Association between body mass index, weight loss and the chance of pregnancy in women with polycystic ovary syndrome and overweight or obesity: a retrospective cohort study in the UK.

STUDY QUESTION: What are the associations between baseline BMI (Study 1) and change in body weight (Study 2) with the likelihood of pregnancy in women with polycystic ovary syndrome (PCOS). SUMMARY ANSWER: In women with PCOS, higher baseline BMI was associated with a lower chance of pregnancy; however, weight loss was associated with an increased chance of pregnancy versus maintaining a stable weight or gaining weight. WHAT IS KNOWN ALREADY: Two studies in large cohorts of Danish women with the intention to become pregnant showed a decline in fecundability ratios with higher BMI. Furthermore, a meta-analysis found that overweight/obesity significantly worsened metabolic and reproductive outcomes in women with PCOS. STUDY DESIGN, SIZE, DURATION: Data were extracted from the UK Clinical Practice Research Datalink GOLD database. Patients included women aged 18-45 years with BMI ≥18.5 (Study 1) or ≥25 kg/m2 (Study 2) at time of PCOS diagnosis (index date). The primary outcome was the time to first pregnancy recorded during 36-months' follow-up, analysed with Cox proportional hazard models and presented as hazard ratios (HRs). PARTICIPANTS/MATERIALS, SETTING, METHODS: Study 1 included 9955 women with PCOS. Study 2 included 7593 women with PCOS and median BMI of 34.0 kg/m2. MAIN RESULTS AND THE ROLE OF CHANCE: Higher BMI was associated with a lower chance of pregnancy in the 3 years following diagnosis. It was estimated that 41% of women with normal weight (18.5-24.9 kg/m2) would become pregnant compared to 17% of women with obesity class III (BMI ≥40.0 kg/m2) during follow-up. Furthermore, the chance of pregnancy for women with obesity class III was estimated to be 63% lower than for women with normal weight, with the same age and glycaemic status (HR 0.37, 95% CI 0.31-0.44; P < 0.0001). A significant inverse association was found between BMI change and chance of pregnancy: 10% weight loss was estimated to increase the chance of pregnancy by 68% for women with baseline BMI of 40 kg/m2 (HR 1.68, 95% CI 1.49-1.90). LIMITATIONS, REASONS FOR CAUTION: Multiple factors influence the chance of pregnancy (the ability and willingness to become pregnant), which was addressed by exclusion criteria employed. The real-world nature of the study means that use of non-prescription contraceptives was not available. Bias may have been introduced by the fact that only around 40% of women with PCOS in the CPRD GOLD database had their BMI recorded during the year prior to PCOS diagnosis. BMI categories used in the analyses may not be applicable to women of all ethnicities. The study population was only representative of women in the UK and results may not be generalizable to other regions. PCOS diagnoses were based on codes entered into the system by primary care providers, and no information was available regarding the criteria used for diagnosis, although symptoms used to diagnose PCOS have not changed over time. WIDER IMPLICATIONS OF THE FINDINGS: Our observations provide further evidence of the benefits of weight loss in women with overweight/obesity and PCOS who are seeking to become pregnant. STUDY FUNDING/COMPETING INTEREST(S): Novo Nordisk A/S. A.H.B. declares fees for consultancy from Novo Nordisk. P.N.L. and C.L.H. are employees of Novo Nordisk. V.S. and A.V. are employees of, and hold shares in, Novo Nordisk. TRIAL REGISTRATION NUMBER: N/A.

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.

Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with an increased biochemical risk profile for cardiovascular disease and an increased prevalence of diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. This is an update of Morley 2017 and only includes studies on metformin. OBJECTIVES: To evaluate the effectiveness and safety of metformin in combination with or in comparison to clomiphene citrate (CC), letrozole and laparoscopic ovarian drilling (LOD) in improving reproductive outcomes and associated gastrointestinal side effects for women with PCOS undergoing ovulation induction. SEARCH METHODS: We searched the following databases from inception to December 2018: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. SELECTION CRITERIA: We included randomised controlled trials of metformin compared with placebo, no treatment, or in combination with or compared with CC, letrozole and LOD for women with PCOS subfertility. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes and ovulation. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes and reproductive outcomes using GRADE methodology. MAIN RESULTS: We included 41 studies (4552 women). Evidence quality ranged from very low to moderate based on GRADE assessment. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatment The evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51; I2 = 0%; 4 studies, 435 women; low-quality evidence). For a live birth rate of 19% following placebo, the live birth rate following metformin would be between 19% and 37%. The metformin group probably experiences more gastrointestinal side effects (OR 4.00, 95% CI 2.63 to 6.09; I2 = 39%; 7 studies, 713 women; moderate-quality evidence). With placebo, the risk of gastrointestinal side effects is 10% whereas with metformin this risk is between 22% and 40%. There are probably higher rates of clinical pregnancy (OR 1.98, 95% CI 1.47 to 2.65; I2 = 30%; 11 studies, 1213 women; moderate-quality evidence). There may be higher rates of ovulation with metformin (OR 2.64, 95% CI 1.85 to 3.75; I2 = 61%; 13 studies, 684 women; low-quality evidence). We are uncertain about the effect on miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35; I2 = 0%; 4 studies, 748 women; low-quality evidence). Metformin plus CC versus CC alone We are uncertain if metformin plus CC improves live birth rates compared to CC alone (OR 1.27, 95% CI 0.98 to 1.65; I2 = 28%; 10 studies, 1219 women; low-quality evidence), but gastrointestinal side effects are probably more common with combined therapy (OR 4.26, 95% CI 2.83 to 6.40; I2 = 8%; 6 studies, 852 women; moderate quality evidence). The live birth rate with CC alone is 24%, which may change to between 23% to 34% with combined therapy. With CC alone, the risk of gastrointestinal side effects is 9%, which increases to between 21% to 37% with combined therapy. The combined therapy group probably has higher rates of clinical pregnancy (OR 1.62, 95% CI 1.32 to 1.99; I2 = 31%; 19 studies, 1790 women; moderate-quality evidence). The combined group may have higher rates of ovulation (OR 1.65, 95% CI 1.35 to 2.03; I2 = 63%;21 studies, 1568 women; low-quality evidence). There was no clear evidence of an effect on miscarriage (OR 1.35, 95% CI 0.91 to 2.00; I2 = 0%; 10 studies, 1206 women; low-quality evidence). Metformin versus CC When all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01; I2 = 86%; 5 studies, 741 women; very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52; 2 studies, 500 women), while the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94; I2 = 78%, 3 studies, 241 women; very low-quality evidence). However, due to the very low quality of the evidence we cannot draw any conclusions. Among obese women taking metformin there may be lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55; I2 = 0%; 2 studies, 500 women; low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43; I2 = 0%; 2 studies, 500 women; low-quality evidence) while among non-obese women, the metformin group may have more pregnancies (OR 1.56, 95% CI 1.06 to 2.29; I2 = 26%; 6 studies, 530 women; low-quality evidence) and no clear difference in ovulation rates (OR 0.80, 95% CI 0.52 to 1.25; I2 = 0%; 5 studies, 352 women; low-quality evidence). We are uncertain whether there is a difference in miscarriage rates between the groups (overall: OR 0.92, 95% CI 0.51 to 1.66; I2 = 36%; 6 studies, 781 women; low-quality evidence) and no studies reported gastrointestinal side effects. AUTHORS' CONCLUSIONS: Our updated review suggests that metformin may be beneficial over placebo for live birth however, more women probably experience gastrointestinal side effects. We are uncertain if metformin plus CC improves live birth rates compared to CC alone, but gastrointestinal side effects are probably increased with combined therapy. When metformin was compared with CC, data for live birth were inconclusive, and the findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. No studies reported gastrointestinal side effects in this comparison. Due to the low quality of the evidence, we are uncertain of the effect of metformin on miscarriage in all three comparisons.

