Does bisphenol A (BPA) participates in the pathogenesis of Polycystic Ovary Syndrome (PCOS)?

PCOS is an endocrine disorder characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. Its etiology is uncertain. It is debated whether BPA would be a component of the environmental factor in the etiology of PCOS. Contamination by BPA can occur from food packaging (exposure during the diet) and through skin absorption and/or inhalation. It can be transferred to the fetus via the placenta or to the infant via breast milk, and it can be found in follicular fluid, fetal serum, and amniotic fluid. The phenolic structure of BPA allows it to interact with Estrogen Receptors (ERs) through genomic signaling, in which BPA binds to nuclear ERα or Erß, or through nongenomic signaling by binding to membrane ERs, prompting a rapid and intense response. With daily and constant exposure, BPA's tendency to bioaccumulate and its ability to activate nongenomic signaling pathways can alter women's metabolic and reproductive function, leading to hyperandrogenism, insulin resistance, obesity, atherogenic dyslipidemia, chronic inflammatory state, and anovulation and favoring PCOS. The harmful changes caused by BPA can be passed on to future generations without the need for additional exposure because of epigenetic modifications. Not only high BPA levels can produce harmful effects, but at low levels, BPA may be harmful when exposure occurs during the most vulnerable periods, such as the fetal and neonatal periods, as well as during the prepubertal age causing an early accumulation of BPA in the body. Learning how BPA participates in the pathogenesis of PCOS poses a challenge and further studies should be conducted.

Hyperandrogenism.

Hyperandrogenism is a common condition encountered by pediatric and adolescent physicians. Most girls with hyperandrogenism represent physiological pubertal variation; pathology may be present in a substantial minority. Systematic evaluation is essential to avoid unnecessary work-up in physiological causes while not missing pathological causes. Polycystic ovarian syndrome (PCOS), unexplained, persistent hyperandrogenism of ovarian origin, is the most common form in adolescent girls. The high prevalence of physiological peripubertal hirsutism, anovulation, and polycystic ovarian morphology results in mislabeling many girls as having the polycystic ovarian syndrome, a disorder with lifelong implications. The use of strict criteria of age-specific anovulation, hyperandrogenism, and duration is essential to reduce their stigmatization. The exclusion of secondary causes by screening tests (cortisol, thyroid profile, prolactin, and 17OHP) is essential before undertaking treatment for PCOS. Lifestyle measures, estrogen-progesterone preparations, antiandrogens, and metformin are the cornerstone of managing the disorder.

The Prevalence of Menstrual Cycle Disorders and Menstrual Cycle-Related Symptoms in Female Athletes: A Systematic Literature Review.

BACKGROUND: Menstrual cycle (MC) disorders and MC-related symptoms can have debilitating effects on the health and performance of female athletes. As the participation of women in sports continues to increase, understanding the prevalence of a range of MC disorders and MC-related symptoms may guide preventive strategies to protect the health and optimise the performance of female athletes. OBJECTIVE: To examine the prevalence of MC disorders and MC-related symptoms among female athletes who are not using hormonal contraceptives and evaluate the assessment methods used to identify MC disorders and MC-related symptoms. METHODS: This systematic review was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Six databases were searched until September 2022 for all original research that reported the prevalence of MC disorders and/or MC-related symptoms in athletes not using hormonal contraceptives, which included the definitions of the MC disorders examined, and the assessment methods used. MC disorders included amenorrhoea, anovulation, dysmenorrhoea, heavy menstrual bleeding (HMB), luteal phase deficiency (LPD), oligomenorrhoea, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). MC-related symptoms included any affective and physical symptoms related to the MC that do not cause significant personal, interpersonal or functional impairment. The prevalence data across eligible studies were combined, and all studies were qualitatively synthesised to evaluate the assessment methods and tools used to identify MC disorders and MC-related symptoms. The methodological quality of studies was assessed using a modified Downs and Black checklist. RESULTS: Sixty studies involving 6380 athletes were included. A wide range of prevalence was observed for all types of MC disorders, with a dearth of data on anovulation and LPD. Based on pooled data, dysmenorrhoea (32.3%; range 7.8-85.6%) was the most prevalent MC disorder. Studies reporting MC-related symptoms mostly examined the premenstrual and menstruation phases, where affective symptoms appeared more prevalent than physical symptoms. A larger proportion of athletes reported symptoms during the initial days of menstruation compared with the premenstrual phase. MC disorders and MC-related symptoms were retrospectively assessed using self-report methods in 90.0% of studies. Most studies (76.7%) in this review were graded as moderate quality. DISCUSSION: MC disorders and MC-related symptoms are commonplace among female athletes, warranting further research examining their impact on performance and preventive/management strategies to optimise athlete health. To increase the quality of future studies, researchers should adopt standardised definitions of MC disorders and assessment methods such as a combination of calendar counting, urinary ovulation tests and a mid-luteal phase serum progesterone measurement when assessing menstrual function. Similarly, standardised diagnostic criteria should be used when examining MC disorders such as HMB, PMS and PMDD. Practically, implementing prospective cycle monitoring that includes ovulation testing, mid-luteal blood sampling (where feasible) and symptom logging throughout the MC could support athletes and practitioners to promptly identify and manage MC disorders and/or MC-related symptoms. TRIAL REGISTRATION: This review has been registered in the PROSPERO database (CRD42021268757).

