Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

INTRODUCTION: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility. METHODS AND ANALYSIS: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores. ETHICS AND DISSEMINATION: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial. TRIAL REGISTRATION NUMBER: NCT05364008.

Traditional management of female infertility in Africa: a scoping review protocol.

INTRODUCTION: Infertility adversely affects the sexual reproductive health and overall quality of life of people. Recent estimates show that about one in six people (both men and women) experience infertility in their lifetime. This scoping review will, therefore, map the existing evidence on traditional management of female infertility in Africa including the effectiveness of the traditional healthcare systems, to inform policy and practice. METHODS: The scoping review will be guided by the Arksey and O'Malley framework in conjunction with the Joanna Briggs Institute updated methodological guidance for scoping reviews. A search strategy will be developed, which will target the following databases: PubMed, Scopus, Embase, CINAHL, Google Scholar and Africa-Wide Information including grey literature. The screening of titles, abstracts and full text will be done by two independent reviewers. Data will be extracted, analysed numerically and thematically. The reporting of the scoping review will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. ETHICS AND DISSEMINATION: This scoping review will not require ethical approval as this is secondary analysis of peer-reviewed articles. The findings of the review will be disseminated on various platforms including conferences, meetings to key stakeholders and in a peer-reviewed journal for wider sharing.

Utilization of traditional herbal medicine formulas for unexplained female infertility in Korea: a retrospective study.

BACKGROUND: This study aimed to investigate the prescription of traditional herbal medicines for the treatment of unexplained female infertility in Korea. By analyzing the relationships among the prescriptions and between the prescriptions and treatment outcomes, we aimed to confirm the utilization of standardized prescriptions and the effectiveness of this standardization. METHODS: The data were derived from the "support projects" of the local government for infertile women to receive Korean medical treatments. The presciption data of 453 participants from 2017 to 2018 were analyzed. Data preprocessing, frequency analysis, and network analysis were conducted. For network analysis, the characteristics of the herbal medicine prescriptions were used to calculate the degree centrality, closeness centrality and eigenvector centrality. Modularity clustering was also performed for cluster analysis. RESULTS: Fifty different prescriptions were used, among which only 22 were used for participants who became pregnant. The recommended standard prescriptions for support projects were used frequently. "BaeranChacksangBang" showed the highest level of in-degree centrality. Among the prescriptions for participants who became pregnant, "JogyeongJongokTang" and "BaeranChacksangBang" were the most influential nodes. "BaeranChacksangBang", "AnjeonYicheonTang", "YukLinZu" and "JogyeongJongokTang" had high closeness centrality among the prescriptions for participants who became pregnant. Clustering analysis of the prescriptions for participants who became pregnant revealed that the prescriptions showed the best modularity when divided into five groups. CONCLUSIONS: These findings depict the utilization of Korean herbal medicine in the real world and the dynamics underlying the herbal medicine prescription patterns for infertile women.

Efficacy of coenzyme Q10 supplementation for male infertility with high sperm DNA fragmentation index: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Infertility is a focal issue in public health and affects human reproduction and survival. Notably, an increasing number of studies in recent decades have found that sperm DNA integrity plays a critical role in the development of healthy embryos. Among the multiple pathogenic factors of sperm DNA fragmentation, oxidative stress has proven to be predominant. Coenzyme Q10 supplementation, which has been used for the treatment of male infertility, has shown good clinical efficacy due to its oxidation resistance, but its efficacy as measured by the sperm DNA fragmentation index remains controversial. To address this issue, we will perform a systematic review and meta-analysis to evaluate the efficacy of coenzyme Q10 for male infertility patients with a high sperm DNA fragmentation index. METHODS AND ANALYSIS: The PubMed, Embase, Cochrane Central Register of Studies and Web of Science databases will be comprehensively searched from inception to 31 December 2022 to identify relevant studies published in the English language using appropriate search strategies. The search terms will be derived from the following concepts: sperm DNA fragmentation, coenzyme Q10 and randomised controlled trials. Two review stages, that is, title and abstract screening and full-text screening, will be performed by two reviewers. The risk of bias, publication bias and evidence grade of the included studies will be assessed using a standardised protocol. Data will be used to calculate effect sizes. Heterogeneity among the studies will be evaluated graphically. Subgroup analysis and sensitivity analysis will be performed if necessary to validate the results. ETHICS AND DISSEMINATION: No ethical approval will be needed, as there will be no participants in this study. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to disseminate the findings through publication and conference presentation. PROSPERO REGISTRATION NUMBER: CRD42022293340.

