The Role of NLRP3 Inflammasome in Obesity and PCOS-A Systematic Review and Meta-Analysis.

Inflammasomes have recently been implicated in the pathogenesis of several chronic inflammatory disorders, such as diabetes and obesity. The aim of this meta-analysis was to investigate the possible role of the NLRP3 inflammasome in obesity and polycystic ovarian syndrome (PCOS). A comprehensive search of electronic databases was conducted to identify studies investigating NLRP3 its related components (Caspase 1, ASC and IL-1ß) in adipose tissue and/or blood from obese individuals compared to non-obese controls. Another search was conducted for studies investigating NLRP3 in PCOS women and animal models. The ssearched databases included Medline, EMBASE, Cochrane Library, PubMed, Clinicaltrials.gov, the EU Clinical Trials Register and the WHO International Clinical Trials Register. The quality and risk of bias for the included articles were assessed using the modified Newcastle-Ottawa scale. Data were extracted and pooled using RevMan software for the calculation of the standardized mean difference (SMD) and 95% confidence interval (CI). Twelve eligible studies were included in the obesity systematic review and nine in the PCOS review. Of the obesity studies, nine (n = 270) were included in the meta-analysis, which showed a significantly higher adipose tissue NLRP3 gene expression in obese (n = 186) versus non-obese (n = 84) participants (SMD 1.07; 95% CI, 0.27, 1.87). Pooled analysis of adipose tissue IL-1ß data from four studies showed significantly higher IL-1ß gene expression levels in adipose tissue from 88 obese participants versus 39 non-obese controls (SMD 0.56; 95% CI, 0.13, 0.99). Meta-analysis of adipose tissue ASC data from four studies showed a significantly higher level in obese (n = 109) versus non-obese (n = 42) individuals (SMD 0.91, 95% CI, 0.30, 1.52). Of the nine PCOS articles, three were human (n = 185) and six were animal studies utilizing PCOS rat/mouse models. All studies apart from one article consistently showed upregulated NLRP3 and its components in PCOS women and animal models. In conclusion, obesity and PCOS seem to be associated with upregulated expression of NLRP3 inflammasome components. Further research is required to validate these findings and to elucidate the role of NLRP3 in obesity and PCOS.

The prevalence of hyperprolactinaemia in subfertile ovulatory women and its impact on fertility treatment outcome.

Subtle hyperprolactinaemia is not an uncommon finding in ovulatory subfertile women. The objective of this study is to evaluate the prevalence of hyperprolactinaemia in subfertile ovulatory and oligo-anovulatory women, and to determine if hyperprolactinaemia influences fertility treatment outcome. All women (n = 1010) who attended the fertility clinic of a UK tertiary hospital during 2015-2019 were included. Out of 804 eligible women analysed, 575 women (71.5%) were ovulatory and 229 (28.5%) were oligo-anovulatory. Prevalence of hyperprolactinaemia was higher in the ovulatory group than in the oligo-anovulatory group (26.8% vs. 14.4%; OR: 2.2; 95% confidence interval (CI): 1.4-3.2). On sub-group analysis, the prevalence of mild, moderate and severe hyperprolactinaemia was 23.0%, 3.7% and 0.2% in ovulatory women and 11.8%, 1.7% and 0.9% in oligo-anovulatory women. Mild hyperprolactinaemia was found to be more prevalent in the ovulatory group (OR: 2.2; 95%CI: 1.4-3.5). Ongoing pregnancy/livebirth rates were similar between hyperprolactinaemic and normoprolactinaemic women (42.8% vs. 46.7%). Hyperprolactinaemia did not have an impact on ongoing pregnancy/livebirth rates in both ovulatory and oligo-anovulatory women (OR:0.8; 95%CI: 0.5-1.1; OR: 1.2; 95%CI: 0.6-2.5, respectively). Hyperprolactinaemia is prevalent among ovulatory women, although most had mildly raised clinically insignificant levels. Elevated prolactin levels in ovulatory women do not seem to impact on pregnancy outcome. Impact StatementWhat is already known on this subject? Prolactin has been linked to ovulation and fertility. Prolactin testing is not generally recommended for subfertile women with regular menstrual cycles, which is a surrogate marker of ovulation. However, some clinicians, particularly in the general practice, still perform prolactin test as part of baseline endocrine profile.What do the results of this study add? Prevalence of hyperprolactinaemia in subfertile ovulatory women was 26.8% (154/575), of which 86% (132/154) were mild. Further, the livebirth/ongoing pregnancy rates were similar between hyperprolactinaemic and normoprolactinaemic women. Prolactin being a sensitive hormone, responsive to even minimal stress and its high levels not influencing clinical pregnancy outcome, prolactin measurement is not needed in women having regular menstrual cycles.What are the implications of these findings for clinical practice and/or further research? Hyperprolactinaemia was not uncommon in ovulatory women, although most had mildly elevated levels. Hyperprolactinaemia did not have any impact on fertility treatment outcome. Serum prolactin should not be tested in ovulating women, as mild elevations are commonly present and have no clinical significance.