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. OBJECTIVES: To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction. SEARCH METHODS: We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. SELECTION CRITERIA: We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes using GRADE methodology. MAIN RESULTS: We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I2 = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I2 = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I2 = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I2 = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I2 = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I2 = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I2 = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I2 = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I2 = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I2 = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I2 = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I2 = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I2 = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I2 = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I2 = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I2 = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I2 = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I2 = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I2=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I2 = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes. AUTHORS' CONCLUSIONS: Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.

A comprehensive review of the new FIGO classification of ovulatory disorders.

BACKGROUND: The World Health Organization (WHO) system for the classification of disorders of ovulation was produced 50 years ago and, by international consensus, has been updated by the International Federation of Gynecology and Obstetrics (FIGO). OBJECTIVE AND RATIONALE: This review outlines in detail each component of the FIGO HyPO-P (hypothalamic, pituitary, ovarian, PCOS) classification with a concise description of each cause, and thereby provides a systematic method for diagnosis and management. SEARCH METHODS: We searched the published articles in the PubMed database in the English-language literature until October 2022, containing the keywords ovulatory disorders; ovulatory dysfunction; anovulation, and each subheading in the FIGO HyPO-P classification. We did not include abstracts or conference proceedings because the data are usually difficult to assess. OUTCOMES: We present the most comprehensive review of all disorders of ovulation, published systematically according to the logical FIGO classification. WIDER IMPLICATIONS: Improving the diagnosis of an individual's ovulatory dysfunction will significantly impact clinical practice by enabling healthcare practitioners to make a precise diagnosis and plan appropriate management.

Multi-stakeholder opinion statement on the care of individuals born with differences of sex development: common ground and opportunities for improvement.

BACKGROUND: In the last 15 years, the care provided for individuals born with differences of sex development (DSD) has evolved, with a strong emphasis on interdisciplinary approaches. However, these developments have not convinced some stakeholders to embrace the current model of care. This care model has also paid insufficient attention to socio-cultural differences and global inequalities. SUMMARY: This article is an opinion statement, resulting from in-depth discussions and reflection among clinicians, patients, and family support organizations based in the US and Europe, where we seek areas of common ground and try to identify opportunities to further develop resources. The product of these conversations is summarized in 10 panels. The corresponding sections provide additional discussion on some of the panel items. KEY MESSAGES: Participants identified areas of agreement and gained a deeper understanding of the reasons behind disagreements on certain matters and identified the necessary steps to foster future consensus. We offer preliminary recommendations for guiding clinical management and resource allocation. By promoting a broader consensus, we aim to enhance the quality of care and well-being for individuals of all ages who have a DSD.

Patient and professional perspectives about using in vitro fertilisation add-ons in the UK and Australia: a qualitative study.

OBJECTIVES: In vitro fertilisation (IVF) add-ons are additional procedures offered alongside an IVF cycle with the aim of improving live birth rates. They are controversial because of the paucity of evidence to support their efficacy and safety, alongside the additional financial cost they often pose to patients. Despite this, they are popular. However, there is limited qualitative research regarding their use. The aims of the VALUE Study were to understand the decision-making process surrounding using or recommending add-ons; report sources of information for add-ons; and explore concerns for safety and effectiveness when considering their use. DESIGN: 'VALUE' is a qualitative semistructured interview study using inductive thematic analysis of anonymised transcriptions. SETTING: Participants were recruited from a broad geographical spread across the UK and Australia from public and private clinical settings. PARTICIPANTS: Patients (n=25) and health professionals (embryologists (n=25) and clinicians (n=24)) were interviewed. A purposive sampling strategy was undertaken. The sampling framework included people having state-subsidised and private cycles, professionals working in public and private sectors, geographical location and professionals of all grades. RESULTS: Patients often made decisions about add-ons based on hope, minimising considerations of safety, efficacy or cost, whereas professionals sought the best outcomes for their patients and wanted to avoid them wasting their money. The driving forces behind add-on use differed: for patients, a professional opinion was the most influential reason, whereas for professionals, it was seen as patient driven. For both groups, applying the available evidence to individual circumstances was very challenging, especially in the sphere of IVF medicine, where the stakes are high. CONCLUSIONS: There is scope to build on the quality of the discourse between patients and professionals. Patients describe valuing their autonomy with add-ons, but for professionals, undertaking informed consent will be critical, no matter where they sit on the spectrum regarding add-ons. TRIAL REGISTRATION: osf.io/vnyb9.

