Prevalence and correlates of diagnosed and probable polycystic ovary syndrome (PCOS) in a cohort of parous women.

OBJECTIVES: To assess correlates of diagnosed and probable polycystic ovary syndrome (PCOS) among parous women. METHODS: This study includes 557 women recruited from multi-specialty clinics in eastern Massachusetts. We categorized women as "diagnosed PCOS" based on medical records and self-reported clinician-diagnoses. Next, we constructed a category of "probable PCOS" for women without a diagnosis but with ≥2 of the following: ovulatory dysfunction (cycle length<21 or ≥35 days), hyperandrogenism (free testosterone>75th percentile), or elevated anti-Müllerian hormone (>75th percentile). We classified the remaining as "no PCOS," and compared characteristics across groups. RESULTS: 9.7% had diagnosed and 9.2% had probable PCOS. The frequency of irregular cycles was similar for diagnosed and probable PCOS. Free testosterone and AMH were higher for probable than diagnosed PCOS. Frequency of irregular cycles and both hormones were higher for the two PCOS groups vs. the no PCOS group. Obesity prevalence for diagnosed PCOS was twice that of probable PCOS (43.9% vs. 19.6%), yet the two groups had similar HbA1c and adiponectin. CONCLUSIONS: Women with probable PCOS are leaner but have comparable glycemic traits to those with a formal diagnosis, highlighting the importance of assessing biochemical profiles among women with irregular cycles, even in the absence of overweight/obesity.

A review of nitric oxide and oxidative stress in typical ovulatory women and in the pathogenesis of ovulatory dysfunction in PCOS.

Polycystic ovary syndrome (PCOS) is a heterogeneous functional endocrine disorder associated with a low-grade, chronic inflammatory state. Patients with PCOS present an increased risk of metabolic comorbidities and often menstrual dysregulation and infertility due to anovulation and/or poor oocyte quality. Multiple mechanisms including oxidative stress and low-grade inflammation are believed to be responsible for oocyte deterioration; however, the influence of nitric oxide (NO) insufficiency in oocyte quality and ovulatory dysfunction in PCOS is still a matter for debate. Higher production of superoxide (O2•-) mediated DNA damage and impaired antioxidant defense have been implicated as contributory factors for the development of PCOS, with reported alteration in superoxide dismutase (SOD) function, an imbalanced zinc/copper ratio, and increased catalase activity. These events may result in decreased hydrogen peroxide (H2O2) accumulation with increased lipid peroxidation events. A decrease in NO, potentially due to increased activity of NO synthase (NOS) inhibitors such as asymmetric dimethylarginine (ADMA), and imbalance in the distribution of reactive oxygen species (ROS), such as decreased H2O2 and increased O2•-, may offset the physiological processes surrounding follicular development, oocyte maturation, and ovulation contributing to the reproductive dysfunction in patients with PCOS. Thus, this proposal aims to evaluate the specific roles of NO, oxidative stress, ROS, and enzymatic and nonenzymatic elements in the pathogenesis of PCOS ovarian dysfunction, including oligo- anovulation and oocyte quality, with the intent to inspire better application of therapeutic options. The authors believe more consideration into the specific roles of oxidative stress, ROS, and enzymatic and nonenzymatic elements may allow for a more thorough understanding of PCOS. Future efforts elaborating on the role of NO in the preoptic nucleus to determine its influence on GnRH firing and follicle-stimulating hormone/Luteinizing hormone (FSH/LH) production with ovulation would be of benefit in PCOS. Consequently, treatment with an ADMA inhibitor or NO donor may prove beneficial to PCOS patients experiencing reproductive dysfunction and infertility.

Analysis of the quality, accuracy, and readability of patient information on polycystic ovarian syndrome (PCOS) on the internet available in English: a cross-sectional study.