The Role of Chronic Inflammation in Polycystic Ovarian Syndrome-A Systematic Review and Meta-Analysis.

Although the current literature associates polycystic ovarian syndrome (PCOS) with chronic inflammation, the evidence for this link remains inconclusive and its causal nature remains unclear. The purpose of this systematic review was to assess the inflammatory status in PCOS women and to determine whether it is related to PCOS or to its associated adiposity. We searched electronic databases including PUBMED, EMBASE and MEDLINE, SCOPUS, DynaMed plus, TRIP, ScienceDirect and Cochrane Library, for studies investigating C-reactive protein (CRP) and other inflammatory makers in PCOS women versus healthy controls. Quality and risk of bias for selected studies were assessed using the modified Newcastle-Ottawa scale. CRP data were extracted and pooled using RevMan for calculation of the standardized mean difference (SMD) and 95% confidence interval (CI). Eighty-five eligible studies were included in the systematic review, of which 63 were included in the meta-analysis. Pooled analysis of the 63 studies revealed significantly higher circulating CRP in PCOS women (n = 4086) versus controls (n = 3120) (SMD 1.26, 95%CI, 0.99, 1.53). Sensitivity meta-analysis of 35 high quality studies including non-obese women showed significantly higher circulating CRP in PCOS women versus controls (SMD 1.80, 95%CI, 1.36, 2.25). In conclusion, circulating CRP is moderately elevated in PCOS women independent of obesity, which is indicative of low-grade chronic inflammation.

The impact of uterine artery embolization on ovarian reserve: A systematic review and meta-analysis.

INTRODUCTION: Uterine artery embolization (UAE) has been gaining increasing popularity as an effective and minimally invasive treatment for uterine fibroids. However, there has been growing concern over the risk of unintended embolization of the utero-ovarian circulation, leading to reduction of ovarian blood supply with subsequent impairment of ovarian reserve. The purpose of this study was to investigate the impact of UAE on circulating anti-Müllerian hormone (AMH) and other markers of ovarian reserve. MATERIAL AND METHODS: This meta-analysis included all published cohort, cross-sectional and case-control studies, as well as randomized trials that investigated the impact of UAE on circulating AMH. Data sources included MEDLINE, EMBASE, Dynamed Plus, ScienceDirect, TRIP database, ClinicalTrials.gov and the Cochrane Library from January 2000 to June 2019. All identified articles were screened, and articles were selected based on the inclusion and exclusion criteria. AMH and other data were extracted from the eligible articles and entered into RevMan software to calculate the weighted mean difference between pre- and post-embolization values. PROSPERO registration number: CRD42017082615. RESULTS: This review included 3 cohort and 3 case-control studies (n = 353). The duration of follow up after UAE ranged between 3 and 12 months. Overall pooled analysis of all studies showed no significant effect of UAE on serum AMH levels (weighted mean difference -0.58 ng/mL; 95% CI -1.5 to 0.36, I2  = 95%). Subgroup analysis according to age of participants (under and over 40 years) and according to follow-up duration (3, 6 and 12 months) showed no significant change in post-embolization circulating AMH. Pooled analysis of serum follicle-stimulating hormone (FSH) concentrations (4 studies, n = 248) revealed no statistically significant change after UAE (weighted mean difference 4.32; 95% CI -0.53 to 9.17; I2  = 95%). Analysis of 2 studies (n = 62) measuring antral follicle count showed a significant decline at 3-month follow up (weighted mean difference -3.28; 95% CI -5.62 to -0.93; I2  = 94%). CONCLUSIONS: Uterine artery embolization for uterine fibroids does not seem to affect ovarian reserve as measured by serum concentrations of AMH and FSH.

The role of oxidative stress in ovarian toxicity induced by haloperidol and clozapine-a histological and biochemical study in albino rats.