Effect of and the association between vitamin D and outcomes of assisted reproductive techniques among infertile men and women: protocol for an overview of systematic reviews and meta-analysis.

INTRODUCTION: Vitamin D is associated with many functions of the human reproductive system. Accordingly, it seems that on infertile couples undergoing assisted reproduction technology (ART), treatment outcomes may be affected by the vitamin D. This overview aims to show the effect of vitamin D on infertility treatments outcomes in recent studies by concluding systematic reviews and meta-analyses to achieve a comprehensive result. METHODS AND ANALYSIS: This overview protocol is being reported according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement and was registered in the International Prospective Register of Systematic Reviews. We will include all peer-reviewed systematic reviews and meta-analyses of randomised controlled trials published from inception until December 2022. PubMed, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Database of Abstracts of Reviews of Effects, Scopus, Cochrane Central Register of Controlled Trials and Embase will be searched from the time of publication of the first articles onwards with a comprehensive search strategy. Endnote V.X7 software (Thomson Reuters, New York, New York, USA) will be used to store and manage records. The results will align with guidelines in the Cochrane Handbook of Systematic Reviews of Interventions and the PRISMA statement. ETHICS AND DISSEMINATION: This overview will be evaluating the effect of vitamin D status and vitamin D supplementing on results of ART in women and men who are undergoing treatment for infertility. The high prevalence of vitamin D deficiency worldwide and its effects on an important issue such as human fertility might be a very influential factor that leads scientists to strongly recommend its use. However, the more critical concern is that there is no definitive agreement in studies on the relationship between vitamin D and an increased chance of better fertility in men and women undergoing infertility treatment. PROSPERO REGISTRATION NUMBER: CRD42021252752.

A Multi-Ingredient Supplement Protects against Obesity and Infertility in Western Diet-Fed Mice.

The Western diet (WD) predisposes to bodyweight gain and obesity and is linked to mitochondrial dysfunction, oxidative damage, inflammation, and multisystem disease, even affecting the reproductive organs, fertility, and pregnancy outcomes. In this study, we investigated the effects of multi-ingredient supplementation (MIS) with antioxidants, phytonutrients, and vitamins ('Fertility Enhancer'; FE) on white adipose tissue (WAT) expansion, nonalcoholic fatty liver disease (NAFLD), and infertility in WD-fed C57BL/6J mice. Five-month-old male (M) and female (F) mice were fed a low-fat diet (LF) or a high fat/sucrose WD (HF) for six weeks, followed by six weeks of LF (3.64 kcal/g), HF (4.56 kcal/g), or HF combined with FE (4.50 kcal/g). A sub-set of animals were sacrificed at 12 weeks, while the remainder were harem-mated in a 1:2 male-to-female ratio, and singly housed during the gestational period. Two-way, factorial ANOVA analysis revealed a main effect of diet on bodyweight (BW), total body fat, % body fat, white adipose tissue mass, and liver lipid content (all p < 0.001), driven by the anti-obesogenic effects of the 'Fertility Enhancer'. Similarly, a main effect of diet was found on PGC1-α mRNA levels (p < 0.05) and mitochondrial protein content (p < 0.001) in perigonadal WAT, with PGC1-α induction and higher complex II and complex III expression in FE vs. HF animals. Copulatory plug counts were higher in FE vs. HE couples (30% vs. 6%), resulting in more litters (4 vs. 0) and higher copulatory success (67% vs. 0%). Although the trends of all histology outcomes were suggestive of a benefit from the FE diet, only the number of atretic follicles and testicular mass were significant. Ovarian IL-1ß mRNA induction was significantly attenuated in the FE group (p < 0.05 vs. HF) with CASP1 attenuation trending lower (p = 0.09 vs. HF), which is indicative of anti-inflammatory benefits of the 'Fertility Enhancer.' We conclude that supplementation with specific phytonutrients, antioxidants, and vitamins may have utility as an adjunctive therapy for weight management, fatty liver disease, and infertility in overweight and obese couples.

