Quality of integrated female oncofertility care is suboptimal: A patient-reported measurement.

BACKGROUND: Clinical practice guidelines recommend to inform female cancer patients about their infertility risks due to cancer treatment. Unfortunately, it seems that guideline adherence is suboptimal. In order to improve quality of integrated female oncofertility care, a systematic assessment of current practice is necessary. METHODS: A multicenter cross-sectional survey study in which a set of systematically developed quality indicators was processed, was conducted among female cancer patients (diagnosed in 2016/2017). These indicators represented all domains in oncofertility care; risk communication, referral, counseling, and decision-making. Indicator scores were calculated, and determinants were assessed by multilevel multivariate analyses. RESULTS: One hundred twenty-one out of 344 female cancer patients participated. Eight out of 11 indicators scored below 90% adherence. Of all patients, 72.7% was informed about their infertility, 51.2% was offered a referral, with 18.8% all aspects were discussed in counseling, and 35.5% received written and/or digital information. Patient's age, strength of wish to conceive, time before cancer treatment, and type of healthcare provider significantly influenced the scores of three indicators. CONCLUSIONS: Current quality of female oncofertility care is far from optimal. Therefore, improvement is needed. To achieve this, improvement strategies that are tailored to the identified determinants and to guideline-specific barriers should be developed.

Exploration of fertility and early menopause related information needs and development of online information for young breast cancer survivors.

BACKGROUND: Approximately half of premenopausal women diagnosed with breast cancer desire to conceive after they finish treatment. Counseling about the risk of infertility prior to cancer treatment has been proven to improve quality of life after cancer treatment. As a result of this, guidelines focus on informing women on this topic prior to treatment. However, it is equally important to provide fertility related information after primary treatment has been completed, when the wish to conceive might become actual. Therefore, the aim of this study was to identify the fertility and early menopause related information needs of young breast cancer survivors and to design, develop and implement online information material with input of stakeholders. METHODS: A phenomenological qualitative study consisting of four phases was performed: identification of information needs through semi-structured interviews from a professional perspective (1) and a patient perspective (2). Exploration of stakeholders perspective regarding development and implementation of online information material (3) and development and implementation of the information material (4). RESULTS: Professionals indicated that there are no guidelines regarding the provision of fertility related information during cancer survivorship. Survivors reported unmet information needs. Women identified the following as most important information needs (a) fertility preservation options, (b) the risk of menopause or infertility, and (c) long term consequences of early menopause. A wide range of stakeholders involved in breast cancer care were interviewed. Based on their proposed design the information material was implemented on a nationwide website aiming at informing and supporting breast cancer patients. CONCLUSIONS: Fertility and early menopause related information needs of young breast cancer survivors and their professionals were identified. Information material has been designed, developed and nationally implemented. This way, professionals in breast cancer care are provided with an information tool that helps them meet the information needs and preferences of their patients.

Complete Purging of Ewing Sarcoma Metastases from Human Ovarian Cortex Tissue Fragments by Inhibiting the mTORC1 Signaling Pathway.

Restoration of fertility by autologous transplantation of ovarian cortex tissue in former cancer patients may lead to the reintroduction of malignancy via the graft. Pharmacological ex vivo purging of ovarian cortex fragments prior to autotransplantation may reduce the risk of reseeding the cancer. In this study we have investigated the capacity of Everolimus (EVE), an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, to eradicate Ewing's sarcoma (ES) from ovarian tissue by a short-term ex vivo treatment. Exposure of experimentally induced ES tumor foci in ovarian tissue to EVE for 24 h completely eliminated the malignant cells without detrimental effects on follicle morphology, survival or early folliculogenesis. This indicates that effective purging of ovarian cortex tissue from contaminating ES tumor foci is possible by short-term exposure to EVE.

Long-Term Risk of Ovarian Cancer and Borderline Tumors After Assisted Reproductive Technology.

