort study. Setting Two fertility centers in tertiary referral university hospitals. Patient(s) A total of 152 women with an elective SET following mild ovarian stimulation (cycle day 5 start of 150 IU/day recombinant FSH and late follicular phase GnRH antagonist cotreatment). Intervention(s) Database analysis. Main outcome measure(s) Ongoing pregnancy. Result(s) The ongoing pregnancy rate per elective SET was 28% (42 of 152). In a multivariate logistic regression analysis, body mass index, the total gonadotrophin dose needed, and number of oocytes retrieved were negatively correlated whereas the availability of a top-quality embryo was positively correlated with ongoing pregnancy. The predictive ability of the model assessed by the area under the receiver operating characteristic curve was 0.68. At a probability cut-off level of 0.20 the model showed a sensitivity of 37% and a specificity of 90%. Conclusion(s) The developed prediction model for ongoing pregnancy provides an evidence-based strategy for guidance under which conditions SET may be performed. After external validation, application of the model may help to improve overall singleton pregnancy rates.

Objective: To assess the effectiveness of controlled ovarian hyperstimulation (COH) in intrauterine insemination (IUI) for subfertile couples with an abnormal postcoital test and a poor prognosis. Design: Randomized clinical trial. Setting: Twenty-four fertility centers in the Netherlands. Patient(s): Subfertile couples with a well-timed nonprogressive PCT and additional factors that reduce fertility. Intervention(s): Couples were randomly allocated to three cycles of IUI with COH or three cycles of IUI without COH. Main Outcome Measure(s): Ongoing pregnancy within three IUI cycles. Result(s): We randomly allocated 132 couples to IUI with COH, and 133, to IUI without COH. We observed 33 pregnancies (25%) in the couples allocated to IUI with COH, of which 28 were ongoing (21%), vs. 28 pregnancies (21%) in the couples allocated to IUI without COH, of which 23 were ongoing (17%; relative risk of an ongoing pregnancy, 1.2; 95% confidence interval, 0.75 to 2.0). Two multiple pregnancies occurred in the IUI with COH group, and one, in the IUI without COH group. Conclusion(s): In couples with an abnormal PCT and a poor prognosis, IUI with COH leads to pregnancy rates comparable to those for IUI without COH. We propose to perform IUI without COH in couples with an abnormal PCT.

Objective To assess the accuracy of antimullerian hormone (AMH) in predicting cumulative live birth rate (CLBR) within 1 year after treatment initiation in GnRH antagonist treatment cycles for in vitro fertilization (IVF). Design Observational (retrospective) substudy as part of an ongoing prospective cohort study. Setting University medical center. Patient(s) A total of 487 patients scheduled for IVF/intracytoplasmic sperm injection (ICSI). Intervention(s) Patients starting their first IVF/ICSI cycle with 150 or 225 IU recombinant FSH and GnRH antagonist cotreatment were included. Serum samples collected before the first IVF treatment were used to determine AMH. Treatment data after treatment initiation for a maximum of 1 year were recorded. Main Outcome Measure(s) Prediction of CLBR with the use of AMH. Result(s) The model for predicting CLBR within 1 year included age at first treatment, AMH, type of infertility, and previous assisted reproductive technology treatment leading to live birth. The accuracy in discriminating between women who did or did not achieve a live birth was only 59%. AMH had intermediate added value in the prediction of CLBR as demonstrated by the net reclassification improvement (total 29.8). A nomogram based on age and AMH was developed by which a subgroup of patients could be identified with the poorest pregnancy prospects. Conclusion(s) The predictive accuracy of AMH for 1-year CLBR in GnRH antagonist treatment cycles was limited and did not yield much additional value on top of age. Withholding treatment based on predictors such as age and AMH, or a combination, remains problematic. Clinical Trial Registration Number www.clinicaltrials.gov, NCT02309073.