Immune Dysfunction in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged individuals with ovaries. It is associated with anovulation and increased risk to fertility and metabolic, cardiovascular, and psychological health. The pathophysiology of PCOS is still inadequately understood, although there is evidence of persistent low-grade inflammation, which correlates with associated visceral obesity. Elevated proinflammatory cytokine markers and altered immune cells have been reported in PCOS and raise the possibility that immune factors contribute to ovulatory dysfunction. Because normal ovulation is modulated by immune cells and cytokines in the ovarian microenvironment, the endocrine and metabolic abnormalities associated with PCOS orchestrate the accompanying adverse effects on ovulation and implantation. This review evaluates the current literature on the relationship between PCOS and immune abnormalities, with a focus on emerging research in the field.

Long-term outcomes of switching to gonadotrophins versus continuing with clomiphene citrate, with or without intrauterine insemination, in women with normogonadotropic anovulation and clomiphene failure: follow-up study of a factorial randomized clinical trial.

STUDY QUESTION: What are the long-term outcomes after allocation to use of gonadotrophins versus clomiphene citrate (CC) with or without IUI in women with normogonadotropic anovulation and clomiphene failure? SUMMARY ANSWER: About four in five women with normogonadotropic anovulation and CC failure had a live birth, with no evidence of a difference in pregnancy outcomes between the allocated groups. WHAT IS KNOWN ALREADY: CC has long been used as first line treatment for ovulation induction in women with normogonadotropic anovulation. Between 2009 and 2015, a two-by-two factorial multicentre randomized clinical trial in 666 women with normogonadotropic anovulation and six cycles of CC failure was performed (M-ovin trial). This study compared a switch to gonadotrophins with continued treatment with CC for another six cycles, with or without IUI within 8 months. Switching to gonadotrophins increased the chance of conception leading to live birth by 11% over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. The addition of IUI did not significantly increase live birth rates. STUDY DESIGN, SIZE, DURATION: In order to investigate the long-term outcomes of switching to gonadotrophins versus continuing treatment with CC, and undergoing IUI versus continuing with intercourse, we conducted a follow-up study. The study population comprised all women who participated in the M-ovin trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participating women were asked to complete a web-based questionnaire. The primary outcome of this study was cumulative live birth. Secondary outcomes included clinical pregnancies, multiple pregnancies, miscarriage, stillbirth, ectopic pregnancy, fertility treatments, neonatal outcomes and pregnancy complications. MAIN RESULTS AND THE ROLE OF CHANCE: We approached 564 women (85%), of whom 374 (66%) responded (184 allocated to gonadotrophins; 190 to CC). After a median follow-up time of 8 years, 154 women in the gonadotrophin group had a live birth (83.7%) versus 150 women in the CC group (78.9%) (relative risk (RR) 1.06, 95% CI 0.96-1.17). A second live birth occurred in 85 of 184 women (49.0%) in the gonadotrophin group and in 85 of 190 women (44.7%) in the CC group (RR 1.03, 95% CI 0.83-1.29). Women allocated to gonadotrophins had a third live birth in 6 of 184 women (3.3%) and women allocated to CC had a third live birth in 14 of 190 women (7.4%). There were respectively 12 and 11 twins in the gonadotrophin and CC groups. The use of fertility treatments in the follow-up period was comparable between both groups. In the IUI group, a first live birth occurred in 158 of 192 women (82.3%) and while in the intercourse group, 146 of 182 women (80.2%) reached at least one live birth (RR: 1.03 95% CI 0.93-1.13; 2.13%, 95% CI -5.95, 10.21). LIMITATIONS, REASONS FOR CAUTION: We have complete follow-up results for 57% of the women.There were 185 women who did not respond to the questionnaire, while 102 women had not been approached due to missing contact details. Five women had not started the original trial. WIDER IMPLICATIONS OF THE FINDINGS: Women with normogonadotropic anovulation and CC failure have a high chance of reaching at least one live birth. In terms of pregnancy rates, the long-term differences between initially switching to gonadotrophins are small compared to continuing treatment with CC. STUDY FUNDING/COMPETING INTEREST(S): The original study received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). A.H. reports consultancy for development and implementation of a lifestyle App, MyFertiCoach, developed by Ferring Pharmaceutical Company. M.G. receives unrestricted grants for scientific research and education from Ferring, Merck and Guerbet. B.W.M. is supported by an NHMRC Investigatorgrant (GNT1176437). B.W.M. reports consultancy for ObsEva and Merck and travel support from Merck. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: This follow-up study was registered in the OSF Register, https://osf.io/pf24m. The original M-ovin trial was registered in the Netherlands Trial Register, number NTR1449.