Oxidative stress has been implicated in reproductive toxicity induced by antipsychotics (APs). This study aims to further investigate the role of AP-induced oxidative stress in reproductive dysfunction. Thirty adult female albino rats were divided into three groups including a control group (n = 10) receiving distilled water, HAL group (n = 10) receiving haloperidol (HAL) (2 mg/kg/day), and CLZ group (n = 10) receiving clozapine (CLZ) (20 mg/kg/day). After 28 days, the rats were anesthetized, blood was withdrawn from their hearts, and ovaries were removed before they were sacrificed. Serum prolactin concentrations were measured. For each rat, one ovary was used for biochemical studies including mitochondrial complexes I and III activities and oxidative stress markers (lipid peroxidation, super oxide dismutase [SOD], catalase [CAT], and reduced glutathione [GSH]). The other ovary was used for histopathological examination and immunohistochemistry staining for p53 and Ki-67. HAL-treated rats showed significantly (p < 0.001) higher serum prolactin concentrations compared with other groups. HAL significantly inhibited complexes I (p < 0.001) and III activities (p < 0.05), while CLZ inhibited only complex I (p < 0.001). Lipid peroxidation was increased by HAL (p < 0.001) and CLZ (p < 0.01). HAL caused significant (p < 0.001) reductions in SOD, CAT, and GSH. CLZ caused a significant decrease in SOD (p < 0.001) and GSH (p < 0.01) with no effect on CAT. Histopathological studies of CLZ- and HAL-treated ovaries showed features suggestive of hyperprolactinemia and oxidative stress. Ki-67- and P53-immunostained sections were suggestive of disruption of cellular proliferation. These findings support the hypothesis that HAL and CLZ induce reproductive dysfunction through mechanisms involving ovarian mitochondrial dysfunction and oxidative stress.

The impact of laparoscopic ovarian drilling on AMH and ovarian reserve: a meta-analysis.

Laparoscopic ovarian drilling (LOD) has been widely used as an effective treatment of anovulatory women with polycystic ovarian syndrome (PCOS). However, there has been a growing concern over a possible damaging effect of this procedure on ovarian reserve. The objective of this study was to investigate the hypothesis that LOD compromises ovarian reserve as measured by post-operative changes in circulating anti-Müllerian hormone (AMH). This meta-analysis included all cohort studies as well as randomised controlled trials (RCTs) investigating serum AMH concentrations and other ovarian reserve markers in women with PCOS undergoing LOD. Various databases were searched including MEDLINE, EMBASE, Dynamed Plus, ScienceDirect, TRIP database, ClinicalTrials.gov and Cochrane Library from January 2000 to December 2016. Sixty studies were identified, of which seven were deemed eligible for this review. AMH data were extracted from each study and entered into the RevMan software to calculate the weighted mean difference (WMD) between pre- and post-operative values. Pooled analysis of all studies (n = 442) revealed a statistically significant decline in serum AMH concentration after LOD (WMD -2.13 ng/mL; 95% confidence interval (CI) -2.97 to -1.30). Subgroup analysis based on duration of follow-up, AMH kit, laterality of surgery and amount of energy applied during LOD consistently showed a statistically significant fall in serum AMH concentration. In conclusion, although LOD seems to markedly reduce circulating AMH, it remains uncertain whether this reflects a real damage to ovarian reserve or normalisation of the high pre-operative serum AMH levels. Further long-term studies on ovarian reserve after LOD are required to address this uncertainty.

Ovarian reserve after salpingectomy: a systematic review and meta-analysis.

INTRODUCTION: Although there has been a growing concern over the possible damaging effect of salpingectomy on ovarian reserve, this issue remains uncertain. The purpose of this meta-analysis was to test the hypothesis that salpingectomy may compromise ovarian reserve. MATERIAL AND METHODS: A detailed search was conducted using MEDLINE, Embase, Dynamed Plus, ScienceDirect, TRIP database and the Cochrane Library from January 2000 to November 2016. All cohort, cross-sectional and randomized controlled studies investigating changes in circulating anti-Müllerian hormone (AMH) after salpingectomy were considered. Thirty-seven studies were identified, of which eight were eligible. Data were extracted and entered into RevMan software for calculation of the weighted mean difference (WMD) and 95% CI. Two groups of studies were analyzed separately: group 1 (six studies, n = 464) comparing data before and after salpingectomy and group 2 (two studies) comparing data in women who have undergone salpingectomy (n = 169) vs. healthy controls (n = 154). RESULTS: Pooled results of group 1 studies showed no statistically significant change in serum AMH concentration after salpingectomy (WMD, -0.10 ng/mL; 95% CI -0.19 to 0.00, I2 = 0%). Similarly, meta-analysis of group 2 showed no statistically significant difference in serum AMH concentration between salpingectomy group and controls (WMD, -0.11 ng/mL; 95% CI -0.37 to 0.14, I2 = 77%). Subgroup analyses based on laterality of surgery, type of AMH kit and participants' age (<40 years) still showed no statistically significant changes in circulating AMH. CONCLUSION: Salpingectomy does not seem to compromise ovarian reserve in the short-term. However, the long-term effect of salpingectomy on ovarian reserve remains uncertain.

The impact of excision of benign nonendometriotic ovarian cysts on ovarian reserve: a systematic review.