Objective: To develop a prognostic model for the outcome of IUI. Design: Retrospective cohort study. Setting: Four fertility centers in The Netherlands. Patient(s): Couples of whom the female partners had a regular cycle and who had been treated with IUI. Intervention(s): Intrauterine insemination with and without ovarian hyperstimulation. Main Outcome Measure(s): Ongoing pregnancy. Result(s): Overall, 3,371 couples were included who underwent 14,968 cycles. There were 1,229 (8.2%) pregnancies, of which 1,000 (6.7%) pregnancies were ongoing. Logistic regression analysis demonstrated that increasing maternal age, longer duration of subfertility, presence of male factor subfertility, one-sided tubal pathology, endometriosis, uterine anomalies, and an increasing number of cycles were unfavorable predictors for an ongoing pregnancy. Cervical factor and the use of ovarian hyperstimulation were favorable predictors. The area under the receiver operating characteristic curve was 0.59. When couples were divided into four categories based on prognosis, the difference between the predicted and observed chance, that is, the calibration, was less than 0.5% in each of the four groups. Conclusion(s): Although our model had a relatively poor discriminative capacity, data on calibration showed that the selected prognostic factors allow distinction between couples with a poor prognosis and couples with a good prognosis. After external validation, this model could be of use in patient counseling and clinical decision making. (C) 2004 by American Society for Reproductive Medicine

Objective: To establish whether initial screening characteristics of normogonadotropic anovulatory infertile women can aid in predicting live birth after induction of ovulation with clomiphene citrate (CC). Design: Prospective longitudinal single-center study. Setting: Specialist academic fertility unit. Patient(s): Two hundred fifty-nine couples with a history of infertility, oligoamenorrhea, and normal follicle-stimulating hormone (FSH) concentrations who have not been previously treated with any ovulation-induction medication. Intervention(s): 50, 100, or 150 mg of oral CC per day, for 5 subsequent days per cycle. Main Outcome Measure(s): Conception leading to live birth after CC administration. Result(s): After receiving CC, 98 (38%) women conceived, leading to live birth. The cumulative live birth rate within 12 months was 42% for the total study population and 56% for the ovulatory women who had received CC. Factors predicting the chances for live birth included free androgen index (testosterone/sex hormone–binding globulin ratio), body mass index, cycle history (oligomenorrhea versus amenorrhea), and the woman's age. Conclusion(s): It is possible to predict the individual chances of live birth after CC administration using two distinct prediction models combined in a nomogram. Applying this nomogram in the clinic may be a step forward in optimizing the decision-making process in the treatment of normogonadotropic anovulatory infertility. Alternative first line of treatment options could be considered for some women who have limited chances for success.

Item does not contain fulltext OBJECTIVE: To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using prospective data in combination with a systematic review and meta-analysis. DESIGN: Nested study within a multicenter randomized controlled trial and a systematic review and meta-analysis. SETTING: Reproductive medicine center in an university hospital. PATIENT(S): 158 in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) patients. INTERVENTION(S): Recombinant follicle-stimulating hormone (FSH) (150-225 IU) administered daily from cycle day 2 onward; GnRH antagonist treatment randomly started on cycle day 2 or 6; assignment into two groups according to P level on cycle day 2: normal or elevated (>4.77 nmol/L or >1.5 ng/mL, respectively). MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) per started cycle. RESULT(S): The incidence of elevated P was 13.3%. A non-statistically-significant difference in OPR was present between the normal and elevated P groups (27.0% vs. 19.0%). No differential impact of early or late GnRH antagonist initiation on the effect of elevated or normal P on OPR was observed. A systematic search of Medline and EMBASE from 1972-2013 was performed to identify studies analyzing elevated early P levels in GnRH antagonists. The meta-analysis (n=1,052) demonstrated that elevated P levels statistically significantly decreased the OPR with 15% (95% CI -23, -7 %). Heterogeneity across the studies, presumably based on varying protocols, may have modulated the effect of elevated P. CONCLUSION(S): From the present meta-analysis it appears that early elevated P levels are associated with a lower OPR in GnRH antagonists. The incidence of such a condition, however, is low. CLINICAL TRIAL REGISTRATION NUMBER: NCT00866034.

Objective: To investigate relations between dose of GnRH antagonist and follicular phase characteristics. Design: Randomized controlled multicenter trial. Setting: Tertiary referral fertility centers. Patient(s): Three hundred and twenty-nine IVF patients. Intervention(s): Ovarian stimulation for IVF with recombinant FSH starting on cycle day 2. From cycle day 7 onwards, cotreatment was provided with 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/d GnRH antagonist. Main Outcome Measure(s): Number of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations. Result(s): In 311 patients, similar follicular growth was observed in all treatment groups. FSH levels increased during the follicular phase. Late follicular phase LH, androstenedione (AD), and E 2 levels showed a GnRH antagonist dose-related decrease ( P 2 levels correlated with total follicular surface area, AD, LH, and FSH (all P 2 levels. Conclusion(s): Follicular growth was unaffected by the dose of GnRH antagonist. A rise in follicular phase FSH serum concentrations during the follicular phase, largely related to exogenous FSH, enabled ongoing follicular growth in all treatment groups. The effect of GnRH antagonist on late follicular phase E 2 levels could not be exclusively attributed to suppression of LH.

