The (cost-) effectiveness Of Surgical excision of Colorectal endometriosis compared to ART treatment trAjectory (TOSCA study) - a study protocol.

Currently, the optimal treatment to increase the chance of pregnancy and live birth in patients with colorectal endometriosis and subfertility is unknown. Evidence suggests that that both surgery and in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are effective in improving live birth rate (LBR) among these women. However, the available evidence is of low quality, reports highly heterogeneous results, lacks direct comparison between both treatment options and does not assess whether a combination strategy results in a higher LBR compared to IVF/ICSI-only treatment. Additionally, the optimal timing of surgery within the treatment trajectory remains unclear. The primary objective of the TOSCA study is to assess the effectiveness of surgical treatment (potentially combined with IVF/ICSI) compared to IVF/ICSI-only treatment to increase the chance of an ongoing pregnancy resulting in a live birth in patients with colorectal endometriosis and subfertility, measured by cumulative LBR. Secondary objectives are to assess and compare quality of life and cost-effectiveness in both groups. Patients will be followed for 40 months after inclusion or until live birth. The TOSCA study is expected to be completed in 6 years.

Discriminatory Value of Steroid Hormones on Polycystic Ovary Syndrome and Clustering of Hyperandrogenism and Metabolic Factors.

OBJECTIVE: We determined (1) if 11-oxygenated androgens better identify polycystic ovary syndrome (PCOS) diagnosis in women with obesity compared to total or free testosterone (T) and free androgen index; (2) how biochemical hyperandrogenism and metabolic factors cluster in a cohort of women with infertility and obesity. METHODS: Women with obesity and PCOS comprised the study group (N = 132). Ovulatory women with obesity and idiopathic, tubal or male factor infertility were the control group (N = 83). Steroid hormones were measured by means of liquid chromatography tandem mass spectrometry. Receiver operating characteristic curves and principal component analysis were used. RESULTS: Women with obesity and PCOS had higher 11-ketotestosterone (11 KT) (1.22 nmol/L [0.84; 1.65] vs 1.05 [0.78; 1.35], P = .04) compared to controls, but not 11ß-hydroxyandrostenedione 4.30 [2.87; 5.92] vs 4.06 [3.22; 5.73], P = .44). 11-ketotestosterone (area under the curve: 0.59) did not better discriminate PCOS in women with obesity compared to: total T (0.84), free T (0.91), and free androgen index (0.85). We identified 4 principal components (PCs) in the PCOS group (72.1% explained variance): (1) insulin resistance status; (2) blood pressure; (3) obesity; (4) androgen status and 4 PCs in the control group (68.7% explained variance) with variables representing metabolism being dispersed in component 2, 3, and 4. CONCLUSIONS: Eleven-oxygenated androgens do not aid in the diagnosis of PCOS in women with obesity. Insulin resistance is the strongest PC in the PCOS group. There is no major dominant characteristic that defines obese non-PCOS women.

[Endometriosis, you won't see it until you think of it]. / Endometriose, je gaat het pas zien als je het doorhebt.

For many people, including health care providers, endometriosis is an unknown disease. It can present in many different ways, making it difficult to diagnose. As a result the diagnosis is often missed and the right treatment cannot be started. This delay can lead to a huge reduction in the quality of life. Based on three cases of endometriosis we show you when to think about this disease. In the cases we describe the most common symptoms of endometriosis are mentioned: pelvic pain, dysmenorrhea and, dyspareunia. It is important to ask a patient with pelvic pain or subfertility about these complaints. If endometriosis is suspected on the basis of these or other complaints, empirical hormonal treatment can be offered to patients who are not trying to conceive at that time.

Live birth is not the only relevant outcome in research assessing assisted reproductive technology.

