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.

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.

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.

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.

Dehydroepiandrosterone for women in the peri- or postmenopausal phase.

BACKGROUND: During menopause a decreasing ovarian follicular response generally causes a fluctuation and eventual decrease in estrogen levels. This can lead to the development of various perimenopausal and postmenopausal symptoms (for example hot flushes, night sweats, vaginal dryness). Dehydroepiandrosterone (DHEA) is one of the main precursors of androgens, which in turn are converted to testosterone and estrogens. It is possible that the administration of DHEA may increase estrogen and testosterone levels in peri- and postmenopausal women to alleviate their symptoms and improve general wellbeing and sexual function (for example libido, dyspareunia, satisfaction). Treatment with DHEA is controversial as there is uncertainty about its effectiveness and safety. This review should clearly outline the evidence for DHEA in the treatment of menopausal symptoms and evaluate its effectiveness and safety by combining the results of randomised controlled trials. OBJECTIVES: To assess the effectiveness and safety of administering DHEA to women with menopausal symptoms in the peri- or postmenopausal phase. SEARCH METHODS: The databases that we searched (3 June 2014) with no language restrictions applied were the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS. We also searched conference abstracts and citation lists in the ISI Web of Knowledge. Ongoing trials were searched in the trials registers. Reference lists of retrieved articles were checked. SELECTION CRITERIA: We included randomised controlled trials comparing any dose and form of DHEA by any route of administration versus any other active intervention, placebo or no treatment for a minimal treatment duration of seven days in peri- and postmenopausal women. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data after assessing eligibility for inclusion and quality of studies. Authors were contacted for additional information. MAIN RESULTS: Twenty-eight trials with 1273 menopausal women were included in this review. Data could be extracted from 16 trials to conduct the meta-analysis. The overall quality of the studies was moderate to low with the majority of studies that were included in the meta-analysis having reasonable methodology. Compared to placebo, DHEA did not improve quality of life (standardised mean difference (SMD) 0.16, 95% confidence interval (CI) -0.03 to 0.34, P = 0.10, 8 studies, 287 women (132 from parallel and 155 from crossover trials), I² = 0%, moderate quality evidence; one trial of the nine that reported on this outcome was removed in a sensitivity analysis as it was judged to be at high risk of bias). DHEA was found to be associated with androgenic side effects (mainly acne) (odds ratio (OR) 3.77, 95% CI 1.36 to 10.4, P = 0.01, 5 studies, 376 women, I² = 10%, moderate quality evidence) when compared to placebo. No associations were found with other adverse effects. It was unclear whether DHEA affected menopausal symptoms as the results from the trials were inconsistent and could not easily be pooled to provide an overall effect due to different types of measurement (for example continuous, dichotomous, change and end scores). DHEA was found to improve sexual function (SMD 0.31, 95% CI 0.07 to 0.55, P = 0.01, 5 studies, 261 women (239 women from parallel trials and 22 women from crossover trials), I² = 0%; one trial judged to be at high risk of bias was removed during sensitivity analysis) compared to placebo.There was no difference in the acne associated with DHEA when comparing studies that used oral DHEA (OR 2.16, 95% CI 0.47 to 9.96, P = 0.90, 3 studies, 136 women, I² = 5%, very low quality evidence) to one study that used skin application of DHEA (OR 2.74, 95% CI 0.10 to 74.87, P = 0.90, 1 study, 22 women, very low quality evidence). The effects did not differ for sexual function when studies using oral DHEA (SMD 0.11, 95% CI -0.13 to 0.35, P = 0.36, 5 studies, 340 women, I² = 0) were compared to a study using intravaginal DHEA (SMD 0.42, 95% CI 0.03 to 0.81, 1 study, 218 women). Test for subgroup differences: Chi² = 1.77, df = 1 (P = 0.18), I² = 43.4%. Insufficient data were available to assess quality of life and menopausal symptoms for this comparison.There were insufficient data available to compare the effects of DHEA to hormone therapy (HT) for quality of life, menopausal symptoms, and adverse effects. No large differences in treatment effects were found for sexual function when comparing DHEA to HT (mean difference (MD) 1.26, 95% CI -0.21 to 2.73, P = 0.09, 2 studies, 41 women, I² = 0%). AUTHORS' CONCLUSIONS: There is no evidence that DHEA improves quality of life but there is some evidence that it is associated with androgenic side effects. There is uncertainty whether DHEA decreases menopausal symptoms, but DHEA may slightly improve sexual function compared with placebo.

Synchronised approach for intrauterine insemination in subfertile couples.