BACKGROUND: Benign nonendometriotic ovarian cysts are very common and often require surgical excision. However, there has been a growing concern over the possible damaging effect of this surgery on ovarian reserve. OBJECTIVE: The aim of this metaanalysis was to investigate the impact of excision of benign nonendometriotic ovarian cysts on ovarian reserve as determined by serum anti-Müllerian hormone level. DATA SOURCES: MEDLINE, Scopus, ScienceDirect, and Embase were searched electronically. STUDY DESIGN: All prospective and retrospective cohort studies as well as randomized trials that analyzed changes of serum anti-Müllerian hormone concentrations after excision of benign nonendometriotic cysts were eligible. Twenty-five studies were identified, of which 10 were included in this analysis. DATA EXTRACTION: Two reviewers performed the data extraction independently. RESULTS: A pooled analysis of 367 patients showed a statistically significant decline in serum anti-Müllerian hormone concentration after ovarian cystectomy (weighted mean difference, -1.14 ng/mL; 95% confidence interval, -1.36 to -0.92; I(2) = 43%). Subgroup analysis including studies with a 3-month follow-up, studies using Gen II anti-Müllerian hormone assay and studies using IOT anti-Müllerian hormone assay improved heterogeneity and still showed significant postoperative decline of circulating anti-Müllerian hormone (weighted mean difference, -1.44 [95% confidence interval, -1.71 to -1.1; I(2) = 0%], -0.88 [95% confidence interval, -1.71 to -0.04; I(2) = 0%], and -1.56 [95% confidence interval, -2.44 to -0.69; I(2) = 22%], respectively). Sensitivity analysis including studies with low risk of bias and excluding studies with possible confounding factors still showed a significant decline in circulating anti-Müllerian hormone. CONCLUSION: Excision of benign nonendometriotic ovarian cyst(s) seems to result in a marked reduction of circulating anti-Müllerian hormone. It remains to be established whether this reflects a real compromise to ovarian reserve.

The Impact of High BMI on Pregnancy Outcomes and Complications in Women with PCOS Undergoing IVF-A Systematic Review and Meta-Analysis.

(1) Background: Current evidence indicates that women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization (IVF) have an increased likelihood of adverse pregnancy outcomes. The objective of this systematic review was to clarify the role of a PCOS-related high body mass index (BMI) in these unfavourable pregnancy outcomes. (2) Methods: A comprehensive search of electronic databases was conducted to identify studies investigating the impact of high BMI on pregnancy outcomes in women with PCOS undergoing IVF. RevMan software (v5.4) was used to calculate the odds ratio (OR) and 95% confidence interval (CI). (3) Results: Nineteen eligible studies (n = 7680) were identified, including 16 retrospective cohort studies (n = 6934), two prospective cohort studies (n = 525), and one cross-sectional study (n = 221). Pooled analysis showed significantly higher odds of clinical pregnancy (OR, 1.16 [95% CI, 1.04-1.29]; z = 2.73; p = 0.006; I2 = 30%) and livebirths (OR, 1.88 [95% CI, 1.56-2.27]; z = 6.54; p < 0.0001; I2 = 55%) in women with PCOS with a normal versus a high BMI. Meta-analysis showed significantly increased odds of miscarriages in women with PCOS with a high versus a normal BMI (OR, 0.76 [95% CI, 0.60-0.95]; z = 2.42; p = 0.02; I2 = 53%). Pooled analysis of three studies (n = 993) showed significantly higher ORs of gestational diabetes mellitus (OR 3.96 [95% CI 1.62-9.68]; z = 3.01; p = 0.003; I2 = 58%) and gestational hypertension (OR 2.16 [95% CI 1.32-3.54]; z = 3.05; p = 0.002; I2 = 68%) in women with PCOS with a high versus a normal BMI. Meta-analysis of three studies reported significantly greater odds of a caesarean section for women with PCOS with a high versus a normal BMI (OR 0.45 [95% CI 0.29-0.69]; z = 3.66; p = 0.0003; I2 = 0%). (4) Conclusions: The increased likelihood of adverse pregnancy outcomes observed in women with PCOS undergoing IVF seems to be attributable to a PCOS-related high BMI.

The Impact of Diet-Induced Weight Loss on Inflammatory Status and Hyperandrogenism in Women with Polycystic Ovarian Syndrome (PCOS)-A Systematic Review and Meta-Analysis.