"It all depends on why it's red": qualitative interviews exploring patient and professional views of a traffic light system for IVF add-ons.

Background IVF add-ons are techniques, medicines or procedures used in addition to standard IVF with the aim of improving the chance of success. The United Kingdom's IVF regulator, ( the Human Fertilisation Embryology Authority (HFEA) developed a traffic light system to categorise add-ons as either green, amber, or red, based on results of randomised controlled trials. Method Qualitative interviews were undertaken to explore understanding and views of the HFEA traffic light system among IVF clinicians, embryologists and IVF patients across Australia and the United Kingdom. Results A total of 73 interviews were conducted. Overall, participants were supportive of the intention of the traffic light system, however many limitations were raised. It was widely recognized that a simple traffic light system necessarily omits information which may be important to understanding the evidence base. In particular, the red category was used in scenarios that patients viewed as having different implications for their decision-making, including 'no evidence' and 'evidence of harm'. Patients were surprised at the absence of any green add-ons and questioned the value of a traffic light system in this context. Many participants considered the website a helpful starting point, but desired more detail, including the contributing studies, results specific to patient demographics (e.g., <35 years and >35 years), and inclusion of more options (e.g. acupuncture). Overall, participants believed the website to be reliable and trustworthy, particularly due to the Government affiliation, and despite some concerns regarding transparency and an overly cautious regulator. Conclusion Participants identified many limitations with the current application of the traffic light system. These could be considered in any future updates to the HFEA website and for others developing similar decision support tools.

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation (anovulation), high levels of male hormones (hyperandrogenaemia) and high levels of insulin (hyperinsulinaemia secondary to increased insulin resistance). Hyperinsulinaemia is associated with an increase in cardiovascular risk and the development of diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating the features of PCOS, including anovulation. OBJECTIVES: To assess the effectiveness of insulin-sensitising drugs in improving reproductive outcomes and metabolic parameters for women with PCOS. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 3rd Quarter 2011), CINAHL (October 2011), MEDLINE (January 1966 to October 2011), and EMBASE (January 1985 to October 2011). SELECTION CRITERIA: Randomised controlled trials of insulin sensitising drugs compared with either placebo, no treatment, or an ovulation induction agent for women with PCOS, menstrual disturbance and subfertility. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and trial quality, and extracted data.   MAIN RESULTS: Forty-four trials (3992 women) were included for analysis, 38 of them using metformin and involving 3495 women.There was no evidence that metformin improved live birth rates, whether it was used alone (pooled OR 1.80, 95% CI 0.52 to 6.16, 3 trials, 115 women) or in combination with clomiphene (pooled OR 1.16, 95% CI 0.85 to 1.56, 7 trials, 907 women). However, clinical pregnancy rates were improved for metformin versus placebo (pooled OR 2.31, 95% CI 1.52 to 3.51, 8 trials, 707 women) and for metformin and clomiphene versus clomiphene alone (pooled OR 1.51, 95% CI 1.17 to 1.96, 11 trials, 1208 women). In the studies that compared metformin and clomiphene alone, there was evidence of an improved live birth rate (pooled OR 0.3, 95% CI 0.17 to 0.52, 2 trials, 500 women) and clinical pregnancy rate (pooled OR 0.34, 95% 0.21 to 0.55, 2 trials, 500 women) in the group of obese women who took clomiphene.Metformin was also associated with a significantly higher incidence of gastrointestinal disturbances than placebo (pooled OR 4.27, 95% CI 2.4 to 7.59, 5 trials, 318 women) but no serious adverse effects were reported. AUTHORS' CONCLUSIONS: In agreement with the previous review, metformin was associated with improved clinical pregnancy but there was no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the role of metformin in improving reproductive outcomes in women with PCOS appears to be limited.