Herbal Medicines for Idiopathic Male Infertility: A Systematic Review.

BACKGROUND: Various medications, surgeries, and assisted reproductive techniques are used to treat male infertility, but the high cost and low effectiveness have made these methods unpopular. The use of herbal medicines such as Withania somnifera, Ceratonia siliqua, Nigella sativa and Alpinia officinarum for the treatment of male infertility has become highly popular in recent years. OBJECTIVE: We conducted this systematic review to evaluate the recent scientific evidence regarding herbal medicines used to treat idiopathic male infertility (IMI). METHODS: Online literature resources were checked using different search engines, including ISI, Web of Knowledge, Medline, PubMed, Scopus, and Google Scholar. Date restrictions were applied to 2020, and the publication language was restricted to English and Persian. The risk of bias was evaluated using the Cochrane method. RESULTS: Out of 851 articles, 14 trials with 1218 participants were included. Of the 15 plants and medicinal products introduced in the selected studies, 12 cases were effective in treating male infertility. Each of these plants or products affects specific components of male fertility for which various mechanisms were mentioned, but most of them had antioxidant effects. No serious side effects were reported. CONCLUSION: Whitania somnifera roots, Alpinia officinarum, Nigella sativa seeds, Tomato, and Ceratonia siliqua and the formulation of Xperm, PHF, Churna Ratnam, Svaguptadi Churna, Y virilin capsule, manix capsule, and Tradafertil tablet revealed successful outcomes in treatment of idiopathic male infertility.

Effect of folic acid supplementation on diminished ovarian reserve: study protocol of a single-centre, open-label, randomised, placebo-controlled clinical trial.

INTRODUCTION: The prevalence of diminished ovarian reserve (DOR), a common gynaecological disorder, is approximately 10% across the world. Failure in early diagnosis and treatment may result in continuous decreases in ovarian function and the resultant loss in an opportunity of pregnancy, which greatly affects the happiness of the women's family and women's physical and mental health. Nevertheless, there has been no effective treatment for such a disorder until now. Folic acid, a member of the vitamin B family, is involved in one-carbon cycle and methylation regulation. It has been found that folic acid affects the whole period of pregnancy, and folic acid supplementation has shown effective to remarkably reduce the incidence of fetal neural tube defects and decrease plasma homocysteic acid levels, thereby resulting in a decline in the incidence of abortion. In addition, folic acid is reported to mediate ovarian functions. It is therefore hypothesised that folic acid may improve DOR. METHODS AND ANALYSIS: A single-centre, open-label, randomised, placebo-controlled clinical trial is designed. We plan to recruit 140 women with DOR at ages of 30-35 years. All participants will be randomised into the folic acid group and placebo group, and each subject will be given a tablet with the same appearance daily for 6 months. The primary outcome is antral follicle count, and the secondary outcomes are ovarian reserve markers, ovarian low-dose stimulation responses and safety. ETHICS AND DISSEMINATION: This study was approved by the Ethics Review Committee of Nanping First Hospital Affiliated to Fujian Medical University on 10 February 2021 (approval number: NPSY202002042). Written informed consent was obtained from all participants prior to randomisation, following a detailed description of the purpose of the study. The results of this clinical trial will be presented at scientific conferences and submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR2100047410.

Effect of non-pharmacological interventions for overweight/obese women with polycystic ovary syndrome on ovulation and pregnancy outcomes: a protocol for a systematic review and network meta-analysis.