Background: Currently, the primary strategy for addressing polycystic ovarian syndrome (PCOS) involves lifestyle modifications, with a focus on weight loss. The purpose of this meta-analysis was to assess the impact of weight loss through dietary interventions on inflammatory status and hyperandrogenism in PCOS women. Methods: A comprehensive search was conducted to identify randomised controlled trials (RCTs) and cohort studies assessing the impact of diet-induced weight loss on circulating inflammatory markers (CRP, IL-6, IL-1ß, TNF-α), androgens (testosterone, androstenedione), SHBG, and luteinising hormone (LH) in PCOS women. The quality and risk of bias of the included studies were assessed using the Cochrane Collaboration's tool for RCTs and the Newcastle-Ottawa Scale for cohort studies. Data were entered into RevMan software v5.9 for the calculation of standard mean difference (SMD) and the 95% confidence interval (95%CI) of circulating inflammatory markers, androgens, and LH between baseline and post-weight loss values. Results: Eleven studies (n = 323) were eligible for the systematic review, of which nine (n = 286) were included in the meta-analysis. Pooled analysis of data revealed a statistically significant decrease in circulating CRP (SMD 0.39, 95%CI 0.22, 0.56; 9 studies, n = 286), IL-6 (SMD 0.37, 95%Cl, 0.12, 0.61; 3 Studies, n = 140), TNF-α (SMD 0.30, 95%Cl, 0.07, 0.53; 4 Studies, n = 162), androstenedione (SMD 0.36, 95%Cl, 0.13, 0.60; 4 studies, n = 147) and LH (SMD 0.30, 95% Cl, 0.09, 0.51; 5 studies, n = 197) after weight loss compared to baseline levels among PCOS women. A meta-analysis of five studies (n = 173) showed a statistically significant increase in circulating SHBG after weight loss compared to baseline levels (SMD -0.43, 95%Cl, -0.65, -0.21). Conclusions: These findings suggest that weight loss induced by dietary interventions seems to improve PCOS-related chronic inflammation and hyperandrogenism. The possible causative relationship between the improvement in inflammation and hyperandrogenism remains to be determined.

The influence of circulating anti-Müllerian hormone on ovarian responsiveness to ovulation induction with gonadotrophins in women with polycystic ovarian syndrome: a pilot study.

BACKGROUND: Women with polycystic ovarian syndrome (PCOS) are known to have elevated circulating Anti-Müllerian hormone (AMH), which has been found to desensitize ovarian follicles to follicle stimulating hormone (FSH). The purpose of this study was to investigate the impact of high circulating AMH on ovarian responsiveness to ovulation induction with gonadotrophins in PCOS women. METHODS: This prospective observational pilot study was conducted in two collaborating Fertility Centres in the UK and Egypt. The study included 20 consecutive anovulatory women with PCOS who underwent 34 cycles of human menopausal gonadotrophin (hMG) ovarian stimulation using chronic low-dose step up protocol. Blood samples were collected for the measurement of serum AMH concentrations in the early follicular (day 2-3) phase in all cycles of hMG treatment. The serum levels of AMH were compared between cycles with good vs. poor response. The good response rates and the total dose and duration of hMG treatment were compared between cycles with high vs. low serum AMH concentrations. RESULTS: Cycles with poor response (no or delayed ovulation requiring >20 days of hMG treatment) had significantly (p = .007) higher median{range} serum AMH concentration (6.5{3.2-13.4}ng/ml) compared to that (4.0{2.2-10.2}ng/ml) of cycles with good response (ovulation within 20 days of hMG treatment). ROC curve showed AMH to be a useful predictor of poor response to hMG stimulation (AUC, 0.772; P = 0.007). Using a cut-off level of 4.7 ng/ml, AMH had a sensitivity of 100% and specificity of 58% in predicting poor response. The good response rate was significantly (p < .001) greater in cycles with lower AMH (<4.7 ng/ml) compared to that in those with AMH > = 4.7 ng/ml (100% vs. 35%, respectively). All cycles with markedly raised serum AMH levels (> 10.2 ng/ml) were associated with poor response. Cycles with high AMH (> = 4.7 ng/ml) required significantly (p < .001) greater amounts (median {range}, 1087{450-1650}IU) and longer duration (20 {12-30}days) of hMG stimulation than cycles with lower AMH (525 {225-900}IU and 8{6-14}days). CONCLUSIONS: PCOS women with markedly raised circulating AMH seem to be resistant to hMG ovulation induction and may require a higher starting dose.

HRT in Women Undergoing Pelvic Clearance for Endometriosis-A Case Report and a National Survey.