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 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 manuscript 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.

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 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 manuscript 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.

UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development.

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional DSD team acts as the first point of contact. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents are as fully informed as possible and have access to specialist psychological support. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Phenotype and metabolic profile of South Asian women with polycystic ovary syndrome (PCOS): results of a large database from a specialist Endocrine Clinic.

BACKGROUND: Compared with other populations, South Asians have a greater propensity to insulin resistance and the metabolic syndrome (MetS). This is the first study to determine the distribution of phenotypes of polycystic ovary syndrome (PCOS) and their relationship to the MetS among indigenous South Asians. METHOD: An evaluation of the phenotype and metabolic characteristics of PCOS was conducted by recruiting consecutive women diagnosed by Rotterdam consensus criteria from an Endocrine clinic in Colombo, Sri Lanka. Prevalence of MetS was determined, in relation to the phenotypic subgroup of PCOS and compared with ethnically matched, BMI- and age-adjusted controls (n =231). RESULTS: Acanthosis nigricans (AN) occurred in 64.6% of women with PCOS (n= 469). MetS occurred in 30.6% of the PCOS group compared with 6.34% of controls (P = 0.0001). Those with PCOS and MetS had significantly higher median BMI, blood pressure (BP), fasting plasma glucose, insulin and triglycerides and lower high-density lipoprotein and sex hormone-binding globulin (SHBG), but similar testosterone concentrations compared with those with PCOS alone. Prevalence of MetS was similar in the four PCOS phenotypes, although oligomenorrhoeic women were more obese compared with the normal cycling hyperandrogenic group. Multivariate logistic regression confirmed age ≥35 years, BMI ≥25 kg/m(2) and AN as significant predictors of MetS in PCOS. Case-control comparisons showed that the presence of PCOS results in higher odds of having the MetS, a high waist circumference, elevated diastolic BP, abnormal fasting lipids and high fasting insulin and plasma testosterone concentrations. CONCLUSIONS: Young indigenous South Asians with PCOS have greater odds of being centrally obese, with a third having the MetS that bears no relationship to the androgenic phenotype. Significant predictors for MetS within the PCOS cohort are advancing age, obesity determined by the Asian cut off (BMI >25 kg/m(2)) and AN, while family history of diabetes, hyperandrogenism and elevated SHBG have no predictive value.

Conventional ovarian stimulation no longer exists: welcome to the age of individualized ovarian stimulation.

The prediction of extremes of ovarian response to stimulation and the irreversibility of reduced ovarian reserve remain important clinical and basic science research issues of IVF treatment. Recommending commencement of ovarian stimulation using any of the available exogenous compounds without knowledge of individual ovarian potentials is simplistic and dangerous because of the possible adverse consequences for the woman. The identification of groups of patients likely to benefit from one protocol than another is central to the workup process of IVF. Determining the agents for ovarian stimulation as well as the combination of them, the daily dose and duration according to some background information should be seen as the way to enhance safety and cost-effectiveness. This discussion paper aims to introduce the concept of individualized ovarian stimulation in routine clinical practice and to generate interest for tailored stimulation protocols.

VALUE study: a protocol for a qualitative semi-structured interview study of IVF add-ons use by patients, clinicians and embryologists in the UK and Australia.