BACKGROUND: Online information about PCOS lacks reliability for patients seeking information about the disease. Thus, we aimed to perform an updated analysis of the quality, accuracy, and readability of patient information on PCOS available online. METHODS: We conducted a cross-sectional study using the top five Google Trends search terms in English associated with PCOS, including "symptoms," "treatment," "test," "pregnancy," and "causes." Five separate searches in Bing, Yahoo, and Google were performed to obtain the first 10 unique webpages for each term that was categorized as commercial, non-profit organization, scientific resources, or private foundation. We used the 16-item DISCERN with Likert-responses (minimum 1, maximum 5) where the total is 80 and lowest is 16, clarity with the 32-item EQIP, where responses of no = 0 and yes = 1 (minimum 0, maximum 32), and accuracy scores with 1 denoting poor and 5 completely accurate information; low scores of each corresponded to poorly reported information. We assessed readability with Flesch-Kincaid reading ease index, where higher scores correspond to reading ease, and lower grades correspond to easier readability with Flesch-Kincaid grade level, Gunning-Fog, Coleman-Liau index, automated readability index, New Dale-Chall Readability, and simple measure of gobbledygook. We additionally assessed word and sentence characteristics. We used Kruskal-Wallis test to compare scores according to webpage categories. RESULTS: Out of 150 webpages, most were commercial (n = 85, 57%), followed by non-profit organizations (n = 44, 29%), scientific resources (n = 13, 9%) and private foundations (n = 6, 4%). Google webpages had higher median DISCERN score ([Md] = 47.0) than Bing ([Md] = 42.0) and Yahoo ([Md] = 43.0) webpages; P = 0.023. No difference in EQIP scores according to search engine was found (P = 0.524). Predominantly, webpages from private foundations had higher DISCERN and EQIP scores, although comparisons were not statistically significant (P = 0.456) and P = 0.653.). Accuracy and readability were similar across search engines and webpage categories (P = 0.915, range 5.0-5.0) and (P = 0.208, range 4.0-5.0). CONCLUSIONS: Quality and clarity of the data were fair according to search engine and category. Accuracy of information was high, showing that the public may encounter accurate information about PCOS. However, the readability of the information was high, reflecting a need for more readable resources about PCOS.

In praise of ovulation induction for the management of anovulatory subfertility.

Rapid advances in assisted reproductive technology have revolutionized fertility treatments for couples worldwide seeking a pregnancy. Although this is promising, concerns are emerging over the overuse of unnecessary assisted conception treatments, particularly among couples with anovulatory subfertility. Some experts are calling for the cessation of ovulation induction as the primary treatment of anovulatory subfertility in favour of more sophisticated assisted conception treatments. In the absence of other causes of subfertility, ovulation induction in patients with type 1 and type 2 anovulation disorders can achieve an up to 80% ovulation rate with a 40% cumulative pregnancy rate and few adverse effects. Considering the various risks and high costs associated with assisted reproductive technology treatments, it is hard to argue for their cost-effectiveness when simpler, safer and cheaper pharmacological ovulation induction could achieve comparable pregnancy rates. We argue here for the safe, effective and ethical use of ovulation induction in this population, supplemented by a judicious use of assisted conception treatments. We emphasize the essential role of ovulation induction as a first-line intervention for couples with anovulatory subfertility delivered within a patient-centred multidisciplinary care model and with a clear escalation pathway to use assisted reproductive technology treatments based on the person's response, characteristics and treatment preference.

Ovulation induction in anovulatory infertility is obsolete.

Women with polycystic ovary syndrome make up the vast majority of patients with anovulatory infertility. The commonly accepted treatment guidelines recommend ovulation induction for timed intercourse as the first-line treatment. After a 2-year treatment period, the cumulative pregnancy rates with a singleton live-born baby reached 71% and 78% in two prospective studies. Despite aiming for monofollicular growth, multifollicular responses with subsequent multiple/higher order multiple pregnancies are a dreaded risk associated with ovarian induction. However, the lengthy treatment, the increase of maternal age and the psychological effects of 'obligatory intercourse' are also factors challenging the concept of ovarian induction as the first treatment approach in anovulatory infertility. Nowadays, individualized IVF treatment with cycle segmentation, freeze-all strategies and single-embryo transfers in frozen embryo transfer cycles dramatically reduces the risk of multiple pregnancies, and a cumulative pregnancy rate of 83% can be achieved over three complete cycles, thereby reducing exposure to fertility medication and time to pregnancy. Although on first sight ovarian induction might present the easier and less costly approach, efficient and individualized IVF treatments with low complication rates and the chance of preventing multiple pregnancies challenge this concept, and it seems that the time has come to abandon ovarian induction in anovulatory infertility.

Clomiphene citrate plus letrozole versus clomiphene citrate alone for ovulation induction in infertile women with ovulatory dysfunction: a randomized controlled trial.