BACKGROUND: Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. METHODS: This nationwide cohort study comprises 30 625 women who received ovarian stimulation for ART in 1983-2000 and 9988 subfertile women not treated with ART. Incident invasive and borderline ovarian tumors were ascertained through linkage with the Netherlands Cancer Registry and the Dutch Pathology Registry until July 2018. Ovarian tumor risk in ART-treated women was compared with risks in the general population and the subfertile non-ART group. Statistical tests were 2-sided. RESULTS: After a median follow-up of 24 years, 158 invasive and 100 borderline ovarian tumors were observed. Ovarian cancer risk in the ART group was increased compared with the general population (standardized incidence ratio [SIR] = 1.43, 95% confidence interval [CI] = 1.18 to 1.71) but not when compared with the non-ART group (age- and parity-adjusted hazard ratio [HR] = 1.02, 95% CI = 0.70 to 1.50). Risk decreased with higher parity and with a larger number of successful ART cycles (resulting in childbirth, Ptrend = .001) but was not associated with the number of unsuccessful ART cycles. Borderline ovarian tumor risk was increased in ART-treated women compared with the general population (SIR = 2.20, 95% CI = 1.66 to 2.86) and with non-ART women (HR = 1.84, 95% CI = 1.08 to 3.14). Risk did not increase with more ART cycles or longer follow-up time. CONCLUSIONS: Increased ovarian cancer risk in ART-treated women compared with the general population is likely explained by nulliparity rather than ART treatment. The increased risk of borderline ovarian tumors after ART must be interpreted with caution because no dose-response relationship was observed.

Development and testing of a tailored online fertility preservation decision aid for female cancer patients.

BACKGROUND: Decision making regarding future fertility can be very difficult for female cancer patients. To support patients in decision making, fertility preservation decision aids (DAs) are being developed. However, to make a well-informed decision, patients need personalized information tailored to their cancer type and treatment. Tailored cancer-specific DAs are not available yet. METHODS: Our DA was systematically developed by a multidisciplinary steering group (n = 21) in an iterative process of draft development, three rounds of alpha testing, and revisions. The drafts were based on current guidelines, literature, and patients' and professionals' needs. RESULTS: In total, 24 cancer-specific DAs were developed. In alpha testing, cancer survivors and professionals considered the DA very helpful in decision making, and scored an 8.5 (scale 1-10). In particular, the cancer-specific information and the tool for recognizing personal values were of great value. Revisions were made to increase readability, personalization, usability, and be more careful in giving any false hope. CONCLUSIONS: A fertility preservation DA containing cancer-specific information is important in the daily care of female cancer patients and should be broadly available. Our final Dutch version is highly appraised, valid, and usable in decision making. After evaluating its effectiveness with newly diagnosed patients, the DA can be translated and adjusted according to (inter)national guidelines.

Key recommendations for high-quality female oncofertility care based on international clinical practice guidelines.

RESEARCH QUESTION: Which guideline-based key recommendations can be selected for high-quality female oncofertility care? DESIGN: The Delphi method was used to select a set of key recommendations for female oncofertility care. First, recommendations from (inter)national clinical practice guidelines were selected in four domains: risk communication, referral, counselling and decision-making. Thereafter, they were scored, per domain, on their importance for high-quality oncofertility care by a multidisciplinary, oncofertility expert panel, consisting of patients, referrers and counsellors, in two Delphi rounds. Finally, the selected key recommendations were presented for approval in a third round. Differences in perspectives between subgroups of the expert panel were analysed. RESULTS: A panel of 86 experts was asked to select key recommendations for high-quality oncofertility care. Eleven key recommendations were selected. Key recommendations in the domains risk communication and referral focused on information provision and offering referral to a reproductive specialist to female cancer patients. With the counselling domain, key recommendations focused on all aspects of counselling, including different methods, safety, pros and cons. In the decision-making domain, key recommendations focused on shared decision-making and supporting the decision with written information. The final set of key recommendations was approved by 91% of the experts. Differences in perspectives were found between subgroups. Patients found recommendations on decision-making and information provision more important. CONCLUSION: A set of 11 key recommendations for high-quality female oncofertility care was selected by a multidisciplinary expert panel. The involvement of the perspectives of patients, referrers and counsellors led to this valid, acceptable and credible set of key recommendations.