INTRODUCTION: For couples undergoing assisted reproduction, a plethora of adjuncts are available; these are known as 'add-ons'. Most add-ons are not supported by good quality randomised trial evidence of efficacy, with some proven to be ineffective. However, estimates suggest that over 70% of fertility clinics provide at least one add-on, often at extra cost to the patient. This study has three aims. First, to undertake a survey of in vitro fertilisation (IVF) clinics in the UK to ascertain which add-ons are being offered and at what cost. Second, to undertake qualitative semi-structured interviews of patients, clinicians and embryologists, to explore their opinions and beliefs surrounding add-ons. Third, to review the interpretation of the Human Fertilisation and Embryology Authority traffic light system, to better understand the information required by IVF patients, clinicians and embryologists when making decisions about add-ons. METHODS AND ANALYSIS: All UK IVF clinics will be contacted by email and invited to complete an online survey. The survey will ask them which add-ons they offer, at what cost per cycle and how information is shared with patients. Semi-structured interviews will be conducted in the UK and Australia with three groups of participants: (i) fertility patients; (ii) clinicians and (iii) embryologists. Participants for the interviews will be recruited via social media channels, website adverts, email and snowball sampling. Up to 20 participants will be recruited for each group in each country. Following an online consent process, interviews will be conducted via video-conferencing software, transcribed verbatim and data subjected to inductive thematic analysis. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Universities of Sheffield, Bath Spa and Melbourne. Findings will be published in a peer-reviewed journal and disseminated to regulatory bodies in the UK and Australia. A lay summary of findings will be shared via Fertility Network, UK.

Metabolism and karyotype analysis of oocytes from patients with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with metabolic disturbances which include impaired insulin signalling and glucose metabolism in ovarian follicles. The oocyte is metabolically dependent upon its follicle environment during development, but it is unclear whether PCOS or polycystic ovarian (PCO) morphology alone affect oocyte metabolism and energy-demanding processes such as meiosis. METHODS: Immature human oocytes were donated by PCOS (n = 14), PCO (n = 14) and control (n = 46) patients attending the assisted conception programme at Leeds Teaching Hospitals NHS Trust. Oocytes were cultured individually and carbohydrate metabolism was assessed during overnight in vitro maturation (IVM). Meiotic status was assessed and oocyte intracellular nicotinamide adenine dinucleotide phosphate (NAD(P)H) content and mitochondria activity were measured prior to karyotype analysis by multifluor in situ hybridization. RESULTS: Patient aetiology had no significant effect on oocyte maturation potential or incidence of numerical chromosome abnormalities (44%), although PCOS and PCO oocytes were more likely to suffer predivision. Group G chromosomes were most likely to be involved in non-disjunction and predivision. PCOS was associated with increased glucose consumption (2.06 +/- 0.43 and 0.54 +/- 0.12 pmol/h for PCOS and control oocytes, respectively) and increased pyruvate consumption (18.4 +/- 1.2 and 13.9 +/- 0.9 pmol/h for PCOS and control oocytes, respectively) during IVM. Prior prescription of metformin significantly attenuated pyruvate consumption by maturing oocytes (8.5 +/- 1.8 pmol/h) from PCOS patients. Oocytes from PCO patients had intermediate metabolism profiles. Higher pyruvate turnover was associated with abnormal oocyte karyotypes (13.4 +/- 1.9 and 19.9 +/- 2.1 pmol/h for normal versus abnormal oocytes, respectively). Similarly, oocyte NAD(P)H content was 1.35-fold higher in abnormal oocytes. CONCLUSIONS: The chromosomal constitution of in vitro matured oocytes from PCOS is similar to that of controls, but aspects of oocyte metabolism are perturbed by PCOS. Elevated pyruvate consumption was associated with abnormal oocyte karyotype.

The adverse effects of obesity on conception and implantation.