BACKGROUND: The aim of this study was to compare the efficacy of the combination of clomiphene citrate (CC) and letrozole to that of CC alone in inducing ovulation in infertile women with ovulatory dysfunction. METHODS: A randomized controlled trial was conducted at a single academic medical center between November 2020 and December 2021. Anovulatory infertility females, aged 18 to 40, were evenly distributed by a computer-generated block of four into two treatment groups. A "combination group" received a daily dose of CC (50 mg) and letrozole (2.5 mg), while a "CC-alone group" received a daily dose of CC alone (50 mg). The study medications were administered on days 3 through 7 of menstrual cycle. The primary outcome was the ovulation rate, defined by serum progesterone levels exceeding 3 ng/mL at the mid-luteal phase. The secondary outcomes were ovulation induction cycle characteristics, endometrial thickness, conception rate, and adverse events. RESULTS: One hundred women (50 per group) were enrolled in the study. The mean age was not significantly different in both groups: 31.8 years in the combination group and 32.4 years in the CC-alone groups (P = 0.54). The prevalence of polycystic ovary syndrome in the combination and CC-alone groups was 48% and 44%, respectively (P = 0.841). According to intention-to-treat analysis, the ovulation rates were 78% and 70% in the combination and CC-alone groups, respectively (P > 0.05). There was no significant difference in the mean endometrial thickness or the number of dominant follicles of the groups. No serious adverse events were observed in either group. CONCLUSIONS: Our study found no significant difference between the combination of CC and letrozole and CC alone in inducing ovulation in infertile women with ovulatory dysfunction in one cycle. The small number of live births precluded any meaningful statistical analysis. Further studies are needed to validate and extend our findings beyond the scope of the current study. TRIAL REGISTRATION: The study was registered at https://www.thaiclinicaltrials.org with the following number: TCTR20201108004 and was approved on 08/11/2020.

Gremlin-1 Level In Polycystic Ovary Syndrome And Its Clinical Correlations; A Case Control Study.

Objectives: To evaluate the involvement of the level of Gremlin-1 in serum and follicular fluid in the diagnosis of polycystic ovary syndrome. Method: The case-controlstudy was conducted at the Kafrelsheikh University Hospital, Egypt, from September 2021 to February 2022, and comprised women with polycystic ovary syndrome and healthy controls. All participants were subjected to a detailed clinical assessment, complete clinical examination and hormonal profile assessment. Gremlin1 concentrationsin plasma and follicular fluid samples were assessed by a double-antibody sandwich enzyme-linked immunosorbent assay kit. Data was analysed using SPSS 20. RESULTS: Of the 90 subjects, 45(50%) were patients with a mean age of 29.53±4.82 years, and 45(50%) were controls with a mean age of 30.89±6.08 (p>0.05). Mean weight, body massindex, waist circumference and waist-hip ratio were significantly higher in patients compared to controls (p<0.05). Serum and follicular fluid Gremlin-1 levels were significantly higher in the patient group (p<0.05). The best cutoff of serum Gremlin-1 in the diagnosis of polycystic ovary syndrome was ≥1.325ng/ml with area under curve 0.857,sensitivity 93.3%,specificity 68.9%, positive predictive value 75%, negative predictive value 91.2% and overall accuracy 81.1%. The best cutoff of follicular fluid Gremlin-1 in the diagnosis of polycystic ovary syndrome was ≥1.725ng/ml with area under curve 0.789,sensitivity 73.3%,specificity 68.9%, positive predictive value 70.2%, negative predictive value 72.1% and overall accuracy 71.1%. CONCLUSIONS: There was a strong correlation between serum and follicular Gremlin-1 levelsin polycystic ovary syndrome patients.

The FIGO Ovulatory Disorders Classification System†.