In assisted reproductive technology (ART) research, live birth has been generally accepted as an important outcome, if not the most important one. However, it has been reported inconsistently in the literature and solely focusing on live birth can lead to misinterpretation of research findings. In this review, we provide an overview on the definitions of live birth, including various denominators and numerators use. We present a series of real clinical examples in ART research to demonstrate the impact of variations in live birth on research findings and the importance of other outcomes, including multiple pregnancy, pregnancy loss, time to pregnancy leading to live birth, other short and long term maternal and offspring health outcomes and cost effectiveness measures. We suggest that outcome choices in ART research should be tailored for the research questions. A holistic outcome assessment beyond live birth would provide a full picture to address research questions in ART in terms of effectiveness and safety, and thus facilitate evidence-based decision making.

Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment: protocol for a systematic review and individual participant data meta-analysis.

INTRODUCTION: Dietary and/or physical activity interventions are often recommended for women with overweight or obesity as the first step prior to fertility treatment. However, randomised controlled trials (RCTs) so far have shown inconsistent results. Therefore, we propose this individual participant data meta-analysis (IPDMA) to evaluate the effectiveness and safety of dietary and/or physical activity interventions in women with infertility and overweight or obesity on reproductive, maternal and perinatal outcomes and to explore if there are subgroup(s) of women who benefit from each specific intervention or their combination (treatment-covariate interactions). METHODS AND ANALYSIS: We will include RCTs with dietary and/or physical activity interventions as core interventions prior to fertility treatment in women with infertility and overweight or obesity. The primary outcome will be live birth. We will search MEDLINE, Embase, Cochrane Central Register of Controlled Trials and trial registries to identify eligible studies. We will approach authors of eligible trials to contribute individual participant data (IPD). We will perform risk of bias assessments according to the Risk of Bias 2 tool and a random-effects IPDMA. We will then explore treatment-covariate interactions for important participant-level characteristics. ETHICS AND DISSEMINATION: Formal ethical approval for the project (Venus-IPD) was exempted by the medical ethics committee of the University Medical Center Groningen (METc code: 2021/563, date: 17 November 2021). Data transfer agreement will be obtained from each participating institute/hospital. Outcomes will be disseminated internationally through the collaborative group, conference presentations and peer-reviewed publication. PROSPERO REGISTRATION NUMBER: CRD42021266201.

Effects of preconception weight loss after lifestyle intervention on fertility outcomes and pregnancy complications.

It is well documented that obesity decreases natural fertility among men and women as well as pregnancy chances after conventional infertility and assisted reproductive technology (ART)-based treatments. Moreover, pregnancy complications are increased in women with overweight and obesity. General guidelines on the treatment of obesity recommend lifestyle intervention, including diet and exercise as the first-line treatment, coupled with or without medical treatments, such as weight loss medication or bariatric surgery, to reduce complications of obesity in adults. In the context of infertility in various countries and infertility clinics, there is a body mass index limit for public refund of infertility treatment of women with obesity. In this respect, it is important to investigate the evidence of effects of lifestyle intervention preceding infertility treatment on reproductive outcomes. The combined results of 15 randomized controlled trials (RCTs) of the effectiveness of preconception lifestyle intervention on reproductive outcomes documented in the latest systemic review and meta-analysis, together with the most recent RCT performed in 2022 are discussed. The current evidence suggests that greater weight loss and increase in clinical pregnancy, live birth, and natural conception rates after lifestyle intervention compared with no intervention were observed, but it seems no beneficial effect of lifestyle intervention preceding ART was observed on these parameters. With respect to potential harm of lifestyle intervention, there is no significant increased risk of early pregnancy loss, although the most recent RCT (not included in the systematic review and meta-analysis) showed a trend toward an increased risk. Complications during pregnancy, such as early pregnancy loss and maternal as well as fetal and neonatal complications, are underreported in most studies and need further analysis in an individual participant data meta-analysis. Limitations of the studies as well as future perspectives and challenges in this field of research will be highlighted.

Fertility preservation for women with breast cancer: a multicentre randomized controlled trial on various ovarian stimulation protocols.

