Search

Objective: To determine the impact of oil -based versus water -based contrast on pregnancy and live birth rates < 5 years after hysterosalpingography (HSG) in infertile women. Design: A 5 -year follow-up study of a multicenter randomized trial. Setting: Hospitals. Patient(s): Infertile women with an ovulatory cycle, 18 - 39 years of age, and having a low risk of tubal pathology. Intervention(s): Use of oil -based versus water -based contrast during HSG. Main Outcome Measure(s): Ongoing pregnancy, live births, time to ongoing pregnancy, second ongoing pregnancy. Result(s): A total of 1,119 women were randomly assigned to HSG with oil -based contrast (n = 557) or water -based contrast (n = 562). After 5 years, 444 of 555 women in the oil group (80.0%) and 419 of 559 women in the water group (75.0%) had an ongoing pregnancy (relative risk [RR] 1.07; 95% con fi dence interval [CI] 1.00 - 1.14), and 415 of 555 women in the oil group (74.8%) and 376 of 559 women in the water group (67.3%) had live births (RR 1.11; 95% CI 1.03 - 1.20). In the oil group, 228 pregnancies (41.1%) were conceived naturally versus 194 (34.7%) pregnancies in the water group (RR 1.18; 95% CI 1.02 - 1.38). The time to ongoing pregnancy was signi fi cantly shorter in the oil group versus the water group (10.0 vs. 13.7 months; hazard ratio, 1.25; 95% CI 1.09 - 1.43). No difference was found in the occurrence of a second ongoing pregnancy. Conclusion(s): During a 5 -year time frame, ongoing pregnancy and live birth rates are higher after tubal fl ushing with oil -based contrast during HSG compared with water -based contrast. More pregnancies are naturally conceived and time to ongoing pregnancy is shorter after HSG with oil -based contrast. Clinical Trial Registration Number: Netherlands Trial Register (NTR) 3270 and NTR6577(www.trialregister.nl). (Fertil Steril (R) 2020;114:155-62. (C) 2020 by American Society for Reproductive Medicine.)

ObjectiveTo investigate the occurrence of live birth in women with Turner syndrome (TS) after ovarian tissue cryopreservation in childhood followed by auto transplantation in adulthood and to find reliable prognostic markers for estimating the ovarian reserve in girls with TS in the future.SettingAn observational cohort study with long-term follow-up in a tertiary fertility clinic in the Netherlands. Patients recruitment between January 2018 and December 2021.Participants100 females aged 2 through 18 years with classical Turner (ie, 45,X0) or Turner variants (ie, 45,X mosaicism or structural anomalies). Girls with Y chromosomal content, minor X deletions with marginal impact on fertility, active HIV, hepatitis B or hepatitis C infection, and/or an absolute contra indication for surgery, anaesthesia or future pregnancy will be excluded.InterventionsOvarian cortical tissue will be harvested by performing a unilateral oophorectomy via laparoscopic approach. Ovarian cortex fragments will be prepared and cryopreserved. One fragment per patient will be used to determine follicular density by conventional histology, and to perform fluorescence in situ hybridisation analysis of ovarian cells. Routine chromosome analysis will be performed on both lymphocytes and buccal cells. A blood sample will be taken for hormonal analysis and all subjects will undergo a transabdominal ultrasound to determine the uterine and ovarian size. Patient characteristics, pregnancy rates and pregnancy outcomes will be collected from the patient’s medical record.Ethics and disseminationThe study protocol has been approved by the Central Committee on Research Involving Human Subjects in November 2017 (CCMO NL57738.000.16).Trial registration numberNCT03381300.

Despite inconclusive evidence, concerns that assisted reproductive technology may be associated with increased risk of ovarian cancer remain. Significant increases in gonadotropin levels and disruption of ovarian epithelium have been proposed as mechanisms to explain this potential association. Several studies investigating this have suggested the observed increased risk in those undergoing assisted reproductive technology (ART) may be more related to nulliparity and subfertility than the treatment itself.This nationwide retrospective cohort study with prospective follow-up aimed to determine long-term ovarian cancer risk among women treated with ART compared with women in the general population and compared with subfertile women not treated with ART. Also investigated was whether unsuccessful ART and successful ART leading to childbirth had different effects on ovarian cancer risk. Women treated with ART between 1983 and 2000 identified in the OMEGA-1 (OvariuMstimulatie En Gynecologische Aandoenginen-1) cohort were included in this analysis. The OMEGA-1 cohort included women starting ovarian stimulation for ART in in vitro fertilization (IVF) clinics in the Netherlands, as well as a comparison cohort of subfertile ART-native women. Eligible women entered into the study cohort on the date of first ART or first clinic visit for subfertility evaluation. Cancer diagnosis data were obtained through the population-based Netherlands Cancer Registry between 1989 and July 2018. Ovarian cancer incidence in the ART and non-ART cohorts were compared, and standardized incidence ratios (SIRs) were calculated based on the observed and expected numbers of tumors in each cohort.The final study cohort consisted of 30,625 ART-treated women and 9988 non-ART-treated women with a median follow-up of 24 years. A total of 158 ovarian cancers were observed in the follow-up period, 158 of which were invasive and 100 borderline. Ovarian cancer risk was increased in the ART group (SIR = 1.43; 95% confidence interval [CI], 1.18-1.71) but not in the non-ART group (SIR = 1.15; 95% CI, 0.81-1.59; P = 0.25) compared with the general population. Nulliparous women had a 2-fold increased risk of ovarian cancer compared with the general population, and each subfertility diagnosis was associated with an increase in ovarian cancer risk in ART-treated women but not in non-ART-treated women. When comparing the ART group and non-ART group and adjusting for age at start and parity, the hazards ratio (HR) for ovarian cancer was 1.02 (95% CI, 0.70-1.50), and this did not increase after more ART cycles. A decreased risk of ovarian cancer was associated with a larger number of successful ART cycles (1 successful ART cycle HR = 0.54; 95% CI, 0.35-0.87; >= 2 cycles HR = 0.37; 95% CI, 0.18-0.73; P = 0.001); however, a larger number of unsuccessful cycles was not associated with a greater risk. Borderline ovarian cancers were more common among both ART and non-ART women compared with the general population (SIR = 2.20; 95% CI, 1.66-2.86; SIR = 1.84; 95% CI, 1.05-2.99, respectively), and more common in ART-treated women compared with non-ART women (HR, 1.84; 95% CI, 1.08-3.14); however, risk did not increase with more ART cycles or follow-up time.The results of this study show an increased risk of ovarian cancer among ART-treated women compared with the general population, but not compared with subfertile women not treated with ART and is attributed to nulliparity.