Objective: To evaluate whether basal FSH (bFSH; measured on menstrual day 1–4) adds relevant clinical information to the prediction of ongoing pregnancy rates (OPRs) after IVF, once age and diagnostic characteristics have been taken into account. Design: Retrospective. Setting: Academic fertility center. Patient(s): 435 women undergoing their first IVF cycle. Intervention(s): None. Main Outcome Measure(s): Ongoing pregnancy rate. Result(s): The likelihood ratio of bFSH as a single prognosticator for treatment failure at a cutoff level of 15 IU/L was 3.87. The proportion of patients with such a bFSH level was 5%. Multivariate logistic regression analysis selected age, bFSH level, and infertility diagnosis as relevant predictors of ongoing pregnancy. When compared to a predictive model for OPRs based on age and infertility diagnosis, the inclusion of bFSH into this model helped to identify more patients (22 vs. 1) whose predicted OPR decreased from a low level (5%–12%) towards an extremely low level ( Conclusion(s): An acceptable performance of bFSH as a single test to predict treatment failure is only obtained above a high cutoff level. Thus, the number of patients for whom bFSH provides relevant information is small. The predictive model including bFSH identified significantly more patients with an extremely poor prognosis than did the predictive model without bFSH. However, predictions based solely on age and infertility diagnosis usually were already poor in these patients. Measurement of bFSH adds little in only a few patients and is, therefore, debatable.

Objective: To evaluate implantation and pregnancy rates in patients undergoing IVF after the transfer of a maximum of two embryos that had been cultured for 3–5 days. Design: Prospective study. Setting: An IVF laboratory at a tertiary referral university hospital. Patient(s): One thousand seven hundred eighty-seven couples who underwent their first IVF cycle between January 1995 and December 1997. Intervention(s): In vitro fertilization and transfer of embryos after 3, 4, or 5 days of culture using a single medium without coculture. Main Outcome Measure(s): Implantation and pregnancy rates. Result(s): Overall implantation and pregnancy rates were not significantly different with different culture periods. Forty-one percent of all available embryos developed into blastocysts on day 5. The transfer of at least one good-quality blastocyst could be performed in 62% of patients. Blastocysts had an implantation rate of 26% per embryo, whereas the implantation rate of eight-cell embryos on day 3 was 18%. Implantation rates for retarded, normal, and advanced embryos were not significantly different with an extended culture period. Conclusion(s): Under the study conditions, the transfer of embryos after 5 days rather than 3 days of embryo culture did not change the overall implantation and pregnancy rates. The implantation potential of embryos available for transfer can be assessed better after an extended culture period. Five days of culture allows the transfer of a reduced number of embryos without decreasing overall pregnancy rates.

Objective To investigate the role of serum antimullerian hormone (AMH) as a predictor of live birth and reproductive stage in subfertile women with elevated basal FSH levels. Design A prospective observational cohort study conducted between February 2005 and June 2009. Setting Tertiary fertility center. Patient(s) Subfertile women with [1] a regular menstrual cycle (mean cycle length 25–35 days); [2] basal FSH concentrations ≥12.3 IU/L; and [3] younger than 40 years (n = 96). Intervention(s) None. Main Outcome Measure(s) Live birth and reproductive stage according to the Stages of Reproductive Aging Workshop. Result(s) A cumulative live birth rate of 63.5% was observed during a median follow-up of 3.3 years (n = 85). The AMH level was significantly associated with live birth. There was evidence of a nonlinear prediction pattern, with an increase in chances of live birth until an AMH level of 1 μg/L. Other ovarian reserve tests and chronological age appeared of limited value in predicting live birth. In addition, AMH was significantly associated with the timing of reproductive stages (n = 68) (i.e., the occurrence of menopausal transition or menopause during follow-up). Conclusion(s) The present findings suggest applicability of AMH determination as a marker for actual fertility in subfertile women with elevated basal FSH levels.