The optimal hormone replacement therapy (HRT) in women who have undergone pelvic clearance for endometriosis remains uncertain with insufficient evidence. The purpose of this case report and the national survey was to highlight the potential HRT-related risks and to establish current HRT practice in this group of women. The case was a 45-year-old woman presenting with recurrence of severe chronic pelvic pain while on oestrogen-only HRT (EO-HRT) for five years after subtotal hysterectomy and bilateral oophorectomy for severe endometriosis. MRI revealed multiple peri-cervical endometriomas and severe right hydroureter/hydronephrosis with complete right renal parenchymal loss. The survey was a 21-item questionnaire administered electronically using SurveyMonkey. It was reviewed and approved by British Menopause Society and British Society of Gynaecological endoscopy and was sent to their members as well as NHS Gynaecologists. A total of 216 physicians responded including 120 (55.6%) Gynaecology Consultants and 96 (44.4%) GPs/Nurses in Menopause clinics. Overall, 68.6% of responders prescribe combined HRT (C-HRT), 11.1% tibolone, 13.0% EO-HRT and 7.8% varied HRT. Fifty-one percent prescribe the progestogen component of C-HRT indefinitely, 22% for 3-6 months and 27% for varied durations. In conclusion, this study highlights the real risk of endometriosis recurrence in EO-HRT users after pelvic clearance for endometriosis. The survey revealed that only two thirds of Gynecologists/Menopause practitioners prescribe combined HRT in this group of women.

Impact of obesity on reproductive outcomes after ovarian ablative therapy in PCOS: a collaborative meta-analysis.

Obesity is known to interfere with reproductive outcomes in polycystic ovary syndrome. There is no consensus regarding the impact of obesity on reproductive outcomes after ovarian ablative therapy (OAT) and there is no level I evidence to answer this question. This systematic review and meta-analysis assessed the strength of the association between obesity and ovulation or pregnancy rates after OAT. MEDLINE and several other databases were searched from 2000 to September 2011 for studies reporting on OAT and reproductive outcomes. Data were synthesized to determine the relative risk of reproductive outcomes (ovulation and pregnancy) in lean (body mass index <25 kg/m(2)) compared with overweight or obese women. The study obtained 15 data sets (14 articles) for analysis, which included 905 subjects in the obese group and 879 subjects in the lean group. Lean women had increased ovulation rates (RR 1.43, 95% CI 1.22-1.66) compared with obese women. Pregnancy rates also showed a similar trend (RR 1.73, 95% CI 1.39-2.17). Reproductive outcomes were generally better in younger women, more recent studies and randomized controlled trials. It is concluded that lean women respond better to OAT than their obese counterparts. These epidemiological observations indicate that obesity alters reproductive outcomes after OAT negatively. Obesity is known to interfere with reproductive outcomes in polycystic ovary syndrome. There is no consensus regarding the impact of obesity on ovarian ablative therapy (OAT) and there is no level I evidence to answer this question. We therefore undertook a systematic review and meta-analysis to assess the strength of the association between obesity and ovulation or pregnancy rates after OAT. We searched MEDLINE and several other databases from 2000 to September 2011 for studies reporting on OAT and reproductive outcomes. Data were synthesized to determine the risk ratio of reproductive outcomes (ovulation and pregnancy) in lean (BMI <25 kg/m(2)) as opposed to overweight or obese women. We obtained 15 datasets (14 articles) for analysis, which included 905 subjects in the obese group and 879 subjects in the lean group. Lean women had increased ovulation rates (RR 1.43, 95% CI 1.22-1.66) as compared to obese women. Pregnancy rates also showed a similar trend (RR 1.73, 95% CI 1.39-2.17). Reproductive outcomes were generally better in younger women, more recent studies and randomized controlled trials. We conclude that lean women respond better to OAT than their obese counterparts. These epidemiological observations indicate that obesity alters reproductive outcomes after OAT negatively.

The Impact of High Circulating Anti-Müllerian Hormone on Endometrial Thickness and Outcome of Assisted Reproductive Technology in Women with Polycystic Ovarian Syndrome: A Cohort Study.

Background: Elevated circulating anti-Müllerian hormone (AMH) in women with the polycystic ovarian syndrome (PCOS) has been found to have a detrimental effect on endometrial function. This may adversely affect the outcome of in vitro fertilisation (IVF) in PCOS women. Aims: To investigate the impact of high serum AMH concentrations on endometrial thickness (ET) and the outcome of IVF in women with PCOS. Settings and Design: This retrospective cohort study included all PCOS women who underwent fresh IVF\intracytoplasmic sperm injection cycles between January 2016 and December 2021 in one major IVF centre. Materials and Methods: PCOS diagnosis was based on Rotterdam criteria, and participants were identified from centre database. All women received antagonist protocol. Primary outcomes were trigger-day ET and live birth rate (LBR). Circulating AMH was correlated with ET and ovarian response. Statistical Analysis Used: AMH levels were compared between women with and without live birth. ET and LBRs were compared between women with AMH <7.0 ng/ml versus those with AMH ≥7.0 ng/ml. Results: The study included 102 PCOS women, of which six were excluded due to poor response (n = 4), hyperresponse (n = 1) or fertilisation failure (n = 1). Of the remaining 96 women, 42 (43.8%) achieved a live birth. There was no statistically significant (P > 0.05) correlation between AMH and ET. Mean ± standard deviation AMH concentration was not significantly (P > 0.05) different between women with live birth (6.5 ± 3.4 ng/ml) and those without (6.5 ± 2.4 ng/ml). High AMH positively correlated with the number of oocytes retrieved, metaphase II oocytes and embryos (P = 0.003, 0.006 and 0.006, respectively). There was no statistically significant (P > 0.05) difference in ET or LBR between women with AMH <7.0 ng/ml (n = 72; ET, 10.7 ± 1.8 mm; LBR, 45.8% [33/72] versus those with AMH ≥7.0 ng/ml (n = 24; ET, 10.8 ± 1.7 mm; LBR, 37.5% [9/24]). Conclusions: High circulating AMH in PCOS women does not seem to negatively affect ET or LBRs during assisted reproductive technology.