STUDY QUESTION: Do cumulative live birth rates (CLBRs) over multiple IVF/ICSI cycles confirm the low prognosis in women stratified according to the POSEIDON criteria? SUMMARY ANSWER: The CLBR of low-prognosis women is ~56% over 18 months of IVF/ICSI treatment and varies between the POSEIDON groups, which is primarily attributable to the impact of female age. WHAT IS KNOWN ALREADY: The POSEIDON group recently proposed a new stratification for low-prognosis women in IVF/ICSI treatment, with the aim to define more homogenous populations for clinical trials and stimulate a patient-tailored therapeutic approach. These new criteria combine qualitative and quantitative parameters to create four groups of low-prognosis women with supposedly similar biologic characteristics. STUDY DESIGN, SIZE, DURATION: This study analyzed the data of a Dutch multicenter observational cohort study including 551 low-prognosis women, aged

Purpose We assessed the uptake of fertility preservation (FP), recovery of ovarian function (OFR) after chemotherapy, live birth after breast cancer, and breast cancer outcomes in women with early-stage breast cancer. Methods Women aged below 41 years and referred to our center for FP counseling between 2008 and 2015 were included. Data on patient and tumor characteristics, ovarian function, cryopreservation (embryo/oocyte) and transfer, live birth, and disease-free survival were collected. Kaplan–Meier analyses were performed for time-to-event analyses including competing risk analyses, and patients with versus without FP were compared using the logrank test. Results Of 118 counseled women with a median age of 31 years (range 19–40), 34 (29%) chose FP. Women who chose FP had less often children, more often a male partner and more often favorable tumor characteristics. The 5-year OFR rate was 92% for the total group of counseled patients. In total, 26 women gave birth. The 5-year live birth rate was 27% for the total group of counseled patients. Only three women applied for transfer of their cryopreserved embryo(s), in two combined with preimplantation genetic diagnosis (PGD) because of BRCA1-mutation carrier ship. The 5-year disease-free survival rate was 91% versus 88%, for patients with versus without FP (P = 0.42). Conclusions Remarkably, most women achieved OFR, probably related to the young age at diagnosis. Most pregnancies occurred spontaneously, two of three women applied for embryo transfer because of the opportunity to apply for PGD.

Purpose We aim to evaluate the safety of PGD. We focus on the congenital malformation rate and additionally report on adverse perinatal outcome. Methods We collated data from a large group of singletons and multiples born after PGD between 1995 and 2014. Data on congenital malformation rates in live born children and terminated pregnancies, misdiagnosis rate, birth parameters, perinatal mortality, and hospital admissions were prospectively collected by questionnaires. Results Four hundred thirty-nine pregnancies in 381 women resulted in 364 live born children. Nine children (2.5%) had major malformations. This percentage is consistent with other PGD cohorts and comparable to the prevalence reported by the European Surveillance of Congenital Anomalies (EUROCAT). We reported one misdiagnosis resulting in a spontaneous abortion of a fetus with an unbalanced chromosome pattern. 20% of the children were born premature (

BACKGROUND: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers.METHODS: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility.RESULTS: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk.CONCLUSION: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.

STUDY QUESTION: Is there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment?SUMMARY ANSWER: In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose.WHAT IS KNOWN ALREADY: In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists.STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping.PARTICIPANTS/MATERIALS, SETTING, METHODS: In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-Müllerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective.MAIN RESULTS AND THE ROLE OF CHANCE: We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95% CI, -0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = €275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were €35). The analysis based on AMH as a tool for dose individualization suggested comparable results.LIMITATIONS, REASONS FOR CAUTION: Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response.WIDER IMPLICATIONS OF THE FINDINGS: Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research.STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other autors have nothing to declare.TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.