Objective To investigate the relation between the implantation rate per embryo after replacement in IVF-ET in relation to female age. Design Retrospective study using linear and biphasic models in a multivariate analysis. Setting Academic tertiary care institution. Intervention(s) In vitro fertilization-ET and determination of gestational sacs at 6 to 7 weeks of pregnancy by ultrasound. Main Outcome Measure(s) Implantation rate as defined by the number of gestational sacs per embryo replaced. Result(s) Woman's age and embryo morphology were strongly related to the implantation rate; indication for IVF-ET and cycle rank number also were related significantly but less strongly. A linear model was built describing the decrease in implantation rate with age, resulting in a decrease of approximately 7%. A biphasic model was tested also and performed significantly better, resulting in a yearly decrease of >20% after 37 years of age. Conclusion(s) The most important independent factors related to the ability of embryos to implant are female age and embryo morphology. The best way to describe the relation with female age is a biphasic model with a discontinuity at approximately 37 years of age.

Objective To compare three methods of segmental lower colon resection for treatment of symptomatic intestinal endometriosis. Design Retrospective case study. Setting Private practice patients in a rural community hospital. Patients Patients with nodular, invasive rectosigmoid endometriosis requiring segmental resection and anastomosis for treatment. Laparotomy patients were matched with laparoscopy patients for severity of intestinal endometriosis. Interventions Segmental resection of the rectosigmoid colon by laparotomy, by a laparoscopic intracorporeal technique or by a laparoscopically assisted transvaginal technique. Main Outcome Measures Length of surgery, length of hospital stay, operating room charges and total hospital charges corrected to 1995 dollars. Results Compared with laparotomy segmental colon resection for endometriosis, laparoscopic transvaginal segmental resection resulted in a shorter length of stay, equivalent operating room charges, and significantly lower total hospital charges. The laparoscopic transvaginal technique is much faster, safer, and less fatiguing to the surgeon than a total intracorporeal technique. Conclusions Laparoscopically assisted transvaginal segmental rectosigmoid resection for endometriosis is a promising technique that is simpler than a laparoscopic intracorporeal segmental resection technique and is less costly than a laparotomy segmental resection technique.

Objective To evaluate the learning curve of hysteroscopic placement of tubal sterilization microinserts by gynecologists in the Netherlands. Design Prospective multicenter study (Canadian Task Force II-2). Setting Ten community (teaching) hospitals in the Netherlands. Patient(s) A total of 631 women who underwent permanent sterilization by tubal microinserts. Intervention(s) Hysteroscopic placement of tubal sterilization microinserts performed by 15 gynecologists experienced in performing operative hysteroscopy, starting from their very first placement. Main Outcome Measure(s) Effect of increasing experience in time on procedure time, pain score, successful bilateral placement, and complications. Result(s) Bilateral successful placement with confirmation of adequate positioning at follow-up evaluation was achieved in 480 (76.1%) patients at first attempt and in 44 (7.0%) at second attempt. Median procedure time was 8.0 minutes (range: 3–40), and 31 (4.9%) patients were lost to follow-up evaluation. Gravidity showed to be a confounding factor and was consequently adjusted for. A learning curve was seen in a statistically significant decrease of procedure time with increasing experience. The decrease in procedure time extended to 11 to 15 cases and was followed by a plateau phase of the subsequent 60 cases. In contrast, pain scores, successful placement, and complication rate appeared not to improve with increasing experience. Conclusion(s) A learning curve for hysteroscopic tubal sterilization was seen for procedure time, but successful placement, pain score, and complication rate were not clearly influenced by increasing experience.

Objective: To determine associations between vitamin B status, homocysteine (tHcy), semen parameters, and sperm DNA damage. Design: Observational study. Setting: A tertiary referral fertility clinic. Patient(s): Two hundred fifty-one men of couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment, with subgroups of fertile (n = 70) and subfertile men (n = 63) defined according to semen concentration and proven fertility. Intervention(s): None. Main Outcome Measure(s): The DNA fragmentation index (DFI) as marker of sperm DNA damage determined using the sperm chromatin structure assay (SCSA), and semen parameters assessed according to World Health Organization criteria; tHcy, folate, cobalamin, and pyridoxine concentrations determined in seminal plasma and blood. Result(s): In the total group of fertile and subfertile men, all biomarkers in blood were statistically significantly correlated with those in seminal plasma. No correlation was found between the biomarkers in blood and the semen parameters. In seminal plasma, both tHcy and cobalamin positively correlated with sperm count. Folate, cobalamin, and pyridoxine were inversely correlated with ejaculate volume. In fertile men, seminal plasma folate showed an inverse correlation with the DNA fragmentation index. Conclusion(s): Low concentrations of folate in seminal plasma may be detrimental for sperm DNA stability. (Fertil Steril (R) 2009;92:548-56. (C) 2009 by American Society for Reproductive Medicine.)