INTRODUCTION: Most overweight/obese women with polycystic ovary syndrome (PCOS) have infertility issues which are difficult to treat. Non-pharmacological interventions used for the management of infertility include lifestyle interventions, acupuncture therapies and nutritional supplements. These interventions have been reported to be beneficial in alleviating infertility among overweight women with PCOS. However, effect and safety of these non-pharmacological interventions vary, and there is no standard method of clinical application. Therefore, it is necessary to conduct a systematic review and network meta-analysis (NMA) to rank these non-pharmacological interventions in terms of effect and determine which one is more effective for clinical application. METHODS AND ANALYSIS: We will retrieve eight databases including Cochrane Library, Medline, Embase, PsycINFO, Chinese National Knowledge Infrastructure, WanFang Data, the Chongqing VIP Database and China Biology Medicine disc from their inceptions onwards. In addition, four clinical trial registries and the related references will be manually retrieved. The primary outcome will be clinical pregnancy. Live birth, ovulation, pregnancy loss, multiple pregnancy and adverse events related to interventions will be considered as the secondary outcomes. STATA software V.15.0 and Aggregate Data Drug Information System V.1.16.8 will be used to conduct pairwise meta-analysis and NMA. The Grading of Recommendations Assessment, Development and Evaluation system will be adopted to evaluate the certainty of evidence. ETHICS AND DISSEMINATION: Ethical approval will not be required because the study will not include the original information of participants. The results will be published in a peer-reviewed journal or disseminated in relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42021283110.

A Cross-Sectional Evaluation of Vitamin D Status and Ovarian Reserve Markers in Subfertile Women: A Single-Center Experience From Pakistan.

Objectives This study was conceived with the objective of assessing the correlation between ovarian reserve markers and vitamin D deficiency (VDD) in a selected group of Pakistani subfertile women presenting at a specialized subfertility treatment centre. The measurements of antral follicle count (AFC), serum anti-Müllerian hormone (AMH), serum follicle-stimulating hormone (FSH), and serum vitamin D (VD) levels were the main tools used for the assessment of ovarian reserve. Materials and methods All female patients aged 18 to 45 years presenting with primary and/or secondary subfertility at the Australian Concept Medical Centre in Karachi, Pakistan from August 2016 to July 2021 were included in the study. The data of all eligible patients were recorded in the pre-defined Performa designed for this study. The Kruskal-Wallis test was applied to report the distribution of the data. The correlation between the categorical variables (25-hydroxyvitamin D [25-OHD] levels with AFC and AMH) was assessed using the chi-square test and Spearman correlation. The comparison was based on vitamin D levels grouped into three categories: deficiency (<20 ng/ml), insufficiency (21-29 ng/ml), and sufficiency (>30 ng/ml). Results One hundred ninety-nine cases were evaluated for AFC and hormone analysis. The mean age and BMI were 32.87±5.49 years and 28.27±4.97 kg/m2.VDD was noted in 127 (68.4%) cases. No significant difference was noted across BMI, age, duration of subfertility, AMH, and FSH across the VD categories. Moreover, a poor correlation was noted between VD, AMH and FSH on the scatter plot, between VD and FSH (r = -0.003, p = 0.966) and between VD and AMH (r = -0.068, p = 0.342), respectively. Conclusions This study showed a high frequency of VDD in Pakistani subfertile women, from a specialized subfertility center in the largest metropolis in the country. However, a statistically significant association was not found between the markers of ovarian reserve and VD, showing no ethnic differences in the native Pakistani population. Hence, VD supplementation is unlikely to have an impact on correcting the ovarian reserve status in subfertile women in Pakistan. However, this is a potential area of interest, and evaluation of other indices of reproduction/ovarian reserve and the effect of confounders is required to test this hypothesis longitudinally.

Evaluation of a stand-alone mobile mindfulness app in people experiencing infertility: the protocol for an exploratory randomised controlled trial (MoMiFer-RCT).