BACKGROUND: In many countries intrauterine insemination (IUI) is the treatment of first choice for a subfertile couple when the infertility work up reveals an ovulatory cycle, at least one open Fallopian tube and sufficient spermatozoa. The final goal of this treatment is to achieve a pregnancy and deliver a healthy (singleton) live birth. The probability of conceiving with IUI depends on various factors including age of the couple, type of subfertility, ovarian stimulation and the timing of insemination. IUI should logically be performed around the moment of ovulation. Since spermatozoa and oocytes have only limited survival time correct timing of the insemination is essential. As it is not known which technique of timing for IUI results in the best treatment outcome, we compared different techniques for timing IUI and different time intervals. OBJECTIVES: To evaluate the effectiveness of different synchronisation methods in natural and stimulated cycles for IUI in subfertile couples. SEARCH METHODS: We searched for all publications which described randomised controlled trials of the timing of IUI. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (1966 to October 2014), EMBASE (1974 to October 2014), MEDLINE (1966 to October 2014) and PsycINFO (inception to October 2014) electronic databases and prospective trial registers. Furthermore, we checked the reference lists of all obtained studies and performed a handsearch of conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different timing methods for IUI were included. The following interventions were evaluated: detection of luteinising hormone (LH) in urine or blood, single test; human chorionic gonadotropin (hCG) administration; combination of LH detection and hCG administration; basal body temperature chart; ultrasound detection of ovulation; gonadotropin-releasing hormone (GnRH) agonist administration; or other timing methods. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials, extracted the data and assessed study risk of bias. We performed statistical analyses in accordance with the guidelines for statistical analysis developed by The Cochrane Collaboration. The overall quality of the evidence was assessed using GRADE methods. MAIN RESULTS: Eighteen RCTs were included in the review, of which 14 were included in the meta-analyses (in total 2279 couples). The evidence was current to October 2013. The quality of the evidence was low or very low for most comparisons . The main limitations in the evidence were failure to describe study methods, serious imprecision and attrition bias.Ten RCTs compared different methods of timing for IUI. We found no evidence of a difference in live birth rates between hCG injection versus LH surge (odds ratio (OR) 1.0, 95% confidence interval (CI) 0.06 to 18, 1 RCT, 24 women, very low quality evidence), urinary hCG versus recombinant hCG (OR 1.17, 95% CI 0.68 to 2.03, 1 RCT, 284 women, low quality evidence) or hCG versus GnRH agonist (OR 1.04, 95% CI 0.42 to 2.6, 3 RCTS, 104 women, I(2) = 0%, low quality evidence).Two RCTs compared the optimum time interval from hCG injection to IUI, comparing different time frames that ranged from 24 hours to 48 hours. Only one of these studies reported live birth rates, and found no difference between the groups (OR 0.52, 95% CI 0.27 to 1.00, 1 RCT, 204 couples). One study compared early versus late hCG administration and one study compared different dosages of hCG, but neither reported the primary outcome of live birth.We found no evidence of a difference between any of the groups in rates of pregnancy or adverse events (multiple pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS)). However, most of these data were very low quality. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether there is any difference in safety and effectiveness between different methods of synchronization of ovulation and insemination. More research is needed.

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.

Natural cycle in vitro fertilisation (IVF) for subfertile couples.

BACKGROUND: Subfertility affects 15% to 20% of couples trying to conceive. In vitro fertilisation (IVF) is one of the assisted reproduction techniques developed to improve chances of achieving pregnancy. In the standard IVF method with controlled ovarian hyperstimulation (COH), growth and development of multiple follicles are stimulated by using gonadotrophins, often combined with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist. Although it is an established method of conception for subfertile couples, the treatment is expensive and has a high risk of adverse effects. Studies have shown that IVF in a natural cycle (NC) or a modified natural cycle (MNC) might be a promising low risk and low cost alternative to the standard stimulated IVF treatment since the available dominant follicle of each cycle is used. In this review, we included available randomised controlled studies comparing natural cycle IVF (NC and MNC) with standard IVF. OBJECTIVES: To compare the efficacy and safety of natural cycle IVF (including both NC-IVF and MNC-IVF) with controlled ovarian hyperstimulation IVF (COH-IVF) in subfertile couples. SEARCH METHODS: An extended search including of the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ClinicalTrials.gov, conference abstracts in the Web of Knowledge, the World Health Organization International Trials Registry Platform search portal, LILACS database, PubMed and the OpenSIGLE database was conducted according to Cochrane guidelines. The last search was on 31st July 2013. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing either natural cycle IVF or modified natural cycle IVF versus standard IVF in subfertile couples were included. DATA COLLECTION AND ANALYSIS: Data selection and extraction and risk of bias assessment were carried out independently by two authors (TA and AC). The primary outcome measures were live birth rate and ovarian hyperstimulation syndrome (OHSS) rate per randomised woman. We calculated Mantel-Haenszel odds ratios for each dichotomous outcome and either the mean difference or the standardised mean difference (SMD) for continuous outcomes, with 95% confidence intervals (CIs). A fixed effect model was used unless there was substantial heterogeneity, in which case a random effects model was used. MAIN RESULTS: Six randomised controlled trials with a total of 788 women were included. The largest of these trials included 396 women eligible for this review.No evidence of a statistically significant difference was found between natural cycle and standard IVF in live birth rates (OR 0.68, 95% CI 0.46 to 1.01, two studies, 425 women, I(2)= 0%, moderate quality evidence). The evidence suggests that for a woman with a 53% chance of live birth using standard IVF, the chance using natural cycle IVF would range from 34% to 53%. There was no evidence of a statistically significant difference between natural cycle and standard IVF in rates of OHSS (OR 0.19, 95% CI 0.01 to 4.06, one study, 60 women, very low quality evidence), clinical pregnancy (OR 0.52 95% CI 0.17 to 1.61, 4 studies, 351 women, I(2)=63%, low quality evidence), ongoing pregnancy (OR 0.72, 95% CI 0.50 to 1.05, three studies, 485 women, I(2)=0%, moderate quality evidence), multiple pregnancy (OR 0.76, 95% CI 0.25 to 2.31, 2 studies, 527 women, I(2)=0%, very low quality evidence), gestational abnormalities (OR 0.44 95% CI 0.03 to 5.93, 1 study, 18 women, very low quality evidence) or cycle cancellations (OR 8.98, 95% CI 0.20 to 393.66, 2 studies, 159 women, I(2)=83%, very low quality evidence). One trial reported that the oocyte retrieval rate was significantly lower in the natural cycle group (MD -4.40, 95% CI -7.87 to -0.93, 60 women, very low quality evidence). There were insufficient data to draw any conclusions about rates of treatment cancellation. Findings on treatment costs were inconsistent and more data are awaited. The evidence was limited by imprecision. Findings for pregnancy rate and for cycle cancellation were sensitive to the choice of statistical model: for these outcomes, use of a fixed effect model suggested a benefit for the standard IVF group. Moreover the largest trial has not yet completed follow up, though data have been reported for over 95% of women. AUTHORS' CONCLUSIONS: Further evidence from well conducted large trials is awaited on natural cycle IVF treatment. Future trials should compare natural cycle IVF with standard IVF. Outcomes should include cumulative live birth and pregnancy rates, the number of treatment cycles necessary to reach live birth, treatment costs and adverse effects.