Objective To evaluate the application in a different fertility clinic of a prediction model for selecting IVF patients for elective single embryo transfer. Design Retrospective analysis of a large database obtained from a tertiary infertility center. Setting University medical center. Patient(s) The model, derived at the "development center" was applied in 494 consecutive first IVF cycles carried out at the "application center." Intervention(s) After adjustment of embryo scoring system to be compatible with that used by the prediction model, it was applied to the development center data. A score chart for predicting the probability of singleton or twin pregnancy was constructed. Main Outcome Measure(s) The area under the receiver operator curve (ROC) was determined to measure the ability of the model to discriminate between ongoing pregnancy and twin pregnancy. Calibration plots were made to assess agreement between predicted and observed pregnancy rates (PR). Results The areas under the ROC for predicting ongoing pregnancy and twin pregnancy were 0.63 and 0.66, respectively. Insertion of a correction factor equivalent to the difference in odds ratios for ongoing PR between the two centers was required to improve the calibration of the model. Conclusion(s) After adaptation, the model performed well in the application center.

OBJECTIVE: To validate a published model for the prediction of the individual FSH response dose for gonadotropin induction of ovulation in polycystic ovary syndrome (PCOS). DESIGN: Structured, complete, and carefully monitored patient-based data collection to test the external validity of the prediction model. SETTING: Twenty-nine hospitals in The Netherlands. PATIENT(S): Eighty-five clomiphene citrate (CC)-resistant women with PCOS. INTERVENTION(S): Ovulation induction in a chronic low-dose step-up FSH regimen. MAIN OUTCOME MEASURE(S): Predicted individual FSH response dose, defined as follicle growth >10 mm in diameter on ultrasound. RESULT(S): The model, using the women's body mass index, CC response, initial serum FSH level, and initial serum insulin-to-glucose ratio was studied in the validation sample. Overall, the FSH response dose predicted by the model was higher than the observed response dose. The predictive performance of the model was poor, with an R(2) of 0.11, and the average prediction error was 35 IU. CONCLUSION(S): The external validity of the model predicting the individual FSH response dose was inadequate in women with CC-resistant PCOS undergoing ovulation induction with recombinant FSH in a low-dose step-up regimen

Objective: To study the cardiometabolic profile characteristics and compare the prevalence of cardiovascular (CV) risk factors between women with different polycystic ovary syndrome (PCOS) phenotypes. Design: A cross-sectional multicenter study analyzing 2,288 well phenotyped women with PCOS. Setting: Specialized reproductive outpatient clinic. Patient(s): Women of reproductive age (18-45 years) diagnosed with PCOS. Intervention(s): Women suspected of oligo- or anovulation underwent a standardized screening consisting of a systematic medical and reproductive history taking, anthropometric measurements, and transvaginal ultrasonography followed by an extensive endocrinologic/metabolic evaluation. Main Outcome Measure(s): Differences in cardiometabolic profile characteristics and CV risk factor prevalence between women with different PCOS phenotypes, i.e., obesity/overweight, hypertension, insulin resistance, dyslipidemia, and metabolic syndrome. Result(s): Women with hyperandrogenic PCOS (n = 1,219; 53.3% of total) presented with a worse cardiometabolic profile and a higher prevalence of CV risk factors, such as obesity and overweight, insulin resistance, and metabolic syndrome, compared with women with nonhyperandrogenic PCOS. In women with nonhyperandrogenic PCOS overweight/obesity (28.5%) and dyslipidemia (low-density lipoprotein cholesterol >= 3.0 mmol/L; 52.2%) were highly prevalent. Conclusion(s): Women with hyperandrogenic PCOS have a worse cardiometabolic profile and higher prevalence of CV risk factors compared with women with nonhyperandrogenic PCOS. However, all women with PCOS should be screened for the presence of CV risk factors, since the frequently found derangements at a young age imply an elevated risk for the development of CV disease later in life. ((C)2014 by American Society for Reproductive Medicine.)

Objective: To provide external validation of the Eimers model, which predicts spontaneous pregnancy among subfertile couples within the first year after the definitive establishment of the diagnostic category. Design: Live birth rates predicted by an adapted version of the Eimers model were tested against observed live birth rates in a Canadian cohort study. Setting: Fertility clinics in university medical centers. Patient(s): One thousand sixty-one couples consulting for subfertility due to cervical hostility, male subfertility, or unexplained subfertility. Intervention(s): None. Main Outcome Measure(s): We measured the discriminative ability and reliability of the predictions from the model. Result(s): The live birth rate was lower in the Canadian population than in the Eimers population. Overall, the prognostic effect of the predictors did not differ significantly in both populations. The model showed moderate predictive power in the Canadian population. With adjustment of the average live birth rate, the reliability of the model was satisfactory. Conclusion(s): The Eimers model gave reliable spontaneous pregnancy predictions in the Canadian validation population after adjustment of the average live birth rate.