Integrating Youth Perspectives: Adopting a Human Rights and Public Health Approach to Climate Action.

Climate change is a multidimensional issue that affects all aspects of society, including public health and human rights. Climate change is already severely impacting people's health and threatening people's guaranteed fundamental rights, including those to life, health, self-determination, and education, among others. Across geographical regions, population groups and communities who are already marginalized due to age, gender, ethnicity, income, and other socioeconomic factors, are those who are disproportionately affected by climate impacts despite having contributed the least to global emissions. Although scholars have been calling for a human rights-based approach and a health perspective to climate action, the literature looking at this multidisciplinary intersection is still nascent, and governments have yet to implement such intersectoral policies. This commentary begins to reflect on the relationship between climate change, human rights, and public health from the perspective of young people engaged in climate action and discourse at the national and international levels. It presents a way forward on what we, as youth climate advocates and researchers, believe is a priority to bring intersectoral integration of human rights and public health approaches to climate change to fruition. First, scholars and practitioners should examine and support youth-led climate interventions that tackle human rights and public health violations incurred by the climate crisis. Second, participatory approaches to climate change must be designed by working synergistically with climate-vulnerable groups, including children and young people, practitioners and scholars in public health and human rights sectors to holistically address the social, health, and environmental impacts of the climate crisis and root causes of injustice. Finally, we recommend more holistic data collection to better inform evidence-based climate policies that operationalize human rights and public health co-benefits.

The impact of insulin resistance on the outcome of laparoscopic ovarian diathermy in women with polycystic ovarian syndrome.

OBJECTIVE: Insulin resistance (IR), which is common in women with polycystic ovarian syndrome (PCOS), may adversely affect the outcome of ovulation induction due to its detrimental effect on ovarian function. The aim of this study was to evaluate the impact of IR on the outcome of laparoscopic ovarian diathermy (LOD). DESIGN: Prospective observational study. SETTING: Tertiary fertility centre. POPULATION: Forty-four anovulatory women with PCOS undergoing LOD. METHODS: Fasting serum concentrations of insulin and glucose were measured before and after LOD. Insulin sensitivity was determined using the homeostasis model assessment (HOMA) index. Values of HOMA index ≥2.1 were considered abnormal, indicating IR. MAIN OUTCOME MEASURES: Ovulation and pregnancy rates were compared between women with and without IR using χ(2) test and odds ratio (OR) with 95% confidence interval (CI). RESULTS: Eighteen women (41%) had elevated HOMA index (≥2.1). There was no change of HOMA index after LOD (median 1.89, range 0.53-8.48 vs. 1.92, range 0.53-8.46). The ovulation rate in women with IR (12 of 18, 67%) was significantly (p=0.013, OR 0.08; 95% CI 0.01-0.74) lower than that (25 of 26, 96%) of women without IR. Likewise, the pregnancy rate (six of 18, 33%) was significantly (p=0.037, OR 0.26; 95% CI 0.07-0.94) lower in women with IR than that of women without IR (17 of 26, 65%). Using a receiver operating characteristics curve, the HOMA index was useful in predicting no ovulation after LOD (area under the curve 0.826). CONCLUSIONS: Insulin resistance appears to have an adverse effect on the outcome of LOD and seems to be a useful prognostic factor.

Assessment of Circulating Anti-Müllerian Hormone in Women Using Hormonal Contraception: A Systematic Review.