Ovulatory disorders are common causes of amenorrhea, abnormal uterine bleeding and infertility and are frequent manifestations of polycystic ovary syndrome (PCOS). There are many potential causes and contributors to ovulatory dysfunction that challenge clinicians, trainees, educators, and those who perform basic, translational, clinical and epidemiological research. Similarly, therapeutic approaches to ovulatory dysfunction potentially involve a spectrum of lifestyle, psychological, medical and procedural interventions. Collaborative research, effective education and consistent clinical care remain challenged by the absence of a consensus comprehensive system for classification of these disorders. The existing and complex system, attributed to the World Health Organization (WHO), was developed more than three decades ago and did not consider more than 30 years of research into these disorders in addition to technical advances in imaging and endocrinology. This article describes the development of a new classification of ovulatory disorders performed under the aegis of the International Federation of Gynecology and Obstetrics (FIGO) and conducted using a rigorously applied Delphi process. The stakeholder organizations and individuals who participated in this process comprised specialty journals, experts at large, national, specialty obstetrical and gynecological societies, and informed lay representatives. After two face-to-face meetings and five Delphi rounds, the result is a three-level multi-tiered system. The system is applied after a preliminary assessment identifies the presence of an ovulatory disorder. The primary level of the system is based on an anatomic model (Hypothalamus, Pituitary, Ovary) that is completed with a separate category for PCOS. This core component of the system is easily remembered using the acronym HyPO-P. Each anatomic category is stratified in the second layer of the system to provide granularity for investigators, clinicians and trainees using the 'GAIN-FIT-PIE' mnemonic (Genetic, Autoimmune, Iatrogenic, Neoplasm; Functional, Infectious and Inflammatory, Trauma and Vascular; Physiological, Idiopathic, Endocrine). The tertiary level allows for specific diagnostic entities. It is anticipated that, if widely adopted, this system will facilitate education, clinical care and the design and interpretation of research in a fashion that better informs progress in this field. Integral to the deployment of this system is a periodic process of reevaluation and appropriate revision, reflecting an improved understanding of this collection of disorders.

Prediction model of persistent ovulatory dysfunction in Korean women with polycystic ovary syndrome.

AIM: There is no validated tool to predict persistent ovulatory dysfunction after medication with oral contraceptives in women with polycystic ovary syndrome (PCOS), which is the most severe subtype of PCOS. We aimed to build a model to predict persistent ovulatory dysfunction after medication of oral contraceptives in women with PCOS. METHODS: A total of 286 patients with PCOS were treated with and without oral contraceptives at a tertiary academic medical center. Data were obtained from the electronic medical record system between January 2016 and March 2019. A risk prediction model was developed using multivariable logistic regression. Model 1 was based on age and chief complaints and Model 2 further included predictors evaluated during a clinic visit. Model 3 additionally included laboratory findings. RESULTS: Of the study population, ovulatory dysfunction was persistent in 117 patients (40.9%). Compared with the simple model (Models 1 and 2), the full prediction model (Model 3) had better Akaike's information criterion (286, 244 vs. 225) and the area under the curve (AUC) increased from 0.74 and 0.79 to 0.84. The full model included 7 covariates measured during the evaluation of PCOS, and two covariates were significant predictors of persistent ovulatory dysfunction in PCOS: age (OR 0.91; 95% CI 0.84-0.97), and anti-Müllerian hormone (OR 1.17; 95% CI 1.09-1.26). This model demonstrated good discrimination (AUC, 0.84) and calibration (Hosmer-Lemeshow goodness of fit test, p = 0.74). CONCLUSIONS: This prediction model was shown to be a useful method for predicting persistent ovulatory dysfunction after oral contraceptive medication in patients with PCOS.

The use of metformin in women with polycystic ovary syndrome: an updated review.

PURPOSES: Polycystic ovary syndrome (PCOS) is a major cause of female infertility, being present in up to 20% of women of childbearing age. Insulin resistance (IR) plays an important role in the pathophysiology of PCOS; therefore, its treatment may benefit women with the syndrome. The main drug used for IR management is metformin (MT). We aim to review the literature on the use of metformin in women with PCOS. METHODS: Using the terms "metformin" and "polycystic ovary syndrome," we conducted a search the PubMed, EMBASE, and Google Scholar databases. The research was restricted to articles published in English. Initially, only published meta-analyses were included, in the absence of meta-analyzes, RCT and well-designed prospective studies were used. RESULTS: Metformin increases success rates and decreases complication rates when used as an adjunctive medication for ovulation induction during low complexity assisted reproduction treatments and during ovarian stimulation for in vitro fertilization in women with PCOS. Evidence about the effect of metformin on fetal and obstetric complication rates is conflicting. Metformin is associated with high incidence of gastrointestinal symptoms; however, serious adverse effects are rare and there is no evidence of teratogenicity. CONCLUSION: For women with PCOS, metformin is a good adjunctive medication for ovulation induction/stimulation for high and low complexity assisted reproduction therapies. The adverse effects are mostly mild, and there is no risk of teratogenicity, but the risk of long-term complications for the offspring is not yet defined. High heterogeneity of the studies limits extrapolation of findings, and further research is needed to determine which women will benefit most from the medication.