// Ingeborg J.H. Vriens 1 , Ashley J.R. De Bie 1 , Maureen J.B. Aarts 1 , Maaike de Boer 1 , Irene E.G. van Hellemond 1 , Joyce H.E. Roijen 1 , Ron J.T. van Golde 2 , Adri C. Voogd 1 , Vivianne C.G. Tjan-Heijnen 1 1 Department of Medical Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands 2 Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Maastricht, The Netherlands Correspondence to: Vivianne C.G. Tjan-Heijnen, email: vcg.tjan.heijnen@mumc.nl Keywords: chemotherapy induced ovarian function failure, breast cancer, chemotherapy, ovarian insufficiency, premenopausal patients Received: July 20, 2016 Accepted: December 26, 2016 Published: January 05, 2017 ABSTRACT Purpose: To assess the incidence of chemotherapy-induced ovarian function failure (COFF) based on estradiol and follicle stimulating hormone (FSH) monitoring in premenopausal women with hormone-receptor positive breast cancer treated with second and third generation (neo-)adjuvant chemotherapy. Results: We identified 115 eligible women. Two years after start of chemotherapy, COFF was significantly more often present in women ≥ 40 years (85.6%) as compared to women < 40 years (8.7%). Only age was significantly associated with COFF two years after start of chemotherapy (HR 12.26; 95% CI 5.21–28.86). In 50% of the patients, premenopausal hormone levels were the first or only evidence of ovarian function recovery (OFR). Materials and Methods: We included all premenopausal women with hormone-receptor positive breast cancer treated with anthracycline-based chemotherapy, with or without taxanes, in our university hospital in the Netherlands in the years 2005-2013. Patients were 3-monthly monitored for ovarian function. Cox proportional hazards model was used to determine the predictive impact of various parameters on the occurrence of COFF. Conclusions: After second- or third generation (neo-)adjuvant chemotherapy, COFF was still present in 8.7% of patients < 40 years after two years. FSH and estradiol monitoring may be relevant for those in whom ovarian function suppression is considered an additional effective endocrine treatment.

Objective: To evaluate the growth, health, and motor development of children born after preimplantation genetic diagnosis (PGD).Design: Observational cohort study and comparison of 5-year-old children born after PGD to similar aged children born after IVF/intracytoplasmic sperm injection (ICSI) and children from families with a genetic disorder born after natural conception (NC).Setting: University hospital.Patient(s): One hundred three children were included in the PGD group. The two control groups consisted of 90 children born after IVF/ICSI and 58 children born after NC.Intervention(s): PGD.Main Outcome Measure(s): We measured height, weight, body circumferences, body mass index, and blood pressure and performed a dysmorphological and neurological examination. We also collected data about the children's medical history, health care consultations, and motor milestones.Result(s): The mean height, weight, and body mass index were comparable for all groups. Six (5.8%) PGD, four (4.4%) IVF/ICSI, and five (8.6%) NC children had a major congenital abnormality. The incidence of acute and chronic illnesses was similar in all groups. Motor milestones were achieved on time, but the IVF/ICSI group had a slightly younger mean sitting age. None of the children had severe neurological problems.Conclusion(s): Five-year-old children born after PGD show normal growth, health, and motor development when compared with children born after IVF/ICSI and NC children from families with a genetic disorder. ((C) 2019 by American Society for Reproductive Medicine.)

Background Obesity in women of reproductive age has deleterious effects on reproductive and offspring health. In this study, we aimed to evaluate the association between the magnitude of periconceptional body-mass index (BMI) change and maternal and neonatal outcomes in obese infertile women who participated in the LIFEstyle study. The LIFEstyle study was a randomized controlled trial, evaluating if a six-month lifestyle intervention program prior to infertility treatment in obese infertile women improved birth rates, compared to prompt infertility treatment. Methods and findings This is an exploratory post hoc analysis of the LIFEstyle study. We recorded periconceptional BMI change in women with an ongoing pregnancy, pooling data of all women, regardless of randomization arm. Periconceptional BMI change was calculated using weight at randomization and the periconceptional weight (measured in kilograms 12 weeks before or after conception and expressed as BMI change in units BMI (kg/m(2))). Subsequently, women were categorized into quartiles according to the magnitude of their periconceptional change in BMI. The odds of maternal and neonatal outcomes were calculated using logistic regression analysis, comparing women in each of the first three weight change quartiles separately, and combined, to women in the fourth quartile. The fourth quartile was chosen as reference group, since these women had the least weight loss. We adjusted for periconceptional BMI, nulliparity and smoking status. In addition, we performed a subgroup analysis for singleton pregnancies. In the LIFEstyle study, 321 obese infertile women achieved an ongoing pregnancy which was conceived within 24 months after randomization. Periconceptional BMI change was available in 244 of these women (76%). Median BMI at randomization was 35.9 kg/m(2). Women in the first quartile (Q1) had a periconceptional BMI change of = 0.1 kg/m(2). There were no significant differences between women in the quartiles regarding rates of excessive gestational weight gain (in term pregnancies), gestational diabetes, preterm birth, induction of labor, spontaneous vaginal birth and Caesarean section. Compared to women in Q4, the adjusted odds ratios, aOR, and 95% confidence interval for a hypertensive complication were; 0.55 (0.22-1.42) for women in Q1, 0.30 (0.12-0.78) for women in Q2, 0.39 (0.16-0.96) for women in Q3 and 0.39 (0.19-0.82) for women in Q1 to Q3 combined. In the subgroup analysis, investigating singleton pregnancies only, the statistically significant decreased rate of a hypertensive complication remained in women in Q2 (aOR 0.27, 95% CI 0.10-0.72) and Q3 (aOR 0.39, 95%Cl 0.16-0.98) and when comparing women in Q1 to Q3 together to women in Q4 (aOR 0.38, 95%Cl 0.18-0.80). Furthermore, there was a significantly decreased aOR (95%C1) of preterm birth in women in Q2 (0.24, 0.06-0.98) and when combining women in Q1 to Q3 (0.37, 0.14-0.97) compared to women in Q4. Conclusions These results suggest that a periconceptional decrease in BMI in obese infertile women could lead to a decrease of the rates of hypertensive pregnancy complications and preterm birth. The results are limited by the exploratory nature of the analyses and further evidence is necessary to provide more definitive conclusions.