Long-term follow-up after successful Essure sterilization: evaluation of patient satisfaction, symptoms, and the influence of negative publicity.

OBJECTIVE: To evaluate long-term patient satisfaction and symptoms after successful Essure sterilization and the influence of negative publicity on patients' opinion. DESIGN: Survey study. SETTING: Two nonacademic hospitals. PATIENT(S): All 924 women who underwent successful Essure sterilization between 2003 and 2009. INTERVENTION(S): A questionnaire was sent between 2008 and 2010 and in 2018. MAIN OUTCOME MEASURE(S): Patient satisfaction, symptoms, and the influence of negative publicity on patients' opinion of Essure sterilization. RESULT(S): After a median follow-up of 29 months, 689 of 924 women (74.6%) responded to the first questionnaire. Of these women, 673 of 689 (97.7%) was satisfied with their Essure sterilization and 607 of 689 (88.1%) recommended Essure sterilization to other women. Of the 689 women, 71 (10.3%) reported having symptoms after Essure sterilization for which they had to consult a physician. Most reported symptoms were menstrual and abdominal pain. After a median follow-up of 144 months, 317 of 577 women (54.9%) responded to the second questionnaire. A total of 157 of 317 (49.5%) women reported having symptoms and in 51 (16.1%) women the Essure devices were surgically removed. Among these women, 29 (57%) reported that their symptoms disappeared afterward and 33 of 51 (65%) women reported that negative publicity had somehow affected their decision to undergo surgery. CONCLUSION(S): After a follow-up of 144 months, approximately 50% of the women reported having symptoms and 16% underwent Essure removal surgery. Publicity had a negative influence on patients' opinion of Essure sterilization, as well as an effect on the decision-making process regarding Essure removal. These data are important when facing women with possible Essure-related complaints.

Improved detection of CFTR variants by targeted next-generation sequencing in male infertility: a case series.

RESEARCH QUESTION: Congenital bilateral absence of vas deferens (CBAVD) is characterized by 'obstructive azoospermia' in male patients with primary infertility. In the routine clinical workup of infertile men, patients with an absence of vas deferens are screened for CFTR variants. However, current genetic testing panels do not cover all variants, missing some CBAVD cases. Here, CFTR testing was explored by targeted next-generation sequencing (NGS) to improve variant detection. DESIGN: Five individuals with heterozygous pathogenic CFTR variants were identified using targeted NGS in a cohort of 1112 idiopathic infertile men with azoospermia or severe oligozoospermia. Pre-screening exclusion criteria were CBAVD by clinical examination with positive CFTR sequence analysis as part of routine fertility workup. RESULTS: Cases 1, 2 and 3 presented with CBAVD after which CFTR screening by mutation panel analysis was negative. Case 4 presented with congenital unilateral absence of vas deferens, after which CFTR panel analysis identified a heterozygous p.(Phe508del) variant. Case 5 presented with a palpable vas deferens so CFTR panel analysis was not offered. In all five men, targeted NGS revealed additional pathogenic variants: p.(Arg117Cys) and p.(Arg1158*) (case 1); p.(Asp110His) and p.(Ser945Leu) (case 2); p.(Arg248Thr) and p.(Phe508Cys) (case 3); p.(Gly463Ser) (case 4); p.(Phe508del) (case 4 and 5); and p.(Arg117His) (case 5). CONCLUSIONS: Targeted NGS led to the detection of five infertile men with CFTR variants who would otherwise have remained undiagnosed after routine genetic screening during the fertility workup for azoospermia or severe oligozoospermia. Given the wide availability of affordable targeted NGS, the data suggest that full gene analysis, and not mutation panels, should be considered to screen CFTR in azoospermic men.

Enhancing the safety of ovarian cortex autotransplantation: cancer cells are purged completely from human ovarian tissue fragments by pharmacological inhibition of YAP/TAZ oncoproteins.