INTRODUCTION: Infertility and its treatment bring a considerable emotional burden. Increasing evidence demonstrates the effectiveness of smartphone-delivered mindfulness apps for reducing symptoms of emotional distress in both clinical and non-clinical populations. Evidence on this topic in women, men and couples experiencing infertility is currently under-represented. The aim of the MoMiFer study is, therefore, to investigate the efficacy of a stand-alone mobile mindfulness app on symptoms of emotional distress and fertility-related quality of life in people experiencing infertility. METHODS AND ANALYSIS: This study is an exploratory randomised controlled trial (RCT) with open enrollment. The primary outcomes are symptoms of emotional distress and fertility-related quality of life. Secondary outcomes are mindfulness skills, repetitive negative thinking, self-compassion, user-rated quality of the stand-alone mobile mindfulness app and use of the app. Experience sampling method and standardised self-report questionnaires are combined within a repeated measures design to measure the effects of the stand-alone mobile mindfulness app on the primary and secondary outcomes, apart from the use of the app. The latter will be evaluated through app tracking. People, including women, men and couples, experiencing infertility (n=60) will be randomised to an intervention group receiving the stand-alone mobile mindfulness app for 3 months or a wait-list control group. The app follows the format and content of Mindfulness-Based Stress Reduction. Data will be collected at baseline, at 1.5 months and 3 months after randomisation. Analysis will be according to intention to treat and based on general linear modelling and multilevel mixed-effects modelling. ETHICS AND DISSEMINATION: This study received approval from the Medical Ethical Committee of the Leuven University Hospital (Belgium). The findings of this exploratory RCT will be disseminated through presentations at public lectures, scientific institutions and meetings, and through peer-reviewed scientific articles. TRIAL REGISTRATION NUMBER: NCT04143828.

Quantitative assessment of pregnancy outcome following recurrent miscarriage clinic care: a prospective cohort study.

OBJECTIVES: To measure pregnancy outcome following attendance at a recurrent miscarriage service and identify factors that influence outcome. DESIGN: Prospective, observational electronic cohort study. SETTING: Participants attending a specialist recurrent miscarriage clinic, with a history of two or more pregnancy losses. 857 new patients attended over a 30-month period and were invited to participate. Participant data were recorded on a bespoke study database, 'Tommy's Net'. PARTICIPANTS: 777 women consented to participate (90.7% of new patients). 639 (82%) women continued within the cohort, and 138 were lost to follow-up. Mean age of active participants was 34 years for women and 37 years for partners, with a mean of 3.5 (1-19) previous pregnancy losses. Rates of obesity (maternal: 23.8%, paternal: 22.4%), smoking (maternal:7.4%, paternal: 19.4%) and alcohol consumption (maternal: 50%, paternal: 79.2%) were high and 55% of participants were not taking folic acid. OUTCOME MEASURES: Biannual collection of pregnancy outcomes, either through prompted self-reporting, or existing hospital systems. RESULTS: 639 (82%) women were followed up. 404 (83.4%) reported conception and 106 (16.6%) reported no pregnancy, at least 6 months following registration. Of those that conceived, 72.8% (294/404) had a viable pregnancy. Maternal smoking and body mass index (BMI) over 30 were significantly higher in those who did not conceive (p=0.001) CONCLUSIONS: Tommy's Net provides a secure electronic repository on data for couples with recurrent pregnancy loss and associated outcomes. The study identified that subfertility, as well as repeated miscarriage, maternal BMI and smoking status, contributed to failure to achieve live birth. Study findings may enable comparison of clinic outcomes and inform the development of a personalised holistic care package.

Evaluating interventions and adjuncts to optimize pregnancy outcomes in subfertile women: an overview review.