BACKGROUND: The prevalence of obesity, an important cardiometabolic risk factor, is rising in women. Lifestyle improvements are the first step in treatment of obesity, but the success depends on factors like timing and motivation. Women are especially receptive to advice about lifestyle before and during pregnancy. Therefore, we hypothesize that the pre-pregnancy period provides the perfect window of opportunity to improve cardiometabolic health and quality of life of obese infertile women, by means of a lifestyle intervention.METHODS AND FINDINGS: Between 2009-2012, 577 infertile women between 18 and 39 years of age, with a Body Mass Index of ≥ 29 kg/m2, were randomized to a six month lifestyle intervention preceding infertility treatment, or to direct infertility treatment. The goal of the intervention was 5-10% weight loss or a BMI < 29 kg/m2. Cardiometabolic outcomes included weight, waist- and hip circumference, body mass index, systolic and diastolic blood pressure, fasting glucose and insulin, HOMA-IR, hs-CRP, lipids and metabolic syndrome. All outcomes were measured by research nurses at randomization, 3 and 6 months. Self-reported quality of life was also measured at 12 months. Three participants withdrew their informed consent, and 63 participants discontinued the intervention program. Intention to treat analysis was conducted. Mixed effects regression models analyses were performed. Results are displayed as estimated mean differences between intervention and control group. Weight (-3.1 kg 95% CI: -4.0 to -2.2 kg; P < .001), waist circumference (-2.4 cm 95% CI: -3.6 to -1.1 cm; P < .001), hip circumference (-3.0 95% CI: -4.2 to -1.9 cm; P < .001), BMI (-1.2 kg/m2 95% CI: -1.5 to -0.8 kg/m2; P < .001), systolic blood pressure (-2.8 mmHg 95% CI: -5.0 to -0.7 mmHg; P = .01) and HOMA-IR (-0.5 95% CI: -0.8 to -0.1; P = .01) were lower in the intervention group compared to controls. Hs-CRP and lipids did not differ between groups. The odds ratio for metabolic syndrome in the intervention group was 0.53 (95% CI: 0.33 to 0.85; P < .01) compared to controls. Physical QoL scores were higher in the lifestyle intervention group (2.2 95% CI: 0.9 to 3.5; P = .001) while mental QoL scores did not differ.CONCLUSIONS: In obese infertile women, a lifestyle intervention prior to infertility treatment improves cardiometabolic health and self-reported physical quality of life (LIFEstyle study: Netherlands Trial Register: NTR1530).

Background To assess the incidence and predictors of (permanent) chemotherapy-induced ovarian function failure (COFF) in premenopausal women with hormone receptor positive breast cancer treated with adjuvant chemotherapy. Patients and methods In our university hospital, patients with COFF and hormone-receptor positive breast cancer are monitored for ovarian function recovery by 3-monthly FSH and estradiol blood levels (serum estradiol is measured by direct immunoassay). In this present study, we collected data from the medical records of all premenopausal women with hormone-receptor positive breast cancer treated with anthracycline-based chemotherapy, with or without the addition of taxanes, who were diagnosed in the years 2005-2012. To meet the definition of COFF, the amenorrhea and ovarian function suppression had to last ≥24 weeks since the last menstruation before or during chemotherapy. Patients with hormone-receptor negative breast cancer were excluded. Results We identified 135 eligible women. Initial oral hormonal therapy consisted of tamoxifen (n= 116) or aromatase inhibitors (AI, n=16, of whom 1 patient younger than 40 years). Median follow-up of the included patients was 25 months (range 3-69 months). The majority of women was older than 40 years (80%). Permanent or temporary COFF was present in 95.6% of patients; that is, in 97.2% of patients of ≥ 40 years versus in 88.8% of patients < 40 years of age, which was not different between age-groups. However, permanent COFF was significantly more often present in women ≥ 40 years (75%) as compared with 11.1% of women < 40 years ( P < 0.03). Patients who developed a permanent COFF had a mean age of 47.4 (SD 3.9) years, whereas patients who developed a temporary COFF had a mean age of 38.0 (SD 6.5). In 57% of the patients, premenopausal hormone levels were the first evidence of ovarian function recovery. The second-last FSH and estradiol values of patients who had an ovarian function recovery were still clearly in postmenopausal range (Figures will be shown at the meeting). Conclusion COFF is seen in 89% of patients < 40 years, but in the majority it was reversible. This is reassuring for those with a childwish. As in a significant proportion of patients FSH and estradiol values are the first sign of ovarian function recovery, close monitoring of ovarian function is required if ovarian function suppression is considered an additional effective hormonal treatment, and with respect to indication of non-hormonal contraceptive devices. We would not recommend AI as single hormonal treatment in young patients with COFF. Citation Format: Vivianne C Tjan-Heijnen, Ingeborg J Vriens, Ashley J Beijers, Maureen J Aarts, Maaike de Boer, Joyce H Royen, Ron J van Golde. One-tenth of patients younger than 40 years develop a permanent chemotherapy-induced ovarian function failure after receiving adjuvant anthracycline-based chemotherapy with or without taxanes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-21-08.