Intrauterine insemination versus fallopian tube sperm perfusion for non-tubal infertility.

BACKGROUND: Intrauterine insemination (IUI) is a common treatment for couples with subfertility that does not involve the fallopian tubes. It is used to bring the sperm close to the released oocyte. Another method of introducing sperm is fallopian tube sperm perfusion (FSP). Fallopian tube sperm perfusion ensures the presence of higher sperm densities in the fallopian tubes at the time of ovulation than does standard IUI. These treatments are often used in combination with ovarian hyperstimulation. OBJECTIVES: To compare intrauterine insemination versus fallopian tube sperm perfusion in the treatment of non-tubal subfertility, for live birth and pregnancy outcomes. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group Trials Register, MEDLINE, CINAHL and EMBASE from inception to September 2013. We also searched study reference lists and trial registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing IUI with FSP in couples with non-tubal subfertility were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed study quality and extracted the data. If studies were sufficiently similar, data were combined using a fixed-effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). A random-effects model was used if substantial statistical heterogeneity was detected. Studies that included participants with unexplained or mixed (non-tubal) subfertility were analysed separately from studies restricted to participants with mild or moderate male factor subfertility. The overall quality of evidence for the main outcomes was summarised using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. MAIN RESULTS: The review included 16 RCTs. Fourteen RCTs (1745 women) were included in the meta-analysis. Only three studies reported live birth per couple. No evidence of a statistically significant difference was noted between IUI and FSP in live birth (OR 0.94, 95% CI 0.59 to 1.49, three RCTs, 633 women, I(2) = 0%, low-quality evidence) or clinical pregnancy (OR 0.75, 95% CI 0.49 to 1.12, 14 RCTs, 1745 women, I(2) = 52%, low-quality evidence). These findings suggest that for a couple with a 13% chance of live birth using FSP, the chance when using IUI will be between 8% and 19%; and that for a couple with a 19% chance of pregnancy using FSP, the chance of pregnancy when using IUI will be between 10% and 20%. Nor was evidence found of a statistically significant difference between IUI and FSP in per-pregnancy of multiple pregnancy (OR 0.96, 95% CI 0.44 to 2.07, eight RCTs, 197 women, I(2) = 0%, low-quality evidence), miscarriage (OR 1.23, 95% CI 0.60 to 2.53, seven RCTs, 199 women, I(2) = 0%, low-quality evidence) or ectopic pregnancy (OR 1.71, 95% CI 0.42 to 6.88, four RCTs, 111 women, I(2) = 0%, very low quality evidence). Substantial heterogeneity was noted for the outcome of clinical pregnancy (I(2) = 54%), for which no clear explanation was provided. AUTHORS' CONCLUSIONS: Currently no clear evidence suggests any difference between IUI and FSP with respect to their effectiveness and safety for treating couples with non-tubal subfertility. However, a high level of uncertainty is evident in the findings, and additional research may be useful.

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.

[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.

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.

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.

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.

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.

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.

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.

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.

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.