BACKGROUND: There is a wealth of information regarding interventions for treating subfertility. The majority of studies exploring interventions for improving conception rates also report on pregnancy outcomes. However, there is no efficient way for clinicians, researchers, funding organizations, decision-making bodies or women themselves to easily access and review the evidence for the effect of adjuvant therapies on key pregnancy outcomes in subfertile women. OBJECTIVE AND RATIONALE: The aim was to summarize all published systematic reviews (SRs) of randomized controlled trials (RCTs) of interventions in the subfertile population, specifically reporting on the pregnancy outcomes of miscarriage and live birth. Furthermore, we aimed to highlight promising interventions and areas that need high-quality evidence. SEARCH METHODS: We searched the Cochrane Database of Systematic Reviews and PubMed clinical queries SR filter (inception until July 2021) with a list of key words to capture all SRs specifying or reporting any miscarriage outcome. Studies were included if they were SRs of RCTs. The population was subfertile women (pregnant or trying to conceive) and any intervention (versus placebo or no treatment) was included. We adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) for determining the quality of the evidence. Exclusion criteria were overview reviews, reviews that exclusively reported on women conceiving via natural conception, reviews including non-randomized study designs or reviews where miscarriage or live birth outcomes were not specified or reported. OUTCOMES: The primary outcome was miscarriage, defined as pregnancy loss <24 weeks of gestation. Data were also extracted for live birth where available. We included 75 published SRs containing 121 251 participants. There were 14 classes of intervention identified: luteal phase, immunotherapy, anticoagulants, hCG, micronutrients, lifestyle, endocrine, surgical, pre-implantation genetic testing for aneuploidies (PGT-As), laboratory techniques, endometrial injury, ART protocols, other adjuncts/techniques in the ART process and complementary interventions. The interventions with at least moderate-quality evidence of benefit in reducing risk of miscarriage or improving the chance of a live birth are: intrauterine hCG at time of cleavage stage embryo transfer, but not blastocyst transfer, antioxidant therapy in males, dehydroepiandrosterone in women and embryo medium containing high hyaluronic acid. Interventions showing potential increased risk of miscarriage or reduced live birth rate are: embryo culture supernatant injection before embryo transfer in frozen cycles and PGT-A with the use of fluorescence in situ hybridization. WIDER IMPLICATIONS: This review provides an overview of key pregnancy outcomes from published SRs of RCTs in subfertile women. It provides access to concisely summarized information and will help clinicians and policy makers identify knowledge gaps in the field, whilst covering a broad range of topics, to help improve pregnancy outcomes for subfertile couples. Further research is required into the following promising interventions: the dose of progesterone for luteal phase support, peripheral blood mononuclear cells for women with recurrent implantation failure, glucocorticoids in women undergoing IVF, low-molecular-weight heparin for unexplained subfertility, intrauterine hCG at the time of cleavage stage embryo or blastocyst transfer and low oxygen concentrations in embryo culture. In addition, there is a need for high-quality, well-designed RCTs in the field of reproductive surgery. Finally, further research is needed to demonstrate the integrated effects of non-pharmacological lifestyle interventions.

Effectiveness of progesterone supplementation in women presenting low progesterone levels on the day of frozen embryo transfer: a randomised controlled trial.

INTRODUCTION: Progesterone is an essential hormone involved in the process of implantation and pregnancy maintenance. Evidence from recent studies has supported the importance of serum progesterone level around the time of embryo transfer in hormonal replacement therapy frozen embryo transfer cycles and recommended the need for individualised luteal support. Low progesterone around the time of embryo transfer is found to be associated with decreased rate of pregnancy after frozen embryo transfer. This single-centre, longitudinal, randomised, interventional controlled study aims to compare the rate of ongoing pregnancy between two groups of women with progesterone level below 10 ng/mL on the day of frozen embryo transfer: the study group using 800 mg vaginal micronised progesterone supplemented with 50 mg intramuscular progesterone per day and the control group using only 800 mg vaginal micronised progesterone. METHODS AND ANALYSIS: We enrol patients who are undergoing frozen embryo transfers with blastocyst-stage or cleavage-stage embryos and who satisfy the inclusion and exclusion criteria. After signing the informed consent, participants are randomised into two groups: the study group using vaginal micronised progesterone supplemented with progesterone intramuscular 50 mg per day and the control group using only vaginal micronised progesterone. Randomisation will be performed using R software at a 1:1 allocation ratio. Sequentially numbered, opaque sealed envelopes are used for allocation. The primary outcome is the rate of ongoing pregnancy. To demonstrate a difference of 10% with regard to rate of ongoing pregnancy, at least 370 participants per arm are required (type I error α=0.05, power=0.8). Assuming a dropout rate of 10%, a total of 824 patients (412 per group) will be invited. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of Tu Du Hospital on 17 May 2021 (reference number: 1251/QD-BVTD). All participants provide informed consent before being enrolled in the study. The results of our study will be submitted to reproductive medicine conferences and journals. TRIAL REGISTRATION NUMBER: NCT04897269.

Preserving effect of Loboob (a traditional multi-herbal formulation) on sperm parameters of male rats with busulfan-induced subfertility.