BACKGROUND Pregnancy rates among infertile women have been reported to increase after hysterosalpingography, but it is unclear whether the type of contrast medium used (oil-based or water-soluble contrast) influences this potential therapeutic effect. METHODSWe performed a multicenter, randomized trial in 27 hospitals in the Netherlands in which infertile women who were undergoing hysterosalpingography were randomly assigned to undergo this procedure with the use of oil-based or water-based contrast. Subsequently, couples received expectant management or the women underwent intrauterine insemination. The primary outcome was ongoing pregnancy within 6 months after randomization. Outcomes were analyzed according to the intention-to-treat principle. RESULTSA total of 1119 women were randomly assigned to hysterosalpingography with oil contrast (557 women) or water contrast (562 women). A total of 220 of 554 women in the oil group (39.7%) and 161 of 554 women in the water group (29.1%) had an ongoing pregnancy (rate ratio, 1.37; 95% confidence interval [CI], 1.16 to 1.61

Preimplantation Genetic Diagnosis (PGD) is a method of testing in vitro embryos as an alternative to prenatal diagnosis with possible termination of pregnancy in case of an affected child. Recently, PGD for hereditary breast and ovarian cancer caused by BRCA1 and BRCA2 mutations has found its way in specialized labs. We describe the route to universal single-cell PGD tests for carriers of BRCA1/2 mutations. Originally, mutation-specific protocols with one or two markers were set up and changed when new couples were not informative. This route of changing protocols was finalized after 2 years with universal tests for both BRCA1 and BRCA2 mutation carriers based on haplotyping of, respectively, 6 (BRCA1) and 8 (BRCA2) microsatellite markers in a multiplex PCR. Using all protocols, 30 couples had a total of 47 PGD cycles performed. Eight cycles were cancelled upon IVF treatment due to hypostimulation. Of the remaining 39 cycles, a total of 261 embryos were biopsied and a genetic diagnosis was obtained in 244 (93%). In 34 of the 39 cycles (84.6%), an embryo transfer was possible and resulted in 8 pregnancies leading to a fetal heart beat per oocyte retrieval of 20.5% and a fetal heart beat per embryonic transfer of 23.5%. The preparation time and costs for set-up and validation of tests are minimized. The informativity of microsatellite markers used in the universal PGD-PCR tests is based on CEPH and deCODE pedigrees, making the tests applicable in 90% of couples coming from these populations.

BACKGROUNDSmall lifestyle-intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcomes, but large randomized, controlled trials are lacking.METHODSWe randomly assigned infertile women with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 29 or higher to a 6-month lifestyle intervention preceding treatment for infertility or to prompt treatment for infertility. The primary outcome was the vaginal birth of a healthy singleton at term within 24 months after randomization. RESULTS We assigned women who did not conceive naturally to one of two treatment strategies: 290 women were assigned to a 6-month lifestyle-intervention program preceding 18 months of infertility treatment (intervention group) and 287 were assigned to prompt infertility treatment for 24 months (control group). A total of 3 women withdrew consent, so 289 women in the intervention group and 285 women in the control group were included in the analysis. The discontinuation rate in the intervention group was 21.8%. In intention-to-treat analyses, the mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group (PCONCLUSIONSIn obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization. (Funded by the Netherlands Organization for Health Research and Development; Netherlands Trial Register number, NTR1530.)

Contains fulltext : 171486.pdf (Publisher’s version ) (Closed access) STUDY QUESTION: Do BRCA1/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Mullerian hormone (AMH) levels? SUMMARY ANSWER: BRCA1/2 mutation carriers do not show a lower serum AMH level in comparison to proven non-carriers, after adjustment for potential confounders. WHAT IS KNOWN ALREADY: It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum AMH levels and BRCA mutation status. Hence, it is yet unclear whether BRCA1/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE, DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 BRCA1/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in AMH levels of 0.40 microg/l (SD +/- 0.12 microg/l, two-sided alpha-error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHOD: Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive BRCA1/2 testing because of a familial BRCA1/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum AMH levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum AMH levels. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 BRCA1/2 mutation carriers and 131 proven non-carriers. The median [range] AMH level in carriers was 1.90 microg/l [0.11-19.00] compared to 1.80 microg/l [0.11-10.00] in non-carriers (P = 0.34). Adjusted linear regression analysis revealed no reduction in AMH level in the carriers (relative change = 0.98 (95%CI, 0.77-1.22); P = 0.76). LIMITATIONS, REASONS FOR CAUTION: Participants were relatively young. Power was insufficient to analyze BRCA1 and BRCA2 mutation carriers separately. AMH levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis. WIDER IMPLICATIONS OF THE FINDINGS: Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent AMH measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care. STUDY FUNDING/COMPETING INTERESTS: This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe & Dome, Organon, and Schering Plough, outside the submitted work. Frank J.M. Broekmans is a member of the external advisory board for Merck Serono (The Netherlands), outside the submitted work. TRIAL REGISTRATION NUMBER: NTR no. 4324.

