Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome : a prospective randomized multinational study

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95 confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.peer-reviewe

Coomarasamy A. The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Hum Reprod 2012

study question: Is there an association between high levels of sperm DNA damage and miscarriage? summary answer: Miscarriage rates are positively correlated with sperm DNA damage levels. what is known already: Most ejaculates contain a subpopulation of sperm with DNA damage, also referred to as DNA fragmentation, in the form of double or single-strand breaks which have been induced in the DNA prior to or following ejaculation. This DNA damage may be particularly elevated in some subfertile men, hence several studies have examined the link between sperm DNA damage levels and conception and miscarriage rates. study design, size, duration: A systematic review and meta-analysis of studies which examined the effect of sperm DNA damage on miscarriage rates was performed. Searches were conducted on MEDLINE, EMBASE and the Cochrane Library without any language restrictions from database inception to January 2012. participants/materials, setting, methods: We used the terms &apos;DNA damage&apos; or &apos;DNA fragmentation&apos; combined with &apos;miscarriage&apos;, &apos;abortion&apos; or &apos;pregnancy&apos; to generate a set of relevant citations. Data extraction was performed by two reviewers. Study quality was assessed using the Newcastle -Ottawa Scale. Meta-analysis of relative risks of miscarriage was performed with a random effects model. Subgroup analyses were performed by the type of DNA damage test, whether the sperm examined were prepared or from raw semen and for pregnancies resulting from IVF or ICSI treatment. main results and the role of chance: We identified 16 cohort studies (2969 couples), 14 of which were prospective. Eight studies used acridine orange-based assays, six the TUNEL assay and two the COMET assay. Meta-analysis showed a significant increase in miscarriage in patients with high DNA damage compared with those with low DNA damage [risk ratio (RR) ¼ 2.16 (1.54, 3.03), P , 0.00001)]. A subgroup analysis showed that the miscarriage association is strongest for the TUNEL assay (RR ¼ 3.94 (2.45, 6.32), P , 0.00001). limitations, reasons for caution: There is some variation in study characteristics, including the use of different assays and different thresholds for DNA damage and the definition of pregnancy loss. wider implications of the findings: The use of methods which select sperm without DNA damage for use in assisted conception treatment may reduce the risk of miscarriage. This finding indicates that assays detecting DNA damage could be considered in those suffering from recurrent pregnancy loss. Further research is necessary to study the mechanisms of DNA damage and the potential therapeutic effects of antioxidant therapy. study funding/competing interest(s): None

Vitamin D and assisted reproductive treatment outcome: A prospective cohort study