OBJECTIVE: Male infertility secondary to exposure to gonadotoxic agents during reproductive age is a concerning issue. The aim of this experimental study was to determine the effect of Loboob on sperm parameters. METHODS: 55 healthy rats were selected, weighted and divided into five groups consisting of 11 rats each. The control group received no medication. Rats in Treatment Group 1 received 10mg/kg Busulfan and rats in Treatment Groups 2, 3, and 4 received 35,70 and 140 mg/kg Loboob respectively in addition to 10mg/kg Busulfan. Finally, the sperm parameters and weights of the rats were compared using the Kolmogorov-Smirnov, non-parametric Kruskal-Wallis, and Dunn-Bonferroni tests. RESULTS: All sperm parameters and weights were significantly decreased among rats receiving Busulfan. All dosages of Loboob were effective to enhance the motility of slow spermatozoa, while only in the rats given 70 and 140 mg/kg of Loboob saw improvements in progressively motile sperm percentages (0.024 and 0.01, respectively). Loboob at a dosage of 140mg/kg improved sperm viability. It did not improve normal morphology sperm or decrease immotile sperm counts. Loboob did not affect mean rat weight. CONCLUSIONS: Loboob offered a dose-dependent protective effect on several sperm parameters in rats with busulfan-induced subfertility.

Strategy to improve the female fertility in the general gynecologist's office: use of a nutritional supplement based on myo-inositol/D-chiro-inositol and antioxidants.

Subfertility is more than a quality-of-life problem as it has a substantial negative public health impact. Polycystic ovary syndrome (PCOS) is one of the most common causes of subfertility, affecting one out of 10 women in reproductive age. Among PCOS women undergoing assisted reproductive technology, treatment based on myo-inositol and high doses of D-chiro-inositol has been shown to increase pregnancy rate and number of live births, reduce ovarian hyperstimulation syndrome and improve oocyte quality. A preparation based on myo-inositol and high doses of D-chiro-inositol, together with antioxidants, vitamins, and minerals, could have beneficial effects and be an optimal strategy to improve female fertility in the general gynecologist's office. The aim of this review is to highlight the role of inositol and its isomers in improving fertility of women with PCOS.

Dehydroepiandrosterone (DHEA) role in enhancement and maintenance of implantation (DREAM): randomised double-blind placebo-controlled trial-study protocol.

INTRODUCTION: Dehydroepiandrosterone (DHEA) is an important precursor of androgen and has been studied and researched extensively for improving the various outcome measures of ovarian stimulation in women with advanced age or poor ovarian response. Androgens also play an important role in the enhancement of endometrial and decidual function by regulating both the transcriptome and secretome of the endometrial stromal cells and have a positive effect on various factors like insulin-like growth factor binding protein 1, homeobox genes (HOXA10, HOXA11), secreted phosphoprotein 1, prolactin which are necessary for implantation. It is well-known that the circulating 'precursor pool' of DHEA declines with age more so in poor ovarian reserve patients and exogenous supplementation may be beneficial in such cases. This double-blinded randomised controlled trial (RCT) aims to test the hypothesis whether transient targeted supplementation of DHEA as an adjuvant to progesterone in frozen embryo transfer (FET) cycles, for women with low serum testosterone, helps in improving live birth rate. METHODS AND ANALYSIS: This study is planned as a double-blinded, placebo-controlled randomised trial and the sample size, calculated for the primary outcome measure-live birth rate, is 140. All participants will be having a flexible antagonist protocol for controlled ovarian stimulation and an elective freeze-all policy for the embryos as per the hospital protocol after written informed consent. For FET, the endometrium will be prepared by hormone replacement treatment protocol. During the FET cycle, the intervention group will be receiving DHEA 25 mg two times a day for 15 days from the day of starting progesterone supplementation and the control group will be receiving a placebo. ETHICS AND DISSEMINATION: The approval of the study was granted by the Clinical Trials Registry-India and the Institutional Ethical Committee of CRAFT Hospital and Research Center. All participants will provide written informed consent before being randomised into allocated treatment groups. The results will be disseminated to doctors and patients through conference presentations, peer-reviewed publications, social media and patient information booklets. TRIAL REGISTRATION NUMBERS: CTRI/2020/06/025918; ECR/1044/Inst/KL/2018.