STUDY QUESTION: Is it possible to eliminate metastasized cancer cells from ovarian cortex fragments prior to autotransplantation without compromising the ovarian tissue or follicles? SUMMARY ANSWER: Ex vivo pharmacological inhibition of YAP/TAZ by Verteporfin enabled us to efficiently eradicate experimentally induced small tumours, derived from leukaemia and rhabdomyosarcoma, from human ovarian tissue fragments. WHAT IS KNOWN ALREADY: Autotransplantation of ovarian tissue fragments that contain metastasized tumour cells may reintroduce the malignancy to the recipient. In order to enhance safety for the patient there is a strong need for protocols that effectively purges the ovarian tissue from malignant cells ex vivo prior to transplantation, without compromising ovarian tissue integrity. STUDY DESIGN, SIZE, DURATION: Tumour foci were experimentally induced in human ovarian cortex tissue fragments derived from at least three patients by micro-injection of cancer cell lines. Next, the tissue fragments were cultured to allow formation of metastasis-like structures followed by a 24 h ex vivo treatment with the YAP/TAZ inhibitor Verteporfin to eradicate the cancer cells. A control treatment was included in all experiments. The purged ovarian cortex fragments were cultured for an additional 6 days to allow any possibly surviving cancer cells to establish new metastatic foci. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human ovarian tissue was obtained after female-to-male sex reassignment surgery. Human rhabdomyosarcoma, leukeamia, breast cancer and Ewing's sarcoma cell lines were utilized for the induction of tumour foci. Tumour specific (immuno)histochemistry and RT-PCR were used for the detection of residual cancer cells after ex vivo treatment. Ovarian tissue and follicle integrity after exposure to Verteporfin was evaluated by histology, a follicular viability assay and a glucose uptake assay. MAIN RESULTS AND THE ROLE OF CHANCE: Metastasized rhabdomyosarcoma and leukaemia cells could be effectively purged from ovarian cortex tissue by a 24 h ex vivo treatment with Verteporfin, while breast cancer and Ewing's sarcoma did not respond to this treatment. Ovarian tissue integrity was not affected by purging, as no statistically significant difference (P > 0.05) was observed in the percentage of morphologically normal follicles, percentage of follicles with apoptotic cells, follicular viability or glucose uptake between the control treated ovarian cortex and Verteporfin treated ovarian cortex. LIMITATIONS, REASONS FOR CAUTION: Our tumour model is based on growth of human cancer cell lines. It is unclear whether these cells reflect the behaviour of malignant cells that have metastasized to the ovary during natural disease progression. Furthermore, the functionality of the ovarian tissue after ex vivo treatment requires further investigation in vivo. WIDER IMPLICATIONS OF THE FINDINGS: The results indicate that ex-vivo tumour cell purging of human ovarian cortex fragments intended for fertility preservation purposes is feasible by short-term pharmacological treatment. Effective purging of the ovarian cortex tissue enhances safety of ovarian cortex autotransplantation for the patient. This increases the likelihood that this form of fertility restoration may become an option for patients with malignancies for which ovarian cortex transplantation is currently considered unsafe. STUDY FUNDING/COMPETING INTEREST(S): Unconditional funding was received from Merck B.V. The Netherlands (Number 2016-FERT-1) and the foundation 'Radboud Oncologie Fonds' (Number KUN 00007682). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: NA.

Clinical practice guidelines for fertility preservation in young women undergoing gonadotoxic treatment: an overview and critical appraisal of methodological quality and content.

RESEARCH QUESTION: What is the methodological quality and content of internationally available clinical practice guidelines (CPGs) on fertility preservation (FP) care in adult women? DESIGN: Internationally available CPGs on FP care in adult women were identified after conducting an extensive literature search and consulting (inter)national key experts. The methodological quality of the CPGs was appraised by an (inter)national panel of experts using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. The content of the best CPGs, scoring ≥60% for the domain 'Rigour of development' of the AGREE II instrument, was extracted and categorized according to their topic. RESULTS: Thirty of the 1808 documents found were included. After consulting (inter)national key experts, 30 CPGs were included, six of which scored ≥60% for their 'Rigour of development'. The number of FP-related topics discussed by these six CPGs ranged from 4 to 12. The number of recommendations provided by the CPGs on these topics varied. The number of topics to which ≥5 recommendations were dedicated ranged from 0 to 4 between CPGs. CONCLUSION: CPGs on the subject of FP care are available, but there is room for improvement in quality and content. Although written for use in daily practice, the CPGs can also be used to develop quality indicators to monitor the quality of current FP care or to evaluate future improvement initiatives.

Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer.

IMPORTANCE: Previous studies of breast cancer risk after in vitro fertilization (IVF) treatment were inconclusive due to limited follow-up. OBJECTIVE: To assess long-term risk of breast cancer after ovarian stimulation for IVF. DESIGN, SETTING, AND PARTICIPANTS: Historical cohort (OMEGA study) with complete follow-up through December 2013 for 96% of the cohort. The cohort included 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women starting other fertility treatments between 1980 and 1995 (non-IVF group) from all 12 IVF clinics in the Netherlands. The median age at end of follow-up was 53.8 years for the IVF group and 55.3 years for the non-IVF group. EXPOSURES: Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was collected from medical records and through mailed questionnaires. MAIN OUTCOMES AND MEASURES: Incidence of invasive and in situ breast cancers in women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Breast cancer risk in the IVF group was compared with risks in the general population (standardized incidence ratios [SIRs]) and the non-IVF group (hazard ratios [HRs]). RESULTS: Among 25,108 women (mean age at baseline, 32.8 years; mean number of IVF cycles, 3.6), 839 cases of invasive breast cancer and 109 cases of in situ breast cancer occurred after a median follow-up of 21.1 years. Breast cancer risk in IVF-treated women was not significantly different from that in the general population (SIR, 1.01 [95% CI, 0.93-1.09]) and from the risk in the non-IVF group (HR, 1.01 [95% CI, 0.86-1.19]). The cumulative incidences of breast cancer at age 55 were 3.0% for the IVF group and 2.9% for the non-IVF group (P = .85). The SIR did not increase with longer time since treatment (≥20 years) in the IVF group (0.92 [95% CI, 0.73-1.15]) or in the non-IVF group (1.03 [95% CI, 0.82-1.29]). Risk was significantly lower for those who underwent 7 or more IVF cycles (HR, 0.55 [95% CI, 0.39-0.77]) vs 1 to 2 IVF cycles and after poor response to the first IVF cycle (HR, 0.77 [95% CI, 0.61-0.96] for <4 vs ≥4 collected oocytes). CONCLUSIONS AND RELEVANCE: Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, IVF treatment compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years. Breast cancer risk among IVF-treated women was also not significantly different from that in the general population. These findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women.

Women's adjustment trajectories during IVF and impact on mental health 11-17 years later.