Background: Vitamin D deficiency has been associated with an increased risk of abnormal pregnancy implantation leading to obstetric complications such as pre-eclampsia and fetal growth restriction. However, the effect of vitamin D on reproductive treatment outcomes in couples undergoing assisted reproductive treatment is poorly understood. This study investigates the association between vitamin D and reproductive treatment outcomes in women undergoing assisted reproductive treatments? Methods: A prospective cohort study conducted at a large tertiary teaching hospital, United Kingdom. Five hundred women undergoing assisted reproductive treatment were recruited between September 2013 and September 2015. All participants had their serum vitamin D measured and their reproductive treatment outcomes collated. Women were categorised in to three groups: vitamin D replete (> 75 nmol/L), insufficient (50-75 nmol/L) and deficient (< 50 nmol/L) according to Endocrine Society guidance. The primary outcome was live birth. Secondary outcomes included biochemical pregnancy, clinical pregnancy and pregnancy loss rates. Results: Vitamin D deficiency was found in 53.2% (266/500) of participants and vitamin D insufficiency was found in 30.8% (154/500) of participants. Only 16% (80/500) of women were vitamin D replete. The live birth rates for vitamin D deficient, insufficient and replete women were 23.2% (57/246), 27.0% (38/141) and 37.7% (29/77) respectively (p = 0.04). The respective live birth rates for vitamin D deficient, insufficient and replete women were 24.3, 27.1, 34.4% after adjustment for key prognostic factors (p = 0.25). Conclusions: Vitamin D deficiency and insufficiency are common in women undergoing assisted reproductive treatments. The crude live birth rate achieved in women undergoing assisted reproductive treatments are associated with serum vitamin D, although statistical significance is lost when adjusting for important prognostic variables. Vitamin D deficiency could be an important condition to treat in women considering fertility treatment. A research trial to investigate the benefits of vitamin D deficiency treatment would test this hypothesis. Trial registration: Clinicaltrials.gov - NCT02187146. © 2019 The Author(s).Funding text #1 The study was funded by the Birmingham Women’s and Children’s NHS Foundation Trust Research and Development Department and was approved by the National Research Ethics Service (NRES) Committee West Midlands – Black Country (REC 13/WM/0258). A total of 504 patients who underwent ART at the Birmingham Women’s Fertility Centre from September 2013 to September 2015 were recruited. Funding text #2 The cohort study was funded by a grant from the Research and Development Department at the Birmingham Women’s and Children’s NHS Foundation Trust. Funding text #3 This study was approved by the National Research Ethics Service (NRES) Committee West Midlands – Black Country (REC 13/WM/0258). All participants provided full written and informed consent. Funding text #4 1Tommy’s National Centre for Miscarriage Research, Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK. 2Birmingham Women’s and Children’s National Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK. 3Spanish Council for Scientific Research, Institute of Environmental Assessment and Water Research, Barcelona, Spain. 4Birmingham Women’s Foundation NHS Trust, Edgbaston B15 2TG, UK.Peer reviewe

Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis.

OBJECTIVE To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes. DESIGN Systematic review and meta-analysis. SETTING Not applicable. PATIENT(S) Women undergoing FET. INTERVENTION(S) We conducted electronic searches of MEDLINE, PubMed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and grey literature (not widely available) from inception to March 2021 to identify cohort studies in which the serum luteal progesterone level was measured around the time of FET. MAIN OUTCOME MEASURE(S) Ongoing pregnancy or live birth rate, clinical pregnancy rate, and miscarriage rate. RESULT(S) Among the studies analyzing serum progesterone level thresholds <10 ng/mL, a higher serum progesterone level was associated with increased rates of ongoing pregnancy or live birth (relative risk [RR] 1.47, 95% confidence interval [CI] 1.28 to 1.70), higher chance of clinical pregnancy (RR 1.31, 95% CI 1.16 to 1.49), and lower risk of miscarriage (RR 0.62, 95% CI 0.50 to 0.77) in cycles using exclusively vaginal progesterone and blastocyst embryos. There was uncertainty about whether progesterone thresholds ≥10 ng/mL were associated with FET outcomes in sensitivity analyses including all studies, owing to high interstudy heterogeneity and wide CIs. CONCLUSION(S) Our findings indicate that there may be a minimum clinically important luteal serum concentration of progesterone required to ensure an optimal endocrine milieu during embryo implantation and early pregnancy after FET treatment. Future clinical trials are required to assess whether administering higher-dose luteal phase support improves outcomes in women with a low serum progesterone level at the time of FET. PROSPERO NUMBER CRD42019157071

The effect of frozen embryo transfer regimen on the association between serum progesterone and live birth: a multicentre prospective cohort study (ProFET)