Effects of moxibustion on reproduction and metabolism of polycystic ovary syndrome: a protocol for meta-analysis and systematic review.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathy in women of reproductive age. Recently, moxibustion, as a complementary and alternative therapy, has been commonly used in assisted reproduction and improvement of metabolic abnormalities in patients with PCOS. Currently, intervention efficacy of the use of moxibustion in PCOS treatment still remains controversial due to lack of high-quality evidence. Consequently, this study protocol was designed to objectively review and evaluate the effectiveness and safety of moxibustion treatment for PCOS. METHODS AND ANALYSIS: Electronic searches will be carried out from inception to May 2021 in the online databases of The Cochrane Library, PubMed, EMBASE, Chinese Biomedical Literature, Chongqing VIP Chinese Science and Technology Periodical Database (VIP) and China National Knowledge Infrastructure. The Chinese Clinical Trial Registry Center and Clinical Trials will be used for searching ongoing trials. Randomised controlled trials and the first period in randomised cross-over trials involving any type of moxibustion for patients with PCOS will be included. Primary outcomes will be the ovulation rate, pregnancy rate and sex hormone levels, and secondary outcomes will be changes in clinical symptoms and metabolic indicators, total effective rate and the incidences of side effects and adverse events. Briefly, two reviewers will independently conduct study selection and data extraction, and the risk of bias will be assessed. Prior to the formal meta-analysis, the heterogeneity of included studies will be assessed. Review Manager Statistical Software (RevMan) V.5.3 will be used for data processing. Finally, the Grading of Recommendations Assessment, Development and Evaluation method will be applied to evaluate the quality of evidence. ETHICS AND DISSEMINATION: Ethical approval is not necessary since this study is designed as a systematic review. This study will be disseminated by a peer-review journal or conference presentation.

Safety of oil-based contrast medium for hysterosalpingography: a systematic review.

Recent meta-analyses have shown that a hysterosalpingography (HSG) with oil-based contrast increases pregnancy rates in subfertile women. However, the frequency of complications during or after an HSG with oil-based contrast in subfertile women and/or their offspring is still unclear. This systematic review and meta-analysis, without restrictions on language, publication date or study design, was performed to fill this knowledge gap. The results show that the most frequently reported complication was intravasation of contrast, which occurred in 2.7% with the use of oil-based contrast (31 cohort studies and randomized controlled trials [RCT], 95% CI 1.7-3.8, absolute event rate 664/19,339), compared with 2.0% with the use of water-based contrast (8 cohort studies and RCT, 95% CI 1.2-3.0, absolute event rate 18/1006). In the cohort studies and RCT there were 18 women with an oil embolism (18/19,339 HSG), all without serious lasting consequences. Four cases with serious consequences of an oil embolism were described (retinal oil embolism [n = 1] and cerebral complaints [n = 3]); these reports did not describe the use of adequate fluoroscopy guidance during HSG. In conclusion, the most frequently reported complication after an HSG with oil-based contrast is intravasation occurring in 2.7%. In total four cases with serious consequences of oil embolisms in subfertile women were published.

2021 European Thyroid Association Guideline on Thyroid Disorders prior to and during Assisted Reproduction.

Severe thyroid dysfunction may lead to menstrual disorders and subfertility. Fertility problems may persist even after restoring normal thyroid function, and then an assisted reproductive technology (ART) may be a solution. Prior to an ART treatment, ovarian stimulation is performed, leading to high oestradiol levels, which may lead to hypothyroidism in women with thyroid autoimmunity (TAI), necessitating levothyroxine (LT4) supplements before pregnancy. Moreover, women with the polycystic ovarian syndrome and idiopathic subfertility have a higher prevalence of TAI. Women with hypothyroidism treated with LT4 prior to ART should have a serum TSH level <2.5 mIU/L. Subfertile women with hyperthyroidism planning an ART procedure should be informed of the increased risk of maternal and foetal complications, and euthyroidism should be restored and maintained for several months prior to an ART treatment. Fertilisation rates and embryo quality may be impaired in women with TSH >4.0 mIU/L and improved with LT4 therapy. In meta-analyses that mainly included women with TSH levels >4.0 mIU/L, LT4 treatment increased live birth rates, but that was not the case in 2 recent interventional studies in euthyroid women with TAI. The importance of the increased use of intracytoplasmic sperm injection as a type of ART on pregnancy outcomes in women with TAI deserves more investigation. For all of the above reasons, women of subfertile couples should be screened routinely for the presence of thyroid disorders.