Previous studies have shown that both exogenous and endogenous estrogens and progestogens increase the risk of breast cancer. it has been suggested that in vitro fertilization (IVF) procedures may increase breast cancer risk. This risk could be could be due to a temporary decrease in estradiol and progesterone levels (during down-regulation of the natural cycle), as well as strongly elevated levels (during stimulation phase). Results of previous studies investigating breast cancer risk after IVF treatment were inconclusive because of limited follow-up. Recent studies have reported no increased risk of this cancer after IVT at a mean follow-up of 8 and 16 years. This historical cohort (OMEGA) study quantified long-term risk of breast cancer after ovarian stimulation for IVF. The aim of the study was to compare the long-term risk of breast cancer among a nationwide cohort of women receiving ovarian stimulation for IVF with that of women receiving other fertility treatments and those in the general population. The study was conducted in 12 IVF clinics in the Netherlands. The cohort was composed of 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women who started other fertility treatments between 1980 and 1995 (non-IVF group) Data were obtained from all 12 IVF clinics. There was complete follow-up through December 2013 for 96% of the cohort. At end of follow-up, the median age was 53.8 years in the IVF group and 55.3 years in the non-IVF group. Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was obtained from medical records and mailed questionnaires. First invasive and in situ breast cancer incidence among women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Risk of breast cancer in the IVF group was compared with risk in the non-IVF group (hazard ratios [HRs]) and the general population (standardized incidence ratios [SIRs]). In the total cohort, the mean age at baseline was 32.8 years, and the mean number of IVF cycles was 3.6. After a median follow-up of 21.1 years, 839 of the cohort had invasive breast cancer, and 109 had in situ breast cancer. Compared with the general population, breast cancer risks were not increased either in the IVF group (SIR, 1.01; 95% confidence interval [CI], 0.93-1.09) or the non-IVF group (SIR, 1.00; 95% CI, 0.88-1.15). At the age of 55 years, cumulative incidence rates of breast cancer were 3.0% in the IVF group and 2.9% in the non-IVF group (P = 0.85). With longer time since treatment (>= 20 years), the SIR did not increase in the IVF group (SIR, 0.92; 95% CI, 0.73-1.15) or in the non-IVF group (SIR, 1.03; 95% CI, 0.82-1.29). Women with 7 or more IVF cycles had a significantly decreased risk of breast cancer than did women who were treated with 1 to 2 IVF cycles; the HR was 0.55, with a 95% CI of 0.39 to 0.77. The risk was also significantly lower (HR, 0.77; 95% CI, 0.61-0.96) after poor response to the first IVF cycle ( = 4 collected oocytes). These data show that IVT treatment did not increase the risk of breast cancer in a cohort of women undergoing fertility treatment in the Netherlands between 1980 and 1995 when compared with women who received non-IVF treatment or those in the general population after a median follow-up of 21 years. These findings are consistent with those from recent reviews showing no significant increase in long-term risk of breast cancer among IVF-treated women.

Contains fulltext : 153119.pdf (Publisher’s version ) (Closed access) QUESTION: What is the effect of a multifaceted intervention with participation of patients on improvement of patient-centredness in fertility care? SUMMARY ANSWER: A multifaceted intervention with participation of patients did not improve total patient-centredness scores provided by women in fertility care. WHAT IS KNOWN ALREADY: We should provide care that takes into account the preferences and needs of patients, i.e. patient-centred care. Especially infertile patients who suffer from a high emotional burden of treatment could benefit from a more patient-centred approach in healthcare. However, the improvement of patient-centred care is still needed, because effective strategies to come to improvement are lacking. STUDY DESIGN, SIZE AND DURATION: A cluster RCT was performed within 32 Dutch fertility clinics, covering about one-third of all Dutch hospitals. After randomization, 16 clinics in the intervention group were exposed to a multifaceted improvement strategy for patient-centred fertility care for 1 year. This strategy comprised audit and feedback, educational outreach visits and patient-mediated interventions. The remaining 16 clinics in the control group performed care as usual. PARTICIPANTS/MATERIALS, SETTING AND METHODS: The clinics' levels of patient-centredness were measured, using the validated Patient-centredness Questionnaire-Infertility (PCQ-Infertility). At baseline measurement, a total of 1620 women in couples undergoing fertility care (this included both male, female, mixed infertility and infertility of unknown cause) in one of the participating clinics were randomly selected to participate in the study and complete the questionnaire. For the after measurement, we randomly selected a comparable sample of 1565 women in infertile couples. Both women who had already started their treatment before the start of the study (67%) and women who started their treatment after the start of this study (33%) were included. To avoid bias, we only included the responses of non-pregnant respondents. MAIN RESULTS AND ROLE OF CHANCE: The final analysis involved 30 clinics. A total of 946 women (response 58.4%) completed their questionnaire at baseline measurement and also a total of 946 women (response 60.4%) at after measurement. After excluding the pregnant patients, respectively 696 and 730 questionnaires were eligible for analysis at baseline and after measurement. The total score of case-mix adjusted PCQ-Infertility at after measurement did not differ significantly between the intervention and control group (B = 0.06; 95% confidence interval (CI) = -0.04-0.15; P = 0.25). However, scores on the continuity of care subscale were significantly higher in the intervention group compared with the control group (B = 0.20; 95% CI = 0.00-0.40; P < 0.05). The addition of three interaction terms to the model had a significant impact: (i) being younger than 36 years, (ii) beginning treatment after the study had started and (iii) using complementary and alternative medicine. If women met all three conditions, the scores in the intervention group were on average 0.31 points higher compared with the control group (95% CI = 0.14-0.48; P =

Purpose: To study the role of the autosomal candidate gene DAZLA (Deleted in AZoospermia Like Autosome) in male subfertility.