Background: The status of ovarian reserve markers during hormonal contraception (HC) remains uncertain with conflicting literature data. The purpose of this study was to assess the impact of HC on circulating anti-Müllerian hormone (AMH) and other ovarian reserve markers. Materials and Methods: A systematic review was conducted, including all cohort, cross-sectional, and randomized controlled studies assessing serum anti Müllerian hormone concentration in women using HC. Data sources included MEDLINE, EMBASE, DynaMed Plus, ScienceDirect, TRIP database, ClinicalTrials.gov, and the Cochrane Library from January 2000 to October 2018. Results: A total of 366 studies were identified, of which 15 were eligible, including 3280 women, mostly using combined HC (CHC). Articles were divided according to duration of HC into short- (2-3 weeks), medium- (2-6 months), long- (>1 year), and varied-term studies. Two study designs were identified, including studies comparing AMH before and during/after CHC and studies comparing CHC users versus nonusers. Short- and medium-term studies (n = 284) reported no change in circulating AMH in women using cyclical CHC for one to six cycles. Apart from one study, all long- and varied-term studies (six studies, n = 1601) consistently showed a marked decline in AMH, antral follicle count, and ovarian volume. Three long-term studies (n = 1324) provided evidence of AMH recovery after discontinuation of HC. Conclusion: Circulating AMH seems to remain unchanged in women using cyclical CHC for up to 6 months, but appears to markedly decline in long-term users with recovery after discontinuation.

Excess androgen production in subcutaneous adipose tissue of women with polycystic ovarian syndrome is not related to insulin or LH.

The purpose of this study was to investigate androgen production and the role of insulin and LH in its regulation in subcutaneous adipose tissue (SAT) of women with polycystic ovarian syndrome (PCOS). Protein and mRNA expression of androgen synthesis enzymes (Cytochrome P450 17A1 [CYP17A1] and Aldo-keto reductase 1C3 [AKR1C3]) were measured in SAT biopsies from women with PCOS, diagnosed according to the Rotterdam criteria (n=15) and healthy controls (n=15). Cultured mature adipocytes (differentiated from SAT biopsies) were treated with insulin ± phosphoinositol-3-kinase inhibitor (LY294002) or LH ± insulin. CYP17A1 and AKR1C3 mRNA expression and testosterone concentrations were measured in treated and untreated adipocyte cultures. AKR1C3 mRNA was significantly (P<0.001) greater in PCOS versus non-PCOS SAT, but CYP17A1 was not significantly different between the two groups. AKR1C3 and CYP17A1 protein expression was not significantly different in PCOS versus non-PCOS SAT. In untreated adipocyte cultures, CYP17A1, AKR1C3 and testosterone levels were significantly higher in the PCOS versus the non-PCOS groups. Addition of insulin increased AKR1C3 mRNA and testosterone levels, but not CYP17A1 mRNA in non-PCOS with no effect on PCOS adipocytes. The stimulatory effects of insulin were not inhibited by LY294002. Addition of LH increased CYP17A1, AKR1C3 and testosterone in non-PCOS adipocytes with no effect in PCOS adipocytes. In conclusion, SAT of women with PCOS produces excess androgen, which may contribute to PCOS-related hyperandrogenaemia. This SAT androgen excess is independent of obesity and is not directly stimulated by insulin or LH.

First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

The expression of activin-betaA- and -betaB-subunits, follistatin, and activin type II receptors in fallopian tubes bearing an ectopic pregnancy.

CONTEXT: Ectopic pregnancy is a major cause of maternal morbidity and mortality with increasing incidence worldwide. OBJECTIVE: We investigated whether epithelia from Fallopian tubes (FTs) bearing an ectopic pregnancy differ from normal tubes in expression of TGF-beta family and related proteins and their receptors. METHODOLOGY: Because it is not possible to collect FTs from women carrying a healthy pregnancy, we studied tissue collected at the time of hysterectomy for benign disease. Women were injected with human chorionic gonadotropin in the days leading up to hysterectomy to produce a state of pseudopregnancy. Pseudopregnancy status was confirmed by the presence of high serum progesterone levels and the decidualization of the endometrium. Fifteen FTs bearing ectopic pregnancy and six pseudopregnant tubes were collected and examined using immunohistochemistry and quantitative RT-PCR. RESULTS: Immunohistochemistry demonstrated clear staining for the betaA- and betaB-subunits, type II receptor group comprising the activin type IIA and type IIB receptors, and follistatin, which increased in intensity from the isthmus to the ampulla in both models. However, the intensity of expression of these molecules was stronger in the ectopic pregnancy group when compared with the pseudopregnant group. Quantitative RT-PCR showed significant decrease in mRNA levels of betaA-subunit, activin type IIA and IIB receptors, and follistatin in ectopic group (P < 0.05) but no changes in betaB-subunit (P > 0.05). Overall, there was an apparent paradox of high concentration of protein but low mRNA expression. CONCLUSION: Activin-A may stimulate tubal decidualization and trophoblast invasion. A better understanding of the mechanism by which an embryo implants in the tubal epithelium may lead to improved methods for early diagnosis and/or management of ectopic pregnancy.