Current pharmacotherapy and future directions for neuroendocrine causes of female infertility.

INTRODUCTION: Infertility is recognized as a major global health issue, often associated with significant psychological distress for affected couples. Causes of female infertility include endocrine conditions leading to oligo/anovulation, in addition to structural causes such as tubal, uterine, or peritoneal disorders. Pharmacological treatments, targeting pathways in the hypothalamic-pituitary-ovarian axis, can improve rates of ovulation, conception, pregnancy, and birth. Some existing therapeutic options are hindered by limited efficacy or by a non-physiological mechanism, which can risk excessive stimulation and treatment-related adverse effects. Therefore, there is a continued need for novel therapies to improve care for patients suffering with infertility. AREAS COVERED: In this review, the authors focus on endocrine causes of oligo/anovulation in women and on advances in assisted reproductive technology. Current pharmacological treatments and putative future therapeutic avenues in development to aid fertility in women are outlined. EXPERT OPINION: A deeper understanding of the reproductive neuroendocrine network governing hypothalamic gonadotropin-releasing hormone release can offer novel therapeutic targets for the treatment of female subfertility, leading to improved clinical outcomes, less invasive routes of administration, and decreased treatment-related side-effects. The ultimate aim of development in female subfertility is to offer therapeutic interventions that are effective, reproducible, associated with minimal risks, and have an acceptable route of administration.

Effects of L-carnitine supplementation for women with polycystic ovary syndrome: a systematic review and meta-analysis.

Background: Polycystic ovary syndrome (PCOS) is a disorder in reproductive age women and is characterized by hyperandrogenic anovulation and oligo-amenorrhea, which leads to infertility. Anovulation in PCOS is associated with low follicle-stimulating hormone levels and the arrest of antral follicle development in the final stages of maturation. L-carnitine (LC) plays a role in fatty acid metabolism, which is found to be lacking in PCOS patients. This systematic review and meta-analysis aimed to determine the effectiveness of LC supplementation for patients with PCOS. Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Psychological Information Database (PsycINFO), and the World Health Organization International Clinical Trials Registry Platform for all randomized control trials, comparing LC alone or in combination with other standard treatments for the treatment of PCOS from inception till June 2021. We independently screened titles and abstracts to identify available trials, and complete texts of the trials were checked for eligibility. Data on the methods, interventions, outcomes, and risk of bias from the included trials were independently extracted by the authors. The estimation of risk ratios and mean differences with a 95 percent confidence interval (CI) was performed using a random-effects model. Results: Nine studies with 995 participants were included in this review. Five comparison groups were involved. In one comparison group, LC reduced the fasting plasma glucose (FPG) (mean differences (MD) -5.10, 95% CI [-6.25 to -3.95]; P = 0.00001), serum low-density lipoprotein (LDL) (MD -25.00, 95% CI [-27.93 to -22.07]; P = 0.00001), serum total cholesterol (MD -21.00, 95% CI [-24.14 to -17.86]; P = 0.00001), and serum triglyceride (TG) (MD -9.00, 95% CI [-11.46 to -6.54]; P = 0.00001) with moderate certainty of evidence. Another comparison group demonstrated that LC lowers the LDL (MD -12.00, 95% CI [-15.80 to -8.20]; P = 0.00001), serum total cholesterol (MD -24.00, 95% CI [-27.61 to -20.39]; P = 0.00001), and serum TG (MD -19.00, 95% CI [-22.79 to -15.21]; P = 0.00001) with moderate certainty of evidence. Conclusion: There was low to moderate certainty of evidence that LC improves Body Mass Index (BMI) and serum LDL, TG, and total cholesterol levels in women with PCOS.

Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 5% to 20% of women worldwide and often leads to anovulatory infertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI, letrozole, is at least as effective as the first-line treatment clomiphene citrate (CC), a selective oestrogen receptor modulator (SERM). OBJECTIVES: To evaluate the effectiveness and safety of AIs (letrozole) (with or without adjuncts) compared to SERMs (with or without adjuncts) for infertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination. SEARCH METHODS: We searched the following sources, from their inception to 4 November 2021, to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase and PsycINFO. We also checked reference lists of relevant trials, searched the trial registers and contacted experts in the field for any additional trials. We did not restrict the searches by language or publication status. SELECTION CRITERIA: We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted the data and assessed risks of bias using RoB 1. We pooled trials where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth rate and OHSS rate. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy rates. We assessed the certainty of the evidence for each comparison using GRADE methods. MAIN RESULTS: This is a substantive update of a previous review; of six previously included trials, we excluded four from this update and moved two to 'awaiting classification' due to concerns about validity of trial data. We included five additional trials for this update that now includes a total of 41 RCTs (6522 women). The AI, letrozole, was used in all trials. Letrozole compared to SERMs with or without adjuncts followed by timed intercourse Live birth rates were higher with letrozole (with or without adjuncts) compared to SERMs followed by timed intercourse (OR 1.72, 95% CI 1.40 to 2.11; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; 11 trials, 2060 participants; high-certainty evidence). This suggests that in women with a 20% chance of live birth using SERMs, the live birth rate in women using letrozole with or without adjuncts would be 27% to 35%. There is high-certainty evidence that OHSS rates are similar with letrozole or SERMs (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.01; I2 = 0%; 10 trials, 1848 participants; high-certainty evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.69, 95% CI 1.45 to 1.98; I2 = 0%; NNTB = 10; 23 trials, 3321 participants; high-certainty evidence). This suggests that in women with a 24% chance of clinical pregnancy using SERMs, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 32% to 39%. There is little or no difference between treatment groups in the rate of miscarriage per pregnancy (25% with SERMs versus 24% with letrozole: OR 0.94, 95% CI 0.66 to 1.32; I2 = 0%; 15 trials, 736 participants; high-certainty evidence) and multiple pregnancy rate (2.2% with SERMs versus 1.6% with letrozole: OR 0.74, 95% CI 0.42 to 1.32; I2 = 0%; 14 trials, 2247 participants; high-certainty evidence). However, a funnel plot showed mild asymmetry, indicating that some trials in favour of SERMs might be missing.  Letrozole compared to laparoscopic ovarian drilling (LOD) One trial reported very low-certainty evidence that live birth rates may be higher with letrozole compared to LOD (OR 2.07, 95% CI 0.99 to 4.32; 1 trial, 141 participants; very low-certainty evidence). This suggests that in women with a 22% chance of live birth using LOD with or without adjuncts, the live birth rate in women using letrozole with or without adjuncts would be 24% to 47%. No trial reported OHSS rates. Due to the low-certainty evidence we are uncertain if letrozole improves pregnancy rates compared to LOD (OR 1.47, 95% CI 0.95 to 2.28; I² = 0%; 3 trials, 367 participants; low-certainty evidence). This suggests that in women with a 29% chance of clinical pregnancy using LOD with or without adjuncts, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 28% to 45%. There seems to be no evidence of a difference in miscarriage rates per pregnancy comparing letrozole to LOD (OR 0.65, 95% CI 0.22 to 1.92; I² = 0%; 3 trials, 122 participants; low-certainty evidence). This also applies to multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 1 trial, 141 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Letrozole appears to improve live birth rates and pregnancy rates in infertile women with anovulatory PCOS, compared to SERMs, when used for ovulation induction, followed by intercourse. There is high-certainty evidence that OHSS rates are similar with letrozole or SERMs. There was high-certainty evidence of no difference in miscarriage rate and multiple pregnancy rate. We are uncertain if letrozole increases live birth rates compared to LOD. In this update, we added good quality trials and removed trials with concerns over data validity, thereby upgrading the certainty of the evidence base.