Objective: To investigate whether follicular phase characteristics associated with ovarian aging can be observed in women of normal reproductive age, who had previously shown a poor response to ovarian hyperstimulation for IVF. Design: Observational, prospective study. Setting: Tertiary fertility center. Patient(s): Eleven regularly cycling, ovulatory women, aged 29–40 years who previously presented with fewer than four dominant follicles after ovarian hyperstimulation for IVF. Intervention(s): Frequent serum hormone assessments and transvaginal ultrasound during the follicular phase of a spontaneous, unstimulated cycle. Main Outcome Measure(s): Duration of the follicular phase; serum LH, FSH, E 2 , P, inhibin A, and inhibin B levels; and number of antral follicles observed by ultrasound. Results were compared with the cycle characteristics of a reference population of 38 healthy normo-ovulatory women aged 20–36 years (as published elsewhere). Result(s): Poor responders had significantly fewer antral follicles than controls. Median FSH concentrations were significantly higher compared with controls, but the majority had FSH levels within the normal range. Follicular phase P levels were significantly higher in poor responders. Duration of the follicular phase, E 2 , and inhibin A and inhibin B serum levels did not differ between poor responders and controls. Conclusion(s): Normo-ovulatory regularly cycling women with a previous poor response to ovarian hyperstimulation for IVF show follicular phase characteristics suggestive of ovarian aging.

Objective: To investigate the effect of GnRH treatment on estrogen levels and sulfatase activity in leiomyoma and myometrium tissue. Design: Retrospective analyses of tissue obtained in a prospective randomized clinical study. Setting: Gynecology departments of eight hospitals in the Netherlands. Patient(s): Thirty-two patients scheduled for leiomyoma surgery. Intervention(s): Patients were randomized to receive either GnRHa (3.75 mg/4 weeks of triptorelin or 3.6 mg/4 weeks of goserelin) or no GnRHa for 4 months. At subsequent surgery, leiomyoma and myometrium samples were collected. Main Outcome Measure(s): Estrone, estradiol, and sulfatase activity levels in leiomyoma and myometrium. Result(s): In myometrium, levels of estrone, estradiol, and sulfatase activity were significantly lower in the treated group (to median values of 46%, 21%, and 61%, respectively). In leiomyomas of treated patients, the reduction in median estrone level (to 65% of untreated value) was comparable to that in myometrium. The reduction in estradiol level in leiomyoma, however, was significantly less than in myometrium (median to 58% vs. 21%), and no significantly lower sulfatase activity was found. Conclusion(s): Estradiol and sulfatase results show that the effect of GnRHa treatment on leiomyoma differs from the effect on myometrium, suggesting a continuing estrogenic stimulus in leiomyoma tissue despite treatment.

Objective: To identify and quantify predictors of poor ovarian response in in vitro fertilization (IVF). Design: Prospective study. Setting: Tertiary fertility center. Patient(s): One hundred twenty women undergoing their first IVF cycle. Intervention(s): Measurement of the number of antral follicles and the total ovarian volume by ultrasound, and of basal levels of FSH, E 2 , and inhibin B on cycle day 3. Main Outcome Measure(s): Ovarian response, and clinical and ongoing pregnancy rates. Result(s): The antral follicle count was the best single predictor for poor ovarian response: area under the receiver operating characteristic curve=0.87. Addition of basal FSH and inhibin B levels to a logistic model with the antral follicle count significantly improved the prediction of poor response; the addition of basal E 2 levels and total ovarian volume did not improve the prediction. To express the discriminative performance of this model toward poor response, a maximum area under the receiver operating characteristic curve of 0.92 was calculated. Poor responders had significantly lower clinical and ongoing pregnancy rates than did normal responders. Conclusion(s): Our data demonstrate that the antral follicle count provides better prognostic information on the occurrence of poor response during hormone stimulation for IVF than does the patient's chronological age and the currently used endocrine markers. However, endocrine tests remain informative. Multivariate models can achieve more accurate predictions of outcomes of complex events like ovarian response in IVF.