Eight-hour time-restricted feeding improves endocrine and metabolic profiles in women with anovulatory polycystic ovary syndrome.

BACKGROUND: Time-restricted feeding (TRF) is a form of intermittent fasting, which is beneficial for weight loss and cardiometabolic health. Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine and metabolic diseases affecting women of childbearing age. It is associated with an increased prevalence of metabolic syndrome, cardiovascular diseases and type 2 diabetes. The effects of TRF on PCOS patients remains undefined, here we investigated the impact of TRF on women with anovulatory PCOS. METHODS: Eighteen PCOS women aged between 18 and 31 with anovulation participated in a 6-week trial which were divided into two consecutive periods: (1) 1-week baseline weight stabilization period and (2) 5-week TRF period. Fifteen participants completed the study. Changes in body weight, body mass index (BMI), Waist-to-Hip Ratio, skeletal muscle mass, body fat mass (BFM), body fat percentage (BF%), visceral fat area (VFA), luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH, total testosterone (TT), sex hormone-binding globulin (SHBG), free androgen index (FAI), fasting glucose, fasting insulin (FINS), homeostasis model assessment-insulin resistance (HOMA-IR), area under the curve (AUC) for insulin (AUCIns), area under the curve (AUC) for glucose (AUCGlu), AUCIns/AUCGlu Ratio, lipids, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase, high-sensitivity C-reactive protein (hsCRP), insulin-like growth factor (IGF-1), menstrual cycle and eating behaviors were evaluated. RESULTS: Significant changes in body weight, BMI, BFM, BF%, VFA, TT, SHBG, FAI, FINS, HOMA-IR, AUCIns, AUCIns/AUCGlu Ratio, ALT, hsCRP and IGF-1 were found after the TRF period. An improvement in menstrual cycle irregularity was detected in 73.3% (11/15) patients. CONCLUSION: The diet of TRF may be beneficial to anovulatory PCOS on weight loss especially reducing body fat, improving menstruation, hyperandrogenemia, insulin resistance and chronic inflammation. Trial registration Clinicaltrial.gov, NCT04580433, registered October 8, 2020, https://clinicaltrials.gov/ct2/show/NCT04580433.

Revisiting the serum level of anti-Müllerian hormone in patients with functional hypothalamic anovulation.

STUDY QUESTION: Are serum levels of anti-Müllerian hormone (AMH) normal in patients with functional hypothalamic anovulation (FHA)? SUMMARY ANSWER: Our study confirms that in the general FHA population, serum AMH levels are not decreased, but if patients with polycystic ovarian morphology (PCOM) are excluded, levels become significantly lower, as in other situations of gonadotropic insufficiency. WHAT IS KNOWN ALREADY: In most situations of low LH (physiological, pharmacological or pathological), serum AMH levels are low. However, paradoxically, many publications have reported normal or even increased serum AMH levels in FHA patients. STUDY DESIGN, SIZE, DURATION: Retrospective observational study conducted in an academic centre. The data concerning the study population was collected between 2006 and 2015 from a database including clinical, biological and ultrasound information. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 45 FHA patients were compared to 37 controls matched based on age and body mass index (BMI). Serum LH, FSH, androstenedione, total testosterone, prolactin and AMH levels were measured by immunoassay. We defined PCOM with strict criteria: a follicle number per ovary (FNPO) ≥ 12 or ≥ 19 per ovary, depending on the date on which the assessment was carried out and the ultrasound device. An AMH level ≥ 35 pmol/l could be a substitute for an excess FNPO. Controls meeting these criteria were not included in this study. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the ranges of AMH levels between FHA and controls. Using strict criteria to define PCOM status, 46.7% of FHA patients had PCOM. After excluding these patients, the levels of AMH were significantly lower (P < 0.002) in FHA patients compared to controls. Within the FHA group, patients with PCOM had significantly higher ranks of AMH levels and BMI than those without PCOM. However, within the PCOM+ subgroup, the ranks of LH, FSH and A levels were still lower than in controls (P < 0.0001, <0.002 and <0.05, respectively). The positive correlation between AMH and LH was significant in the controls but not in the FHA group. However, in the FHA PCOM+, there was a strong positive correlation between BMI and LH. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study; our controls did not represent the general population as they were recruited in an ART centre; we used a modified classification for PCOM using follicle count and/or AMH level with in-house thresholds to define the follicle excess; the AMH assay used is no longer commercially available. WIDER IMPLICATIONS OF THE FINDINGS: Besides biasing the results of AMH assay in FHA patients, the presence of PCOM in FHA patients despite low gonadotropin and androgen levels raises the issue of epigenetically acquired amplification of androgen and/or FSH sensitivity within granulosa cells from polycystic ovaries. In terms of clinical practice, it seems important not to diagnose a low ovarian reserve in FHA patients too quickly on the basis of a decreased AMH level alone. On the contrary, a high AMH level in the context of a menstrual disorder and PCOM should not lead to a misdiagnosis of polycystic ovary syndrome (PCOS) if the basal LH is low. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Cannabis use while trying to conceive: a prospective cohort study evaluating associations with fecundability, live birth and pregnancy loss.