Ovarian Drilling: Back to the Future.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. The complex metabolic dysregulation at the base of this syndrome often renders infertility management challenging. Many pharmacological strategies have been applied for the induction of ovulation with a non-negligible rate of severe complications such as ovarian hyperstimulation syndrome and multiple pregnancies. Ovarian drilling (OD) is currently being adopted as a second-line treatment, to be performed in case of medical therapy. Laparoscopic ovarian drilling (LOD), the contemporary version of ovarian wedge resection, is considered effective for gonadotropins in terms of live birth rates, but without the risks of iatrogenic complications in gonadotropin therapy. Its endocrinal effects are longer lasting and, after the accomplishment of this procedure, ovarian responsiveness to successive ovulation induction agents is enhanced. Traditional LOD, however, is burdened by the potential risks of iatrogenic adhesions and decreased ovarian reserve and, therefore, should only be considered in selected cases. To overcome these limits, novel tailored and mini-invasive approaches, which are still waiting for wide acceptance, have been introduced, although their role is still not well-clarified and none of them have provided enough evidence in terms of efficacy and safety.

Female obesity and infertility: outcomes and regulatory guidance.

Obesity has been associated with reduced fertility, although the dynamics and mechanisms which link excess weight to reduced fertility are not yet fully clarified. Obese women, especially those with central obesity, are less likely to conceive per cycle. Obese women suffer from perturbations of the hypothalamus-pituitary-ovary axis, disturbances of the menstrual cycle and are up to three times more likely to suffer from oligo/anovulation. A delicate hormonal balance regulates follicular development and the maturation of oocytes and it has been observed that obesity can alter the hormonal environment: adipocytes, in fact, are responsible for the production of a hormone called leptin (present in high quantities in obese women) which has been associated with reduced fecundity. In addition to compromising ovulation, obesity negatively affects the development and implantation of the endometrium. The expression of polycystic ovary syndrome (PCOS) is regulated, in part, by weight, so obese women with PCOS often have a more severe phenotype and higher subfertility rates. Furthermore, obesity impairs women's response to medically assisted procreation (MAP) treatments. The authors have set out to delineate a broad-ranging overview of obesity's impact on female fertility, by drawing upon sources spanning the 1994-2022 period. Assisted reproductive technology (ART) procedures are also discussed as they relate to obese patients. In addition the dynamics by which maternal obesity reportedly affects fetal, neonatal and child development have also been briefly enunciated.

Polycystic ovarian syndrome-current pharmacotherapy and clinical implications.

Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism. The treatment in PCOS is mainly symptomatic and involves lifestyle interventions and medications such as Metformin, Oral contraceptives and Antiandrogens. However, the management of PCOS is challenging and current interventions are not able to deal with outcomes of this syndrome. This review encompasses latest pharmacotherapeutic and non-pharmacotherapeutic interventions currently in use to tackle various symptomatic contentions in PCOS. Our focus has been mainly on novel therapeutic modalities for treatment/management of PCOS, like use of newer insulin sensitizers viz., Inositols, Glucagon-like peptide-1(GLP-1) agonists, Dipeptidyl pepdidase-4 (DPP-4) inhibitors, and sodium-glucose transport protein 2 (SGLT2) inhibitors. Also, evidence suggesting the use of vitamin D, statins, and Letrozole as emerging therapies in PCOS have been summarized in this review. Additionally, novel cosmetic techniques like electrolysis, laser and use of topically applied eflornithine to tackle the most distressing feature of facial hirsutism associated with PCOS, non-pharmacological therapy like acupuncture and the role of herbal medicine in PCOS management have also been discussed.

The effect of obesity on human reproductive health and foetal life.