STUDY QUESTION: What is the association between serum progesterone levels on the day of frozen embryo transfer (FET) and the probability of live birth in women undergoing different FET regimens? SUMMARY ANSWER: Overall, serum progesterone levels <7.8 ng/ml were associated with reduced odds of live birth, although the association between serum progesterone levels and the probability of live birth appeared to vary according to the route of progesterone administration. WHAT IS KNOWN ALREADY: Progesterone is essential for pregnancy success. A recent systematic review showed that in FET cycles using vaginal progesterone for endometrial preparation, lower serum progesterone levels (<10 ng/ml) were associated with a reduction in live birth rates and higher chance of miscarriage. However, there was uncertainty about the association between serum progesterone levels and treatment outcomes in natural cycle FET (NC-FET) and HRT-FET using non-vaginal routes of progesterone administration. STUDY DESIGN, SIZE, DURATION: This was a multicentre (n = 8) prospective cohort study conducted in the UK between January 2020 and February 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women having NC-FET or HRT-FET treatment with progesterone administration by any available route. Women underwent venepuncture on the day of embryo transfer. Participants and clinical personnel were blinded to the serum progesterone levels. We conducted unadjusted and multivariable logistic regression analyses to investigate the association between serum progesterone levels on the day of FET and treatment outcomes according to the type of cycle and route of exogenous progesterone administration. Our primary outcome was the live birth rate per participant. MAIN RESULTS AND THE ROLE OF CHANCE: We studied a total of 402 women. The mean (SD) serum progesterone level was 14.9 (7.5) ng/ml. Overall, the mean adjusted probability of live birth increased non-linearly from 37.6% (95% CI 26.3–48.9%) to 45.5% (95% CI 32.1–58.9%) as serum progesterone rose between the 10th (7.8 ng/ml) and 90th (24.0 ng/ml) centiles. In comparison to participants whose serum progesterone level was ≥7.8 ng/ml, those with lower progesterone (<7.8 ng/ml, 10th centile) experienced fewer live births (28.2% versus 40.0%, adjusted odds ratio [aOR] 0.41, 95% CI 0.18–0.91, P = 0.028), lower odds of clinical pregnancy (30.8% versus 45.1%, aOR 0.36, 95% CI 0.16–0.79, P = 0.011) and a trend towards increased odds of miscarriage (42.1% versus 28.7%, aOR 2.58, 95% CI 0.88–7.62, P = 0.086). In women receiving vaginal progesterone, the mean adjusted probability of live birth increased as serum progesterone levels rose, whereas women having exclusively subcutaneous progesterone experienced a reduction in the mean probability of live birth as progesterone levels rose beyond 16.3 ng/ml. The combination of vaginal and subcutaneous routes appeared to exert little impact upon the mean probability of live birth in relation to serum progesterone levels. LIMITATIONS, REASONS FOR CAUTION: The final sample size was smaller than originally planned, although our study was adequately powered to confidently identify a difference in live birth between optimal and inadequate progesterone levels. Furthermore, our cohort did not include women receiving oral or rectal progestogens. WIDER IMPLICATIONS OF THE FINDINGS: Our results corroborate existing evidence suggesting that lower serum progesterone levels hinder FET success. However, the relationship between serum progesterone and the probability of live birth appears to be non-linear in women receiving exclusively subcutaneous progesterone, suggesting that in this subgroup of women, high serum progesterone may also be detrimental to treatment success. STUDY FUNDING/COMPETING INTERESTS: This work was supported by CARE Fertility and a doctoral research fellowship (awarded to P.M.) by the Tommy’s Charity and the University of Birmingham. M.J.P. is supported by the NIHR Birmingham Biomedical Research Centre. S.F. is a minor shareholder of CARE Fertility but has no financial or other interest with progesterone testing or manufacturing companies. P.L. reports personal fees from Pharmasure, outside the submitted work. G.P. reports personal fees from Besins Healthcare, outside the submitted work. M.W. reports personal fees from Ferring Pharmaceuticals, outside the submitted work. The remaining authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT04170517

Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo

Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present study compares the major insulin signalling pathways in skeletal muscle isolated from PCOS and controls. We measured whole-body insulin sensitivity and insulin signalling in skeletal muscle biopsies taken before and after acute exposure to hyper-insulinaemia in nine women diagnosed with PCOS and seven controls. We examined the expression, basal activity and response to in vivo insulin Stimulation of three signalling molecules within these human Muscle samples, namely IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was it severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and,in accompanying trend towards. higher basal phosphorylation of ERK 1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported its defective in some previous PCOS Studies. Most importantly, the molecular defect identified was independent of adiposity. The altered response of ERK to insulin in PCOS was the most obvious signalling defect associated with insulin resistance in muscle from these patients