STUDY QUESTION: Do patients present different adjustment trajectories during and after IVF treatment? SUMMARY ANSWER: Most women show resilient trajectories during and after IVF treatment but 37% show temporary or chronic maladjustment during IVF and 10% are maladjusted 11-17 years after treatment. WHAT IS KNOWN ALREADY: Research on patient psychosocial adjustment during treatment has contributed to identifying the most distressful stages of IVF treatment and profiling patients at risk for emotional maladjustment at these specific stages. This knowledge is currently driving the deliverance of psychosocial care at fertility clinics by tailoring it to patients' risk profiles and specific treatment stages. However, current care does not take into consideration how individuals adjust across the entire treatment pathway. This can be assessed by profiling individual adjustment trajectories. STUDY DESIGN, SIZE, DURATION: A longitudinal cohort study with five assessment moments that combines data from two different studies, the STRESSIVF and OMEGA projects. Participants enrolled in the STRESSIVF study (started IVF in 1998-2000) were assessed before and after the first IVF treatment cycle and 6 months and 2.5 years after the last IVF cycle. A subset participated in the OMEGA project (started IVF in 1995-2000) and reported on their mental health 11-17 years after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three hundred and forty-eight women participated in the STRESSIVF project and 108 of these in the OMEGA. Anxiety was measured with the State and Trait Anxiety Inventory, depression with the Beck Depression Inventory and mental health with the Mental Health Inventory. Latent class growth mixed modelling was carried out to identify distinct anxiety and depression trajectories over the four STRESSIVF study assessment moments. Multinominal logistic regressions were conducted to investigate predictors of trajectory membership, and stepwise linear regressions were performed to investigate if adjustment trajectories predicted mental health 11-17 years after IVF treatment. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 67 and 86% of women showed normal levels of anxiety and depression, respectively, throughout treatment (resilient trajectories), 24 and 33% experienced anxiety and depression only during treatment (recovery trajectories), 4.6 and 4.9% experienced anxiety and depression only after treatment (delayed trajectories), and 4.3% showed chronic anxiety (chronic trajectory, not identified for depression). Non-resilient trajectories were associated with unsuccessful treatment, marital dissatisfaction, lack of social support and negative infertility cognitions. One in 10 women had a delayed or chronic trajectory and these trajectories predicted serious mental health impairment 11-17 years after treatment. LIMITATIONS, REASONS FOR CAUTION: The study only focuses on women. In the OMEGA project adjustment was assessed using a mental health measure. Although we could investigate how trajectories predicted mental health, it would have been preferable to map anxiety and depression trajectories up to 11-17 years after treatment. Missing analysis showed selective dropout from the study but this was accounted for by using mixed models and imputation procedures. Finally, data on other life stressors were not collected; therefore any contribution from these events cannot be assessed. WIDER IMPLICATIONS OF THE FINDINGS: Fertility health-care providers have been called upon considering their responsibility in supporting patients in the aftermath of treatment. Results show it is possible to profile different groups of at-risk women at the start of the treatment and tailor psychosocial support to risk profile to promote health adjustment during treatment and thereafter. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from the Dutch Cancer Society (2006-3631) and the Praeventiefonds (28-3012). No competing interests exist.

Beneficial value of testicular sperm extraction-AgarCyto in addition to the standard testicular biopsy for diagnosis of testicular germ cell tumors in nonobstructive azoospermia.

OBJECTIVE: To study whether immunohistochemical detection of germ cell neoplasia in situ (GCNIS) in AgarCytos, made of the remnants of the testicular sperm extraction (TESE) specimen, is equally accurate as in a standard testicular biopsy. DESIGN: Prospective cohort study performed between January 2013 and May 2014. SETTING: University hospital. PATIENT(S): All men with nonobstructive azoospermia (n = 197) undergoing a urological work-up followed by a unilateral or bilateral TESE for fertility treatment were consecutively included. INTERVENTION(S): An AgarCyto was made of the remnants of these TESE biopsies. Simultaneously a standard testicular biopsy was performed. For all cases a routine hematoxylin-eosin (H & E) staining was performed as well as immunohistochemistry (PLAP and OCT3/4) to detect GCNIS. MAIN OUTCOME MEASURE(S): The presence or absence of GCNIS in the TESE-AgarCyto and standard testicular biopsy. RESULT(S): Six men (3.0%) were diagnosed with a germ cell (pre)malignancy by immunohistochemistry. No cases were encountered in which the TESE-AgarCyto was negative, whereas the standard testicular biopsy was positive for GCNIS. In one case the TESE-AgarCyto detected a premalignancy that was missed by standard testicular biopsy. Unfortunately a standard testicular biopsy was not available for direct comparison in 50% of the GCNIS-positive patients due to various reasons. CONCLUSION(S): Because GCNIS is heterogeneously distributed in the testis, the TESE-AgarCyto can diagnose GCNIS even when the standard testicular biopsy is negative. Direct comparison of accuracy, however, is not reliable due to the low prevalence of GCNIS and the lack of a standard biopsy when an orchidectomy was performed simultaneously with TESE.

Effect of maternal and treatment-related factors on the prevalence of birth defects after PESA-ICSI and TESE-ICSI: a retrospective cohort study.