Obesity in both women and men is regarded as one of the many factors that may contribute to impaired reproductive health. Obesity can be accompanied by several neuroendocrine and ovarian dysfunctions, including chronic oligo/anovulation, menstrual irregularities, subfertility, and the increased risk of pregnancy in women. Insulin resistance, elevated triglyceride and fatty acid levels, and the secretion of adipocytokines caused by the excessive accumulation of adipose tissue associated with obesity adversely affect reproductive functions. Alterations in sperm quality and motility and hormone levels related to a rise in body mass index (BMI) may predispose men to infertility. The mechanisms of action of obesity on male infertility include endocrinopathy, erectile dysfunction, epididymitis, increased leptin and adipocytes, increased aromatase, inflammatory cytokines secreted by fat tissue, and sperm DNA fragmentation. This study reports that an increased BMI may lead to low semen quality, poor sperm motility, and reduced fertilization rates in men as well as anovulation, pregnancy loss, diminished pregnancy, and low live birth rates in women. Having optimal weight with balanced nutrition enables one to maintain a continuity of reproductive health throughout the entire life cycle, which is extremely important in terms of having a healthy embryo, including pre-foetal life, in the continuity of pregnancy and having a live birth.

Association of Overweight and Consistent Anovulation among Infertile Women with Regular Menstrual Cycle: A Case-control Study.

OBJECTIVE: It has been suggested that excess body weight could represent a risk factor for infertility outcomes. The present study aimed to evaluate the association of overweight and anovulation among infertile women with regular menstrual cycles. METHODS: We conducted a retrospective case-control study with consistently anovulatory patients undergoing assisted reproduction treatment. The patients were stratified into normal weight (body mass index [BMI]: 18.5-24.9kg/m2) and overweight (BMI: 25.0-29.9kg/m2).Those with polycystic ovary syndrome or obesity were excluded. The groups were matched for age, duration of infertility, prolactin, follicle stimulating hormone (FSH), thydroid stimulating hormone (TSH), luteinizing hormone (LH), and estradiol levels. RESULTS: Overweight was significantly associated with anovulation, when using the World Health Organization (WHO) criteria for anovulation: progesterone levels > 5.65 ng/ml and ultrasonography evidence of follicle collapse (odds ratio [OR]: 2.69; 95% confidence interval [CI95%]: 1.04-6.98). CONCLUSION: Body mass index above the normal range jeopardizes ovulation among non-obese infertile women with regular menstrual cycles.

OBJETIVO: O excesso de peso corporal tem sido associado como fator de risco para infertilidade. Este estudo teve como objetivo avaliar a associação de sobrepeso e anovulação entre mulheres inférteis com ciclos menstruais regulares. MéTODOS: Realizamos um estudo retrospectivo de caso-controle com mulheres com anovulação consistente em tratamento por reprodução assistida. As pacientes foram estratificadas entre aquelas com peso normal (índice de massa corporal [IMC]: 18,5­24,9 Kg/m2) e as com sobrepeso (IMC: 25,0­29,9 Kg/m2). As pacientes com síndrome do ovário policístico ou obesidade foram excluídas. Os grupos foram pareados por idade, duração da infertilidade, níveis de prolactina, hormônio folículo-estimulante (FSH), hormônio tiroestimulante (TSH), hormônio luteinizante (LH) e estradiol. RESULTADOS: O excesso de peso associou-se significativamente à anovulaçãoquando usados os critérios de anovulação da Organização Mundial de Saúde (OMS): níveis de progesterona > 5,65 ng/ml e evidência ultrassonográfica de colapso folicular (razão de chances [RC]: 2,69; IC95%: 1,04­6,98). CONCLUSãO: O IMC acima da faixa normal compromete a ovulação em mulheres inférteis não obesas com ciclos menstruais regulares.

Association of Overweight and Consistent Anovulation among Infertile Women with Regular Menstrual Cycle: A Case-control Study / Associação entre sobrepeso e anovulação consistente em mulheres inférteis com ciclo menstrual regular: Um estudo de caso-controle

Abstract Objective It has been suggested that excess body weight could represent a risk factor for infertility outcomes. The present study aimed to evaluate the association of overweight and anovulation among infertile women with regular menstrual cycles. Methods We conducted a retrospective case-control study with consistently anovulatory patients undergoing assisted reproduction treatment. The patients were stratified into normal weight (body mass index [BMI]: 18.5-24.9kg/m2) and overweight (BMI: 25.0- 29.9kg/m2).Those with polycystic ovary syndrome or obesity were excluded. The groups were matched for age, duration of infertility, prolactin, follicle stimulating hormone (FSH), thydroid stimulating hormone (TSH), luteinizing hormone (LH), and estradiol levels. Results Overweight was significantly associated with anovulation, when using the World Health Organization (WHO) criteria for anovulation: progesterone levels>5.65 ng/ml and ultrasonography evidence of follicle collapse (odds ratio [OR]: 2.69; 95% confidence interval [CI95%]: 1.04-6.98). Conclusion Body mass index above the normal range jeopardizes ovulation among non-obese infertile women with regular menstrual cycles.