STUDY QUESTION: Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation? SUMMARY ANSWER: Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer. WHAT IS KNOWN ALREADY: Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown. STUDY DESIGN, SIZE, DURATION: This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18-43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration. PARTICIPANTS/MATERIALS, SETTING, METHODS: During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference -1.13, 95% CI -5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI -4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was -1.11 (95% CI -5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI -4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome. LIMITATIONS, REASONS FOR CAUTION: The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS: Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women's future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant (2011.WO23.C129) of 'Stichting Pink Ribbon', a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work. TRIAL REGISTRATION NUMBER: NTR4108. TRIAL REGISTRATION DATE: 6 August 2013. DATE OF FIRST PATIENT'S ENROLMENT: 30 January 2014.

Local and Systemic Oxidative Stress Biomarkers for Male Infertility: The ORION Study.

Infertility problems occur in around 10% of all couples worldwide, with male-factor infertility as the sole contributor in 20-30% of these cases. Oxidative stress (OS) is suggested to be associated with the pathophysiology of male infertility. In spermatozoa, OS can lead to damage to the cell membrane, resulting in disruption of DNA integrity and a decrease in motility. Established biomarkers for OS include free thiols and malondialdehyde (MDA), both representing different components of the reactive species interactome (RSI). This exploratory study aimed to investigate seminal plasma-free thiol and MDA levels in relation to semen parameters as defined by the World Health Organization (WHO) to determine if these markers are adequate to define local OS status. Furthermore, this study investigated if there is a relation between systemic and local OS status by comparing seminal concentrations of free thiol (R-SH, sulfhydryl groups, representing the extracellular redox status) and MDA (lipid peroxidation product) levels to those measured in serum. Free thiol and MDA measurements in both serum and semen plasma were performed in 50 males (18-55 y) of couples seeking fertility treatment. A significant positive correlation was found between seminal plasma-free thiol levels and sperm concentration and progressive motility (r = 0.383, p = 0.008 and r = 0.333, p = 0.022, respectively). In addition, a significant positive correlation was found between MDA levels in seminal plasma and sperm concentration (r = 0.314, p = 0.031). This study supports that seminal plasma-free thiols may be promising as local OS biomarkers. No associations were observed between local and systemic OS biomarker concentrations.

Protocol for developing a core outcome set for male infertility research: an international consensus development study.

STUDY QUESTION: We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research. WHAT IS KNOWN ALREADY: Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research. STUDY DESIGN SIZE DURATION: Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health's consensus development conference. PARTICIPANTS/MATERIALS SETTING METHODS: An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes. STUDY FUNDING/COMPETING INTERESTS: This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open. K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586. TRIAL REGISTRATION DATE: N/A. DATE OF FIRST PATIENT'S ENROLMENT: N/A.

Preconception insulin resistance and neonatal birth weight in women with obesity: role of bile acids.

RESEARCH QUESTION: Does maternal preconception insulin resistance affect neonatal birth weight among women with obesity? Is insulin resistance associated with circulating bile acids? Do bile acids influence the association between maternal preconception insulin resistance and neonatal birth weight? DESIGN: An exploratory post-hoc analysis of the LIFEstyle randomized controlled trial comparing lifestyle intervention with conventional infertility treatment in women with a BMI of ≥29 kg/m2. Fasting blood samples were collected at randomization and after 3 and 6 months in 469 women. Insulin resistance was quantified using the homeostasis model assessment of insulin resistance (HOMA-IR). Bile acid sub-species were determined by liquid chromatography with tandem mass spectrometry. Singletons were included (n = 238). Birth weight Z-scores were adjusted for age, offspring gender and parity. Multilevel analysis and linear regressions were used. RESULTS: A total of 913 pairs of simultaneous preconception HOMA-IR (median [Q25; Q75]: 2.96 [2.07; 4.16]) and total bile acid measurements (1.79 [1.10; 2.94]) µmol/l were taken. Preconception HOMA-IR was positively associated with total bile acids (adjusted B 0.15; 95% CI 0.09 to 0.22; P < 0.001) and all bile acid sub-species. At the last measurement before pregnancy, HOMA-IR (2.71 [1.91; 3.74]) was positively related to birth weight Z-score (mean ± SD 0.4 ± 1.1; adjusted B 0.08; 95% CI 0.01 to 0.14; P = 0.03). None of the preconception bile acids measured were associated with birth weight. CONCLUSION: Maternal preconception insulin resistance is an important determinant of neonatal birth weight in women with obesity, whereas preconception bile acids are not.