STUDY QUESTION: Is cannabis use assessed via urinary metabolites and self-report during preconception associated with fecundability, live birth and pregnancy loss? SUMMARY ANSWER: Preconception cannabis use was associated with reduced fecundability among women with a history of pregnancy loss attempting pregnancy despite an increased frequency of intercourse. WHAT IS KNOWN ALREADY: Cannabis use continues to rise despite limited evidence of safety during critical windows of pregnancy establishment. While existing studies suggest that self-reported cannabis use is not associated with fecundability, self-report may not be reliable. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out including 1228 women followed for up to six cycles while attempting pregnancy (2006 to 2012), and throughout pregnancy if they conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-40 years with a history of pregnancy loss (n = 1228) were recruited from four clinical centers. Women self-reported preconception cannabis use at baseline and urinary tetrahydrocannabinol metabolites were measured throughout preconception and early pregnancy (up to four times during the study: at baseline, after 6 months of follow-up or at the beginning of the conception cycle, and weeks 4 and 8 of pregnancy). Time to hCG-detected pregnancy, and incidence of live birth and pregnancy loss were prospectively assessed. Fecundability odds ratios (FOR) and 95% CI were estimated using discrete time Cox proportional hazards models, and risk ratios (RRs) and 95% CI using log-binomial regression adjusting for age, race, BMI, education level, baseline urine cotinine, alcohol use and antidepressant use. MAIN RESULTS AND THE ROLE OF CHANCE: Preconception cannabis use was 5% (62/1228), based on combined urinary metabolite measurements and self-report, and 1.3% (11/789) used cannabis during the first 8 weeks of gestation based on urinary metabolites only. Women with preconception cannabis use had reduced fecundability (FOR 0.59; 95% CI 0.38, 0.92). Preconception cannabis use was also associated with increased frequency of intercourse per cycle (9.4 ± 7 versus 7.5 ± 7 days; P = 0.02) and higher LH (percentage change 64%, 95% CI 3, 161) and higher LH:FSH ratio (percentage change 39%, 95% CI 7, 81). There were also suggestive, though imprecise, associations with anovulation (RR 1.92, 95% CI 0.88, 4.18), and live birth (42% (19/45) cannabis users versus 55% (578/1043) nonusers; RR 0.80, 95% CI 0.57, 1.12). No associations were observed between preconception cannabis use and pregnancy loss (RR 0.81, 95% CI 0.46, 1.42). Similar results were observed after additional adjustment for parity, income, employment status and stress. We were unable to estimate associations between cannabis use during early pregnancy and pregnancy loss due to limited sample size. LIMITATIONS, REASONS FOR CAUTION: Owing to the relatively few cannabis users in our study, we had limited ability to make conclusions regarding live birth and pregnancy loss, and were unable to account for male partner use. While results were similar after excluding smokers, alcohol use and any drug use in the past year, some residual confounding may persist due to these potential co-exposures. WIDER IMPLICATIONS OF THE FINDINGS: These findings highlight potential risks on fecundability among women attempting pregnancy with a history of pregnancy loss and the need for expanded evidence regarding the reproductive health effects of cannabis use in the current climate of increasing legalization. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Jeannie G. Radoc has been funded by the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the National Institutes of Health and generous contributions to the Foundation for the National Institutes of Health from the Doris Duke Charitable Foundation (DDCF Grant # 2014194), Genentech, Elsevier, and other private donors. The authors report no conflict of interest in this work and have nothing to disclose. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.

A review on inositol's potential in cyclic disturbances of adipose-endocrinology-associated polycystic ovary syndrome.