Couples dealing with microdeletions of the Y chromosome have to make decisions about their reproductive future. Do they opt for intracytoplasmic sperm injection (ICSI), artificial insemination with donor insemination (AID) or no treatment? We analysed this decision in 28 couples and investigated the role of the counsellor and the counselling process on the final decision of the couple. Ten counsellors from six fertility clinics in The Netherlands and Belgium were interviewed about their genetic counselling of couples dealing with microdeletions. The answers to the questionnaire were converted to 11 dichotomous variables. Of the 1627 tested men in the six centres, 37 (2.3%) had a microdeletion in the AZFc region, a subregion of the AZF region on the Y chromosome important for normal spermatogenesis. The decisions of 28 of them could be analysed. Most couples chose ICSI (79%). The remaining couples chose donor insemination (7%) or refrained from treatment (14%). Several variables, including the counselling procedure, the counsellor and the available treatments in the fertility centre, influenced the decision of the couple. In conclusion, most couples dealing with microdeletions in the AZF region choose ICSI. Several aspects of the process of genetic counselling appear to be related to the final decision.

Almost every female classic galactosemia patient develops primary ovarian insufficiency (POI) as a diet-independent complication of the disease. This is a major concern for patients and their parents, and physicians are often asked about possible options to preserve fertility. Unfortunately, there are no recommendations on fertility preservation in this group. The unique pathophysiology of classic galactosemia with a severely reduced follicle pool at an early age requires an adjusted approach. In this article recommendations for physicians based on current knowledge concerning galactosemia and fertility preservation are made. Fertility preservation is only likely to be successful in very young prepubertal patients. In this group, cryopreservation of ovarian tissue is currently the only available technique. However, this technique is not ready for clinical application, it is considered experimental and reduces the ovarian reserve. Fertility preservation at an early age also raises ethical questions that should be taken into account. In addition, spontaneous conception despite POI is well described in classic galactosemia. The uncertainty surrounding fertility preservation and the significant chance of spontaneous pregnancy warrant counseling towards conservative application of these techniques. We propose that fertility preservation should only be offered with appropriate institutional research ethics approval to classic galactosemia girls at a young prepubertal age.

Background Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI. Methods/Design We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI. Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included. Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total). An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm). Discussion The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women. Trial registration number Netherlands Trial register NTR1449

Contains fulltext : 109739.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. METHODS/DESIGN: Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. DISCUSSION: The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. TRIAL REGISTRATION: NTR2657.

Contains fulltext : 109856.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: In in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) treatment a large drop is present between embryo transfer and occurrence of pregnancy. The implantation rate per embryo transferred is only 30%. Studies have shown that minor intrauterine abnormalities can be found in 11-45% of infertile women with a normal transvaginal sonography or hysterosalpingography. Two randomised controlled trials have indicated that detection and treatment of these abnormalities by office hysteroscopy after two failed IVF cycles leads to a 9-13% increase in pregnancy rate. Therefore, screening of all infertile women for intracavitary pathology prior to the start of IVF/ICSI is increasingly advocated. In absence of a scientific basis for such a policy, this study will assess the effects and costs of screening for and treatment of unsuspected intrauterine abnormalities by routine office hysteroscopy, with or without saline infusion sonography (SIS), prior to a first IVF/ICSI cycle. METHODS/DESIGN: Multicenter randomised controlled trial in asymptomatic subfertile women, indicated for a first IVF/ICSI treatment cycle, with normal findings at transvaginal sonography. Women with recurrent miscarriages, prior hysteroscopy treatment and intermenstrual blood loss will not be included. Participants will be randomised for a routine fertility work-up with additional (SIS and) hysteroscopy with on-the-spot-treatment of predefined intrauterine abnormalities versus the regular fertility work-up without additional diagnostic tests. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months of IVF/ICSI treatment after randomisation. Secondary study outcome parameters are the cumulative implantation rate; cumulative miscarriage rate; patient preference and patient tolerance of a SIS and hysteroscopy procedure. All data will be analysed according to the intention-to-treat principle, using univariate and multivariate logistic regression and cox regression. Cost-effectiveness analysis will be performed to evaluate the costs of the additional tests as routine procedure. In total 700 patients will be included in this study. DISCUSSION: The results of this study will help to clarify the significance of hysteroscopy prior to IVF treatment. TRIAL REGISTRATION: NCT01242852.

Genetic factors can attribute to male subfertility. A case-control study was carried out to investigate familial occurrence of male subfertility and the phenotypic characteristics of familial male subfertility. The medical data and family histories of 253 severely subfertile men who were candidates for intracytoplasmic sperm injection were compared to the data from 243 randomly selected men. The prevalence of male fertility problems among brothers and maternal uncles of subfertile men was significantly higher than among controls (brothers 10.4% vs 0.5% and maternal uncles 1.7% vs 0.2%). The phenotypes of subfertile men with a positive family history more often showed normal levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) compared to the phenotypes of subfertile men with a negative family history. In addition, subfertile men with a positive family history had a lower percentage of motile sperm. Genetic aberrations, including a chromosomal abnormality or a microdeletion of the Y chromosome, were present in 13.8% of the severely subfertile men. Male subfertility appears to have a familial occurrence, especially among brothers and maternal uncles. Furthermore, examination of the data suggests that subfertile men with a familial occurrence of male subfertility more often have normal levels of FSH and LH and a lower percentage of motile sperm.