Effectiveness of a 6-Month Lifestyle Intervention on Diet, Physical Activity, Quality of Life, and Markers of Cardiometabolic Health in Women with PCOS and Obesity and Non-PCOS Obese Controls: One Size Fits All?

Little is known about the difference in effectiveness of lifestyle intervention between women with PCOS and non-PCOS women. In a post hoc longitudinal analysis of a randomized, controlled trial, we aimed to investigate whether infertile women with PCOS and obesity (N = 87) responded differently to a 6-month lifestyle intervention program than infertile non-PCOS obese controls (N = 172). We evaluated several aspects of the intervention such as changes in diet, physical activity, and dropout rate, as well as the effect on weight, quality of life (QoL), and cardiometabolic outcomes. Multilevel analyses were used, and analyses were adjusted for baseline characteristics such as age, education, and smoking. Although BMI in both groups significantly decreased at 3 months and 6 months, there were no significant differences between the groups at 3 months (adjusted B: -0.3, 95% CI: -0.9 to 0.3, p = 0.35) and 6 months (adjusted B: 0.5, 95% CI: -0.4 to 1.4, p = 0.29). Women with PCOS and non-PCOS women had similar compliance with the lifestyle intervention in terms of actual change in diet and physical activity. Mental QoL scores were not different at either 3 or 6 months. Physical QoL scores were lower in women with PCOS compared with non-PCOS women at 3 months (adjusted B: -2.4, 95% CI: -4.8 to -0.06, p = 0.045) but not at 6 months. Cardiometabolic parameters did not differ between the groups. Our results showed that infertile women with PCOS and obesity and non-PCOS obese controls responded largely similarly to our lifestyle intervention and achieved the same level of improvement in markers of cardiometabolic health.

Dietary Intake, Eating Behavior, Physical Activity, and Quality of Life in Infertile Women with PCOS and Obesity Compared with Non-PCOS Obese Controls.

To personalize lifestyle advice for women with polycystic ovary syndrome (PCOS) and obesity, detailed information regarding dietary intake, eating behavior, physical activity levels, and quality of life (QoL) may be useful. We aimed to investigate in a post-hoc cross-sectional analysis within a large multicenter randomized controlled trial in women with infertility whether there are significant differences in dietary intake (vegetables, fruits, sugary drinks, alcoholic beverages, savory snacks, and sweet snacks); eating behavior (emotional eating, external eating, and restricted eating); physical activity; and QoL between women with PCOS and obesity and non-PCOS obese controls. Participants were asked to complete the food frequency questionnaire (FFQ), the Dutch Eating Behavior Questionnaire (DEBQ), the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH), and the 36-item Short Form Health Survey (SF-36) at study entry (PCOS: n = 170; non-PCOS: n = 321, mean BMI: 36). Linear and binary (multinomial) logistic regressions were used, and the analyses were adjusted for age, waist-hip circumference ratio, and homeostasis model assessment of insulin resistance (HOMA-IR). No statistically significant differences in dietary intake or physical activity were observed between the two groups. The overall score of emotional eating was 34.6 ± 11.2 in the PCOS group and 34.1 ± 11.3 in the non-PCOS group (p = 0.11). QoL scores (physical and mental) did not differ between PCOS and non-PCOS women. These findings suggest that infertile women with PCOS and obesity and infertile non-PCOS obese controls do not have different dietary habits and have similar mental and physical QoL.

The Effect of Lifestyle Intervention on Systemic Oxidative Stress in Women with Obesity and Infertility: A Post-Hoc Analysis of a Randomized Controlled Trial.