Resumo Objetivo O excesso de peso corporal tem sido associado como fator de risco para infertilidade. Este estudo teve como objetivo avaliar a associação de sobrepeso e anovulação entre mulheres inférteis com ciclos menstruais regulares. Métodos Realizamos um estudo retrospectivo de caso-controle com mulheres com anovulação consistente em tratamento por reprodução assistida. As pacientes foram estratificadas entre aquelas com peso normal (índice de massa corporal [IMC]: 18,5- 24,9 Kg/m2) e as com sobrepeso (IMC: 25,0-29,9 Kg/m2). As pacientes com síndrome do ovário policístico ou obesidade foram excluídas. Os grupos foram pareados por idade, duração da infertilidade, níveis de prolactina, hormônio folículo-estimulante (FSH), hormônio tiroestimulante (TSH), hormônio luteinizante (LH) e estradiol. Resultados O excesso de peso associou-se significativamente à anovulaçãoquando usados os critérios de anovulação da Organização Mundial de Saúde (OMS): níveis de progesterona>5,65 ng/ml e evidência ultrassonográfica de colapso folicular (razão de chances [RC]: 2,69; IC95%: 1,04-6,98). Conclusão O IMC acima da faixa normal compromete a ovulação em mulheres inférteis não obesas com ciclos menstruais regulares.

An Update on Contraception in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women, characterized by hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology. Combined oral contraceptives (COCs), along with lifestyle modifications, represent the first-line medical treatment for the long-term management of PCOS. Containing low doses of estrogen and different types of progestin, COCs restore menstrual cyclicity, improve hyperandrogenism, and provide additional benefits such as reducing the risk of endometrial cancer. However, potential cardiometabolic risk associated with these agents has been a concern. COCs increase the risk of venous thromboembolism (VTE), related both to the dose of estrogen and the type of progestin involved. Arterial thrombotic events related to COC use occur much less frequently, and usually not a concern for young patients. All patients diagnosed with PCOS should be carefully evaluated for cardiometabolic risk factors at baseline, before initiating a COC. Age, smoking, obesity, glucose intolerance or diabetes, hypertension, dyslipidemia, thrombophilia, and family history of VTE should be recorded. Patients should be re-assessed at consecutive visits, more closely if any baseline cardiometabolic risk factor is present. Individual risk assessment is the key in order to avoid unfavorable outcomes related to COC use in women with PCOS.

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.

Association of metabolic and inflammatory markers with polycystic ovarian syndrome (PCOS): an update.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is the most prevalent metabolic disorder in reproductive-age women. It is indeed a multifactorial condition evidenced by ovarian dysfunction, hyperandrogenaemia, infertility, hormonal imbalance and chronic anovulation. Experimental evidence infers that PCOS women are prone to cardiovascular problems and insulin resistance. PURPOSE: To furnish the details about the association of inflammatory markers in PCOS. DESIGN: An extensive literature search on PubMed, science direct and google scholar has been performed for articles about PCOS and inflammation in PCOS. A comprehensive analysis using original articles, reviews, systemic and meta-analysis was conducted for better understanding the relationship between inflammatory cytokines and PCOS. RESULTS: The inflammatory markers perform a substantial part in managing the functions of the ovary. Any disturbances in their levels can lead to ovarian dysfunction. Inflammatory markers are associated with PCOS pathogenesis. The interplay between inflammatory cytokines in the PCOS ovary strongly implies that inflammation is one of the most potent risk factors of PCOS. CONCLUSION: Inflammatory markers have a significant role in regulating the ovary. This manuscript highlights the significance of metabolic and inflammatory markers with PCOS. Since PCOS is always considered as a metabolic disorder, researchers can also consider focusing on the relationship between the inflammatory markers in PCOS to establish a new treatment or management of the disease and to improve women's health.

A patient-specific model combining antimüllerian hormone and body mass index as a predictor of polycystic ovary syndrome and other oligo-anovulation disorders.