Family history is widely used in clinical practice and research in order to study genetic aspects of disorders in general, and is recommended as a tool in the assessment of male subfertility. Unfortunately, little is known about the validity of this tool. In this survey, we sent questionnaires to 474 randomly selected men aged 25-40 years in order to collect data on subfertility among them and their relatives. A nonresponder study was also conducted in order to evaluate selection bias. A personal interview was also performed with some respondents in order to gauge how well the data corresponded with questionnaires that were returned. Two hundred forty-three men (51.3%) completed the questionnaire. The responders reported a significantly lower prevalence of subfertility among their relatives than among themselves. Among brothers, the reported prevalence was about 5 times lower (ie, 3.6%) than among responders (15.3%). The nonresponder study and personal interviews showed that these differences were not caused by a selective response to the survey or by the use of a questionnaire instead of a personal interview. We conclude that subfertility among relatives is severely underestimated through the use of family history, probably because of the taboo of discussing subfertility. Knowledge of subfertility may spread selectively within families, causing substantial misclassification. Therefore, researchers and clinicians should be aware that an inquiry of family history is likely to lead to underestimation of subfertility among relatives.

Item does not contain fulltext OBJECTIVE: To report the familial occurrence of severe oligoasthenoteratozoospermia in a man and five male relatives related through their mothers. DESIGN: Case report. SETTING: University medical center. PATIENT(S): Six affected family members. MAIN OUTCOME MEASURE(S): Blood and semen samples were collected from all affected males and some of their healthy male relatives. Pedigree analysis and exclusion of X-linked disorder were done. RESULT(S): Analysis suggested that familial nonsyndromic male factor infertility was present. CONCLUSION(S): The family described in this report suggests the existence of an autosomal dominant trait of male infertility with sex-limited expression.

Item does not contain fulltext PURPOSE: Increased length of the CAG repeat in the androgen receptor gene may be related to male subfertility. Expansion to 38-62 CAG repeats leads to the neurodegenerative disorder with male infertility called Kennedy's disease. Recently it was suggested that slight expansion is related to male subfertility. In this study we investigated the association of male subfertility with the length of CAG repeats in the androgen receptor. MATERIALS AND METHODS: CAG repeat length in the androgen receptor gene was investigated in 75 subfertile men, who were mainly candidates for intracytoplasmic sperm injection. Sperm parameters varied from azoospermia to severe oligoasthenoteratozoospermia. The control group consisted of 70 men who predominantly had bladder cancer. DNA was isolated from peripheral blood and genotyping was performed with polymerase chain reaction based methods. RESULTS: No statistically significant difference in the mean length of the CAG repeat plus or minus standard deviation was noted in subfertile men and controls (22.2 +/- 3.1 and 21.7 +/- 3.4, respectively). The length of the CAG repeat in the androgen receptor was not related to the degree of impaired spermatogenesis or clinical characteristics of the subfertile men. CONCLUSIONS: Increased length of CAG repeats in the androgen receptor gene is not a risk factor for male subfertility.

Item does not contain fulltext Microdeletions of the azoospermia factor (AZF) region of the Y chromosome occur in between 1 and 29% of oligozoospermic and azoospermic men, and most deletions are found in the AZFc region. These men can father children when intracytoplasmic sperm injection (ICSI) is used, but the success rate is unclear. Thus, the success rate of 19 ICSI treatments in eight couples with a microdeletion in the AZFc region of the Y chromosome was analysed retrospectively. These were compared with a control group of 239 ICSI treatments in 107 couples undergoing ICSI treatment with ejaculated spermatozoa. The fertilization rate was significantly lower in the group of Y-deleted men (55%; 95% CI: 41-69%) compared with controls (71%; 95% CI: 67-74%; P < 0.01). The embryo quality was also significantly poorer among Y-deleted men (P

Intracytoplasmic sperm injection (ICSI) has caused a revolution in the treatment of severe male infertility. The direct injection of a single spermatozoon into the oocyte enables pregnancies in couples of whom the man has severe oligozoospermia or even azoospermia. This therapeutic revolution has unfortunately not been accompanied by a revolution in the knowledge of the etiology of the underlying problem. There are indications that genetic factors play a major role, and this may have serious consequences for the offspring.

Preimplantation genetic diagnosis (PGD) is a reproductive option for BRCA1/2 mutation carriers wishing to avoid transmission of the predisposition for hereditary breast and ovarian cancer (HBOC) to their offspring. Embryos obtained by in vitro fertilisation (IVF/ICSI) are tested for the presence of the mutation. Only BRCA-negative embryos are transferred into the uterus. The suitability and outcome of PGD for HBOC are evaluated in an observational cohort study on treatments carried out in two of Western-Europe's largest PGD centres from 2006 until 2012. Male carriers, asymptomatic female carriers and breast cancer survivors were eligible. If available, PGD on embryos cryopreserved before chemotherapy was possible. Generic PGD-PCR tests were developed based on haplotyping, if necessary combined with mutation detection. 70 Couples underwent PGD for BRCA1/2. 42/71 carriers (59.2 %) were female, six (14.3 %) of whom have had breast cancer prior to PGD. In total, 145 PGD cycles were performed. 720 embryos were tested, identifying 294 (40.8 %) as BRCA-negative. Of fresh IVF/PGD cycles, 23.9 % resulted in a clinical pregnancy. Three cycles involved PGD on embryos cryopreserved before chemotherapy; two of these women delivered a healthy child. Overall, 38 children were liveborn. Two BRCA1 carriers were diagnosed with breast cancer shortly after PGD treatment, despite negative screening prior to PGD. PGD for HBOC proved to be suitable, yielding good pregnancy rates for asymptomatic carriers as well as breast cancer survivors. Because of two cases of breast cancer shortly after treatment, maternal safety of IVF(PGD) in female carriers needs further evaluation.