We aimed to study whether lifestyle intervention could reduce systemic oxidative stress (OS) and the association between OS and cardiometabolic outcomes in women with obesity and infertility. From 2009 to 2012, infertile women with a BMI ≥ 29 kg/m2 were randomly assigned to a six-month lifestyle intervention followed by infertility treatment (N = 289) or to prompt infertility treatment (N = 285). Fasting serum free thiols (FT) concentrations were determined by colorimetry at baseline, at three and six months after randomization. Generalized estimating equations and restricted cubic spline regressions were used to estimate mean differences in serum FT levels between groups and to explore associations between serum FT levels and cardiometabolic outcomes. Baseline serum FT levels did not differ between the two groups (N = 203 in the intervention group vs N = 226 in the control group, 222.1 ± 48.0 µM vs 229.9 ± 47.8 µM, p = 0.09). Body weight decreased by 3.70 kg in the intervention group compared with the control group at six months (95% confidence interval [CI]: -7.61 to 0.21, p = 0.06). No differences in serum FT levels were observed between groups at either three months (N = 142 vs N = 150, mean differences: -1.03 µM, 95% CI: -8.37 to 6.32, p = 0.78) or six months (N = 104 vs N = 96, mean differences: 2.19 µM, 95% CI: -5.90 to 10.28, p = 0.60). In a pooled analysis of all available measurements, triglycerides (crude B: 5.29, 95% CI: 1.08 to 9.50, p = 0.01), insulin (crude B: 0.62, 95% CI: 0.26 to 0.98, p = 0.001), and homeostasis model assessment of insulin resistance (crude B: 2.50, 95% CI: 1.16 to 3.38, p < 0.001) were positively associated with serum FT levels. High-sensitivity C-reactive protein (hs-CRP) was negatively associated with serum FT levels (crude B: -0.60, 95% CI: -1.11 to -0.10, p = 0.02). The change in hs-CRP during the lifestyle intervention was strongly and inversely associated with serum FT levels (crude B: -0.41, 95% CI: -0.70 to -0.13, p = 0.005). No significant deviations from linear associations were observed between serum FT and hs-CRP. We do not observe an improvement in systemic OS in women with obesity and infertility with modest weight loss. There were potential associations between OS and biomarkers of cardiometabolic health. Trial registration: This trial was registered on 16 November 2008 at the Dutch trial register (NTR1530).

Long-term male fertility after treatment with radioactive iodine for differentiated thyroid carcinoma.

CONTEXT: Whilst radioactive iodine (RAI) is often administered in the treatment for differentiated thyroid carcinoma (DTC), long-term data on male fertility after RAI are scarce. OBJECTIVE: To evaluate long-term male fertility after RAI for DTC, and to compare semen quality before and after RAI. DESIGN, SETTING, AND PATIENTS: Multicenter study including males with DTC ≥2 years after their final RAI treatment with a cumulative activity of ≥3.7 GBq. MAIN OUTCOME MEASURE(S): Semen analysis, hormonal evaluation, and a fertility-focused questionnaire. Cut-off scores for 'low semen quality' were based on reference values of the general population as defined by the World Health Organization (WHO). RESULTS: Fifty-one participants had a median age of 40.5 (interquartile range (IQR): 34.0-49.6) years upon evaluation and a median follow-up of 5.8 (IQR: 3.0-9.5) years after their last RAI administration. The median cumulative administered activity of RAI was 7.4 (range: 3.7-23.3) GBq. The proportion of males with a low semen volume, concentration, progressive motility, or total motile sperm count did not differ from the 10th percentile cut-off of a general population (P = 0.500, P = 0.131, P = 0.094, and P = 0.500, respectively). Cryopreserved semen was used by 1 participant of the 20 who had preserved semen. CONCLUSIONS: Participants had a normal long-term semen quality. The proportion of participants with low semen quality parameters scoring below the 10th percentile did not differ from the general population. Cryopreservation of semen of males with DTC is not crucial for conceiving a child after RAI administration but may be considered in individual cases.