INTRODUCTION: We performed a retrospective cohort study with the aim to evaluate the effect of maternal and treatment-related factors on the prevalence of birth defects after intracytoplasmic sperm injection (ICSI) using percutaneous epididymal sperm aspiration (PESA) and testicular sperm extraction (TESE). MATERIAL AND METHODS: 643 newborns born after PESA-ICSI (n = 406) and TESE-ICSI (n = 237) in Radboud University Medical Center, after a gestational age of 12 weeks, 1 January 2002-1 January 2011 and 1 March-1 November 2014, respectively, were included in this study. Three sources of data were used for analysis: questionnaires, national obstetrics registration forms, and a lab-database of all ICSI treatments. Data were analyzed using generalized estimating equations and logistic regression analysis. RESULTS: The prevalence of major birth defects in newborns born after PESA-ICSI was 6.9% and after TESE-ICSI was 5.9% (odds ratio 0.89, 95% confidence interval 0.46-1.75). No significant association was found between maternal or treatment-related factors and the prevalence of birth defects. CONCLUSIONS: We found a similar overall prevalence of birth defects in newborns born after PESA-ICSI and TESE-ICSI. The maternal and treatment-related factors investigated did not show a significantly increased cumulative risk of birth defects.

Predictors and risk model development for menopausal age in fragile X premutation carriers.

PURPOSE: Women who carry a fragile X mental retardation 1 premutation are at risk for fragile X-associated primary ovarian insufficiency and should be counseled for a potentially reduced fertility. Multiple factors can affect the age of onset and severity of fragile X-associated primary ovarian insufficiency. In this study, we assessed the predictive power of several factors with menopausal age, a surrogate measure of onset of fragile X-associated primary ovarian insufficiency. METHODS: Genetic, environmental, and reproductive factors were analyzed by Cox proportional hazard models in 1068 women, 385 of fragile X families ascertained through the Nijmegen study and 683 of fragile X families or general population families ascertained through the Atlanta study. RESULTS: The highest association with menopausal age among fragile X mental retardation 1 premutation carriers was found for risk index by CGG repeat size (hazard ratio, 1.43) and smoking (hazard ratio, 1.34). Women from the Nijmegen cohort showed an overall lower age at menopause onset, for which a correction was made. A prediction model based on these two parameters, mean menopausal age of first-degree relatives with the same mutation status and the correction for ascertainment site, estimated the probability of becoming postmenopausal for premutation carriers, with a margin of 7-10%. CONCLUSION: We conclude that this model serves as a first step toward clinical application of fragile X-associated primary ovarian insufficiency prediction.

Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure.

OBJECTIVE: To describe general and sexual well-being in women with premature ovarian failure (POF) and to investigate whether there is a relationship between androgen levels and sexual functioning. DESIGN: Women with POF and healthy volunteers with regular menstrual cycles participated. Participants completed a written questionnaire and underwent hormonal screening. The questionnaire included standardized measures: the Questionnaire for Screening Sexual Dysfunctions, the Shortened Fatigue Questionnaire, and the Symptom Check List-90. Serum hormone measurements included estradiol, total testosterone, bioavailable testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. RESULTS: Eighty-one women with POF and 68 control women participated in the study. Compared with control women, women with POF reported more complaints of anxiety, depression, somatization, sensitivity, hostility, and psychological distress. Overall women with POF were less satisfied with their sexual life. They had fewer sexual fantasies and masturbated less frequently. Sexual contact was associated with less sexual arousal, reduced lubrication, and increased genital pain. However, the frequency of desire to have sexual contact and the frequency of actual sexual contact with the partner did not differ between women with POF and control women. Women with POF had lower levels of estradiol, total testosterone, and androstenedione. Multiple regression analysis revealed that androgen levels had only a weak influence on sexual functioning; higher total testosterone levels were associated with increased frequency of desire for sexual contact, and higher androstenedione levels were associated with elevated frequency of sexual contact. CONCLUSIONS: Women with POF have diminished general and sexual well-being and are less satisfied with their sexual lives than control women. Although women with POF had lower androgen levels, we did not find an important independent role for androgens in various aspects of sexual functioning.