Since the lack of certainty in identifying polycystic ovary syndrome (PCOS) demonstrates confusion regarding the disorder's pathophysiology and its therapeutic approaches, systematic screening of women under diagnostic guidelines of the NIH reported that about 4-10 percent of reproductive women aged 20-44 years suffer from PCOS. Not all females with PCOS-defining biochemical and clinical characteristics and about 22% of PCOS women have no symptoms. PCOS is a heterogeneous phenotypic and clinical condition, combined with metabolic implications. The root cause of PCOS is the major issue of IR or irregular androgen secretion and constant effort is being made in identifying the dynamic pathogenic network underlying the syndrome. Regardless of PCOS initiating cause, IR therapy and hyperinsulinemia can restore metabolic and hormonal homeostasis, and minimize ovarian dysfunction. Thus, the impact of insulin on ovaries in hyperinsulinemic individuals can account for many of the PCOS characteristics and is important for developing treatment strategies. Therefore, our primary aim is to investigate the proper understanding of endocrine disruption during PCOS and secondary to the therapeutic potential of inositol in reestablishing the equilibrium of ovarian dysfunction, anovulation, and eventually infertility.

Adiposity is associated with anovulation independent of serum free testosterone: A prospective cohort study.

BACKGROUND: Obesity, a body mass index (BMI) ≥30 kg/m2 , is linked to infertility, potentially through a greater risk of anovulation due to elevated androgens. Yet, previous studies have not directly assessed the impact of adiposity, or body fat, on anovulation in the absence of clinical infertility. OBJECTIVE: To characterise the associations between adiposity and anovulation among women menstruating on a regular basis. METHODS: Women from the EAGeR trial (n = 1200), a randomised controlled trial of low-dose aspirin and pregnancy loss among women trying to conceive, were used to estimate associations between adiposity and incident anovulation. Participants completed baseline questionnaires and anthropometry, and provided blood specimens. Women used fertility monitors for up to six consecutive menstrual cycles, with collection of daily first morning voids for hormone analysis in the first two menstrual cycles for prospective assessment of anovulation. Anovulation was assessed by urine pregnanediol glucuronide or luteinising hormone concentration or the fertility monitor. Weighted mixed-effects log-binomial regression was used to estimate associations between measures of adiposity and incident anovulation, adjusted for free (bioavailable) testosterone, anti-Mullerian hormone (AMH), serum lipids, and demographic and life style factors. RESULTS: 343 (28.3%) women experienced at least one anovulatory cycle. Anovulation risk was higher per kg/m2 greater BMI (relative risk [RR] 1.03, 95% confidence interval (CI) 1.01, 1.04), cm waist circumference (RR 1.01, 95% CI 1.00, 1.02), mm subscapular skinfold (RR 1.02, 95% CI 1.01, 1.03), and mm middle upper arm circumference (RR 1.04, 95% CI 1.01, 1.06) adjusted for serum free testosterone, AMH, lipids, and other factors. CONCLUSIONS: Adiposity may be associated with anovulation through pathways other than testosterone among regularly menstruating women. This may account in part for reported associations between greater adiposity and infertility among women having menstrual cycles regularly. Understanding the association between adiposity and anovulation might lead to targeted interventions for preventing infertility.

Oxygen saturation during sleep as a predictor of inflammation in anovulatory women.

PURPOSE: To evaluate the inflammatory profile of premenopausal women with anovulatory cycles, regular menstrual cycles, or using contraceptives, and the associations with sleep and health-related parameters. METHODS: Subjects completed questionnaires including the Pittsburgh Sleep Quality Index and the Epworth sleepiness scale, underwent whole-night polysomnography, and had blood collected for analysis of inflammatory, cardiovascular, and hormonal parameters. Women of reproductive age were categorized into three groups for comparisons: anovulatory menstrual cycles, regular menstrual cycles, and hormonal contraceptive use. RESULTS: Women with anovulatory menstrual cycles (n = 20) had higher circulating levels of the proinflammatory cytokine IL-6 compared with women who had regular menstrual cycles (n = 191) and those on hormonal contraception (n = 72). No other classical marker of low-grade inflammation was significantly different. Subjective and objective sleep data were similar among groups. However, the mean peripheral oxygen saturation (SpO2) during sleep was reduced in anovulatory women. The analysis of associated variables of the inflammatory profile demonstrated that mean SpO2 during sleep was a predictive factor of IL-6 levels. CONCLUSIONS: Our data suggest that in premenopausal women with anovulation, a proinflammatory condition mediated by IL-6 is associated with lower oxygen levels during sleep. These findings reflect the balance between gynecological status, the immune system, and sleep, pointing to the need to control for these factors in clinical practice and research contexts.

Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations.

STUDY QUESTION: Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility? SUMMARY ANSWER: PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility. WHAT IS KNOWN ALREADY: PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD. STUDY DESIGN, SIZE, DURATION: In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Five women aged 19-38 years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients. MAIN RESULTS AND THE ROLE OF CHANCE: All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies. LIMITATIONS, REASONS FOR CAUTION: The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD. WIDER IMPLICATIONS OF THE FINDINGS: The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used for this study. There are no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Metabolic impact of current therapeutic strategies in Polycystic Ovary Syndrome: a preliminary study.

PURPOSE: To investigate the metabolic impact of currently used therapies in polycystic ovary syndrome (PCOS). METHODS: This is an observational, retrospective and transversal protocol. A small cohort of 133 patients, aged 14-48 years, diagnosed with PCOS was divided into four experimental groups: 1) untreated PCOS patients (n = 51); 2) PCOS patients treated with one of the following therapies (n = 82): a) combined oral contraceptives (COC, n = 35); b) metformin (n = 11); and c) inositols (n = 36). RESULTS: Although only < 10% of patients included in this cohort can be strictly encompassed in the development of metabolic syndrome, approximately 20% had insulin resistance. In PCOS patients, COC treatment modified the hormonal profile and worsened lipid parameters (increasing cholesterol and triglyceride levels) and insulin resistance, whereas inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride levels. In these women, obesity was associated with greater alterations in lipid and glycemic metabolism and with higher blood pressure levels. PCOS patients with phenotype A presented vaster alterations in lipid metabolism and higher values of glycosylated hemoglobin as well as blood pressure compared to other PCOS phenotypes. CONCLUSIONS: Results in this paper suggest that inositol therapies (alone or combined with COC) are the most useful therapies with the best benefits against PCOS symptoms. Thus, integrative treatment may become a more efficient long-term choice to control PCOS symptoms. Furthermore, obesity can be considered as an adverse symptom and calorie restriction a key element of combined treatment in PCOS, not only for fertility management but also in long-term metabolic sequelae.

Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5-10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5-15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30-90% and final pregnancy rates of 13-88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of "toxic" follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the "hypothalamus-pituitary-ovary" axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.

[Polycystic ovary syndrome : the advantages of multidisciplinary management]. / Le syndrome des ovaires micropolykystiques : l'avantage d'une prise en charge multidisciplinaire.

The polycystic ovary syndrome is one of the most frequent endocrine disorders in women of reproductive age. The first signs and symptoms of the disease may be present as early as puberty. Diagnostic criteria include hyperandrogenism (clinical or biological), ovulatory dysfunction and polycystic ovarian morphology on ultrasound. The consequences of the syndrome are multiple. These consist of fertility issues and metabolic anomalies with increased cardiovascular risk, but also sleep disturbances, increased risk of endometrial hyperplasia and endometrial cancer and a potentially important psychological impact with decreased quality of life. The management of polycystic ovary syndrome is multidisciplinary and treatment is variable, depending on symptoms and the patient's desire for fertility. In all cases, measures aiming to improve the metabolic dysfunction are essential, going from adopting a healthy lifestyle to adequate therapy of each metabolic anomaly.

Le syndrome des ovaires micropolykystiques est une des endocrinopathies les plus fréquentes de la femme en âge de reproduction. Les premiers signes et symptômes peuvent se manifester dès la puberté. Les critères de diagnostic reposent sur une hyperandrogénie (clinique ou biologique), une anovulation chronique et un aspect d'ovaires micropolykystiques à l'échographie. Les conséquences du syndrome sont multiples, essentiellement concernant les troubles de la fertilité et les perturbations métaboliques avec un risque cardio-vasculaire augmenté, mais également des anomalies du sommeil, un risque augmenté d'hyperplasie endométriale et de cancer endométrial et un impact psychologique parfois important avec diminution de la qualité de vie. La prise en charge est multi-disciplinaire et le traitement variable, en fonction des symptômes et des souhaits de fertilité de la patiente. Dans tous les cas, une prise en charge métabolique, avec une hygiène de vie saine et des traitements visant les perturbations métaboliques individuelles, est essentielle.