Lifestyle intervention prior to IVF does not improve embryo utilization rate and cumulative live birth rate in women with obesity: a nested cohort study.

STUDY QUESTION: Does lifestyle intervention consisting of an energy-restricted diet, enhancement of physical activity and motivational counseling prior to IVF improve embryo utilization rate (EUR) and cumulative live birth rate (CLBR) in women with obesity? SUMMARY ANSWER: A 6-month lifestyle intervention preceding IVF improved neither EUR nor CLBR in women with obesity in the first IVF treatment cycle where at least one oocyte was retrieved. WHAT IS KNOWN ALREADY: A randomized controlled trial (RCT) evaluating the efficacy of a low caloric liquid formula diet (LCD) preceding IVF in women with obesity was unable to demonstrate an effect of LCD on embryo quality and live birth rate: in this study, only one fresh embryo transfer (ET) or, in case of freeze-all strategy, the first transfer with frozen-thawed embryos was reported. We hypothesized that any effect on embryo quality of a lifestyle intervention in women with obesity undergoing IVF treatment is better revealed by EUR and CLBR after transfer of all fresh and frozen-thawed embryos. STUDY DESIGN SIZE DURATION: This is a nested cohort study within an RCT, the LIFEstyle study. The original study examined whether a 6-month lifestyle intervention prior to infertility treatment in women with obesity improved live birth rate, compared to prompt infertility treatment within 24 months after randomization. In the original study between 2009 and 2012, 577 (three women withdrew informed consent) women with obesity and infertility were assigned to a lifestyle intervention followed by infertility treatment (n = 289) or to prompt infertility treatment (n = 285). PARTICIPANTS/MATERIALS SETTING METHODS: Only participants from the LIFEstyle study who received IVF treatment were eligible for the current analysis. In total, 137 participants (n = 58 in the intervention group and n = 79 in the control group) started the first cycle. In 25 participants, the first cycle was cancelled prior to oocyte retrieval mostly due to poor response. Sixteen participants started a second or third consecutive cycle. The first cycle with successful oocyte retrieval was used for this analysis, resulting in analysis of 51 participants in the intervention group and 72 participants in the control group. Considering differences in embryo scoring methods and ET day strategy between IVF centers, we used EUR as a proxy for embryo quality. EUR was defined as the proportion of inseminated/injected oocytes per cycle that was transferred or cryopreserved as an embryo. Analysis was performed per cycle and per oocyte/embryo. CLBR was defined as the percentage of participants with at least one live birth from the first fresh and subsequent frozen-thawed ET(s). In addition, we calculated the Z-score for singleton neonatal birthweight and compared these outcomes between the two groups. MAIN RESULTS AND THE ROLE OF CHANCE: The overall mean age was 31.6 years and the mean BMI was 35.4 ± 3.2 kg/m2 in the intervention group, and 34.9 ± 2.9 kg/m2 in the control group. The weight change at 6 months was in favor of the intervention group (mean difference in kg vs the control group: -3.14, 95% CI: -5.73 to -0.56). The median (Q25; Q75) number of oocytes retrieved was 4.00 (2.00; 8.00) in the intervention group versus 6.00 (4.00; 9.75) in the control group, and was not significantly different, as was the number of oocytes inseminated/injected (4.00 [2.00; 8.00] vs 6.00 [3.00; 8.75]), normal fertilized embryos (2.00 [0.50; 5.00] vs 3.00 [1.00; 5.00]) and the number of cryopreserved embryos (2.00 [1.25; 4.75] vs 2.00 [1.00; 4.00]). The median (Q25; Q75) EUR was 33.3% (12.5%; 60.0%) in the intervention group and 33.3% (16.7%; 50.0%) in the control group in the per cycle analysis (adjusted B: 2.7%, 95% CI: -8.6% to 14.0%). In the per oocyte/embryo analysis, in total, 280 oocytes were injected or inseminated in the intervention group, 113 were utilized (transferred or cryopreserved, EUR = 40.4%); in the control group, EUR was 30.8% (142/461). The lifestyle intervention did not significantly improve EUR (adjusted odds ratio [OR]: 1.36, 95% CI: 0.94-1.98) in the per oocyte/embryo analysis, taking into account the interdependency of the oocytes per participant. CLBR was not significantly different between the intervention group and the control group after adjusting for type of infertility (male factor and unexplained) and smoking (27.5% vs 22.2%, adjusted OR: 1.03, 95% CI: 0.43-2.47). Singleton neonatal birthweight and Z-score were not significantly different between the two groups. LIMITATIONS REASONS FOR CAUTION: This study is a nested cohort study within an RCT, and no power calculation was performed. The randomization was not stratified for indicated treatment, and although we corrected our analyses for baseline differences, there may be residual confounding. The limited absolute weight loss and the short duration of the lifestyle intervention might be insufficient to affect EUR and CLBR. WIDER IMPLICATIONS OF THE FINDINGS: Our data do not support the hypothesis of a beneficial short-term effect of lifestyle intervention on EUR and CLBR after IVF in women with obesity, although more studies are needed as there may be a potential clinically relevant effect on EUR. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). A.H. has received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds Stock options for ObsEva. B.W.J.M. has received research funding from Guerbet, Ferring and Merck. F.J.M.B. reports personal fees from membership of the external advisory board for Merck Serono and a research support grant from Merck Serono, outside the submitted work. TRIAL REGISTRATION NUMBER: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). https://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530.