OBJECTIVE: To determine whether a patient-specific predictive model combining antimüllerian hormone (AMH) levels and body mass index (BMI) can aid in the diagnosis of polycystic ovary syndrome (PCOS) and other ovulatory dysfunction disorders (OVDYS) among infertile women. DESIGN: Retrospective cohort study. SETTING: Academic fertility center. PATIENT(S): One thousand and ten infertile women undergoing 3,160 intrauterine insemination (IUI) cycles, stratified by diagnosis in three groups: PCOS, OVDYS, and other etiologies. INTERVENTION(S): Ovulation induction followed by IUI or ultrasound-monitored natural cycles. MAIN OUTCOME MEASURE(S): The probability of either PCOS or OVDYS diagnosis based on AMH levels alone and a patient-specific predictive model that combines serum AMH and patient's BMI. RESULT(S): Median and interquartile range (IQR) for the serum AMH levels (ng/mL) were the highest in women with PCOS, and lowest in those with other infertility causes. Overall, for every 1 ng/mL increase in AMH, the odds of PCOS and OVDYS versus other causes increased by 55% and 24%, respectively. Postestimation from multivariate logistic regression models showed that PCOS diagnosis can be predicted with lower AMH values in women with a higher BMI compared with the AMH values predicting PCOS in normal-weight or underweight patients. The receiver operating characteristic curves reinforced these findings, and the best cutoffs for PCOS diagnosis were 7.5, 4.4, and 4.1 ng/mL for women belonging to the BMI groups 18.5-24.9, 25.0-29.9, and ≥30.0 kg/m2, respectively. CONCLUSION(S): Taking into account AMH and BMI, we developed a model that predicts the probability of an oligo-anovulation diagnosis, thus facilitating patient-specific counseling in the infertility setting.

Prevalence of metabolic syndrome in women with polycystic ovary syndrome and the factors associated: A cross sectional study at a tertiary care center in Hyderabad, south-eastern India.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) and polycystic ovary syndrome (PCOS) are two interrelated but distinct endocrine problems with several health consequences secondary to insulin resistance. This study aimed to determine the prevalence of MetS in women with PCOS. METHODS: This was a cross sectional study carried out from May 2017 to October 2017 at the gynecology outpatient clinic of a tertiary care private hospital in Hyderabad, India. Eligible women diagnosed with PCOS according to Rotterdam criteria were enrolled. The primary outcome was the prevalence of MetS diagnosed by the modified NCEP ATP III criteria. RESULTS: The study comprised 382 patients with a mean age of 26.8 ± 5.3 years. MetS was present in 147 (38.5%) women with PCOS. The most frequently observed individual components of MetS were increased waist circumference and decreased HDL cholesterol. When predictors for MetS were analyzed by multivariate regression, BMI (aOR 1.14; 1.06-1.23; p ≪0.001) and age (aOR 1.12; 1.06-1.17; p ≪0.001) were significantly associated with MetS; however, the effect size was modest. CONCLUSION: A high prevalence of MetS was observed in women with PCOS at this tertiary center in Hyderabad, with abdominal obesity and low HDL cholesterol as predominant components. We believe that universal screening of all PCOS women is a reasonable option.

EVALUATION OF THE RISK FACTORS OF CERVICAL INSUFFICIENCY IN WOMEN WITH INFERTILITY ASSOCIATED WITH ANOVULATION.

Cervical insufficiency is a common problem in obstetrical care. There are not enough studies about its development in women with infertility. The aim of the article was to determine the risk factors of the development of cervical insufficiency in women with infertility associated with anovulation. The object of the study were 308 pregnant women (110 pregnant women with cervical insufficiency and without infertility, 92 pregnant women with infertility associated with anovulation and with cervical insufficiency, 76 pregnant women with infertility associated with anovulation and without cervical insufficiency, 30 pregnant women without cervical insufficiency and infertility (controls)). We analyzed the data of obstetrical anamnesis, gynecological diseases, extragenital pathology. In fertile women with cervical insufficiency the traumatic factor of the cervix (previous labors, gynecological procedures connected with cervical dilatation) was the main in the development of this pathology. While in the women with infertility associated with anovulation the forming of cervical insufficiency was associated with hormonal reasons (hyperandrogenism (OR=3.04, 95 % CI=1.15-8.05, p=0.03), diminished ovarian reserve (OR=6.00, 95 % CI=1.97-18.24, p=0.002), controlled ovarian stimulation with gonadotropin and clomiphene citrate use (OR=3.69, 95% CI=1.93-7.04, p<0.001), use of additional reproductive technology (OR=1.95, 95 % CI=1.05-3.63, p=0.03).