Less effect of intranasal than oral hormone therapy on factors associated with venous thrombosis risk in healthy postmenopausal women.

OBJECTIVE: To compare the effects of intranasal and oral administration of 17beta-estradiol (E2) and norethisterone(acetate) [NET(A)] in healthy postmenopausal women on activated protein C (APC) resistance and other hemostatic parameters associated with venous thrombosis. METHODS AND RESULTS: In this 2-center, randomized, double-blind, 1-year trial, 90 postmenopausal women (56.6+/-4.7 years of age) received daily either an intranasal spray with 175 microg/275 microg E2/NET (n=47) or 1 mg/0.5 mg oral E2/NETA (n = 43). Normalized APC sensitivity ratios (nAPCsr) were determined with a thrombin generation-based APC resistance test. After 1 year, the increase in nAPCsr was smaller in the intranasal than in the oral group: 11% (95% CI, 1% to 22%) versus 53% (95% CI, 37% to 72%). Overall, the decrease in antithrombin and increase in prothrombin fragment 1+2 (F1+2) were smaller and the decrease in free protein S larger in the intranasal compared with the oral group after 1 year. In both groups, the decreases in protein C and prothrombin, and the increase in d-dimer were similar. CONCLUSIONS: Compared with oral E2/NETA therapy, intranasal administration of E2/NET had less effect on APC resistance and on a number of other parameters associated with venous thrombosis. This observation suggests the possibility of a lower venous thrombosis risk for intranasal E2/NET compared with oral therapy.

Prevalence of ovarian adrenal rest tumours and polycystic ovaries in females with congenital adrenal hyperplasia: results of ultrasonography and MR imaging.

The aim of the investigation was to assess the prevalence of ovarian adrenal rest tumours and polycystic ovaries in female patients with congenital adrenal hyperplasia (CAH). Thirteen female CAH patients (median age 19.8 years, range 14.8-23.5 years) underwent transvaginal (n=6) or transabdominal (n=7) ultrasonography by a gynaecologist and MR imaging (n=13) of the ovaries (pre and post contrast-enhanced T1- and T2-weighted images). Ovarian adrenal rest tumours were defined as small hypoechoic and multifocal nodules on ultrasound and isointense lesions on T1- and hypointense on T2-weighted MR images (derived from characteristics of testicular adrenal rest tumours). Polycystic ovaries were defined as the presence of > or = 10 follicles arranged peripherally around or scattered throughout increased stroma. No ovarian adrenal rest tumours were found either on ultrasound, or by MR imaging. Polycystic ovaries were found in 2 of the 13 patients (15.4%), both with ultrasound and MR. No ovarian adrenal rest tumours were detected in these female CAH patients, which suggests that ovarian adrenal rest tumours in CAH females are rare. The prevalence of polycystic ovaries corresponded to that in the general population. From these results, we would suggest that routine ovarian imaging in CAH females is not indicated. However, when ovarian dysfunction is present, ovarian imaging is advised, first by ultrasonography, to detect ovarian adrenal rest tumours or polycystic ovaries.

Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

UNLABELLED: Fertility in women with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency appears to be reduced. The purpose of this review is to summarize the reported evidence about subfertility in women with CAH and to review the causes of reduced fertility. Compared with a non-CAH female population, pregnancy and live-birth rates are severely reduced in salt-wasting patients, mildly reduced in simple virilizing patients, and normal in nonclassical patients. Several factors have been suggested to contribute to the impaired fertility in CAH females: adrenal overproduction of androgens and progestins (17-hydroxyprogesterone and progesterone), ovarian hyperandrogenism, polycystic ovary syndrome, ovarian adrenal rest tumors, neuroendocrine factors, genital surgery, and psychological factors such as delayed psychosexual development, reduced sexual activity and low maternal feelings. It is obvious that these factors are interrelated. Improving endocrine, surgical, and psychological management could contribute to improving fertility chances in these patients. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader will be able to define the various types of CAH, to describe the fertility issues in the CAH patients, to outline the various other causes of hyperandrogenism, and to list the treatment options for the patient with CAH.