Male subfertility and oxidative stress.

To date 15% of couples are suffering from infertility with 45-50% of males being responsible. With an increase in paternal age as well as various environmental and lifestyle factors worsening these figures are expected to increase. As the so-called free radical theory of infertility suggests, free radicals or reactive oxygen species (ROS) play an essential role in this process. However, ROS also fulfill important functions for instance in sperm maturation. The aim of this review article is to discuss the role reactive oxygen species play in male fertility and how these are influenced by lifestyle, age or disease. We will further discuss how these ROS are measured and how they can be avoided during in-vitro fertilization.

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.

Long-Term Effects of Radioiodine Treatment on Female Fertility in Survivors of Childhood Differentiated Thyroid Carcinoma.

Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of 131I administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group (p = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) µg/L vs. 1.6 (IQR 0.6-3.1) µg/L, respectively, p = 0.244]. The cumulative dose of 131I was not associated with AMH levels in DTC survivors (rs = 0.210, p = 0.130). Conclusions: Female survivors of DTC who received 131I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure.

Is there an immune modulating role for follicular fluid in endometriosis? A narrative review.

Follicular fluid (FF) surrounds the granulosa cell-oocyte complex and is one of the mediating factors in the communication between the cells within the follicle. Literature reveals that human FF and its components are key factors to the success of natural fertilization. Among other substances, FF consists of multiple cytokines and immune cells, including interleukin 6 (IL6), IL12, sHLA-G, macrophages, NK cells and lymphocytes. Together, these cells and cytokines might influence the oocyte-granulosa-cell complex. Altered balances of immune content might be involved in changes on folliculogenesis, oocyte maturation, oocyte quality and ovulation. Furthermore, these altered balances are possibly involved in infertility associated with immune-mediated diseases such as endometriosis. The aim of this narrative review is to elaborate on the function and contents of FF and its immunological profile in patients with endometriosis. A comprehensive literature search was performed for the published literature on FF (immune) contents, FF function and FF content alterations in endometriosis patients. In FF of patients with endometriosis, elevated levels of macrophages and several cytokines have been reported. The role of specific immune cells in FF and a clarification of the biological mechanism in healthy women and endometriosis patients remain largely unknown. Future studies in this field will give us more insight in the role of FF immune cells and the effect of altered balances in patients with endometriosis.