Whilst many multiparous women are obese (body mass index >30 kg/m(2)), obesity has been associated with impaired fecundity; however, the mechanism which links obesity to reduced fertility remains to be fully elucidated. Obese women, particularly those with central obesity, are less likely to conceive per cycle. Obese women suffer perturbations to the hypothalamic-pituitary-ovarian axis, menstrual cycle disturbance and are up to three times more likely to suffer oligo-/anovulation. A fine hormonal balance regulates follicular development and oocyte maturation, and it has been observed that obesity can alter the hormonal milieu. Leptin, a hormone produced by adipocytes, is elevated in obese women, and raised leptin has been associated with impaired fecundity. Obesity impairs ovulation but has also been observed to detrimentally affect endometrial development and implantation. The expression of polycystic ovary syndrome (PCOS) is regulated, in part, by weight, and so obese women with PCOS often have a more severe phenotype and experience more subfertility. Obesity also impairs the response of women to assisted conception treatments. Weight loss through lifestyle modification or bariatric surgery has been demonstrated to restore menstrual cyclicity and ovulation and improve the likelihood of conception. In this article, we will discuss the effect of obesity upon key reproductive mechanisms and its relation to fertility treatments.

Do South Asian women with PCOS have poorer health-related quality of life than Caucasian women with PCOS? A comparative cross-sectional study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common chronic endocrine disorder affecting women of reproductive age. This study aimed to compare the HRQoL of South Asian and white Caucasian women with PCOS, given that it is particularly common among women of South Asian origin and they have been shown to have more severe symptoms. METHODS: The Polycystic Ovary Syndrome Questionnaire (PCOSQ) and the Short Form-36 (SF-36) were administered in a cross-sectional survey to 42 South Asian and 129 Caucasian women diagnosed with PCOS recruited from the gynaecology outpatient clinics of two university teaching hospitals in Sheffield and Leeds. Additional clinical data was abstracted from medical notes. Normative data, collected as part of the Oxford Health and Lifestyles II survey, was obtained to compare SF-36 results with ethnically matched women from the general UK population. Using the SF-36, normative HRQoL scores for women of South Asian origin were lower than for Caucasian women. Given this lower baseline we tested whether the same relationship holds true among those with PCOS. RESULTS: Although HRQoL scores for women with PCOS were lower than normative data for both groups, South Asian women with PCOS did not have poorer HRQoL than their Caucasian counterparts. For both the SF-36 and PCOSQ, mean scores were broadly the same for both Asian and Caucasian women. For both groups, the worst two HRQoL domains as measured on the PCOSQ were 'infertility' and 'weight', with respective scores of 35.3 and 42.3 for Asian women with PCOS compared to 38.6 and 35.4 for Caucasian women with PCOS. The highest scoring domain for South Asian women with PCOS was 'menstrual problems' (55.3), indicating best health, and was the only statistically significant difference from Caucasian women (p = 0.01). On the SF-36, the lowest scoring domain was 'Energy & Vitality' for Caucasian women with PCOS, but this was significantly higher for Asian women with PCOS (p = 0.01). The best health status for both groups was 'physical functioning', although this was significantly lower for South Asian women with PCOS (p = 0.005). Interestingly, only two domains differed significantly from the normative data for the Asian women with PCOS, while seven domains were significantly different for the Caucasian women with PCOS compared to their normative counterparts. CONCLUSIONS: The HRQoL differences that exist between South Asian and Caucasian women in the general population do not appear to be replicated amongst women with PCOS. PCOS reduces HRQoL to broadly similar levels, regardless of ethnicity and differences in the normative baseline HRQoL of these groups.

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by anovulation, hyperandrogaenemia and insulin resistance. Hyperinsulinaemia is associated with an increase in cardiovascular risk and the development of diabetes mellitus. If insulin sensitising agents such as metformin are effective in treating features of PCOS, then they could have wider health benefits than just treating the symptoms of the syndrome. OBJECTIVES: To assess the effectiveness of insulin sensitising drugs in improving reproductive outcomes and metabolic parameters for women with PCOS and menstrual disturbance. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched September 2008), the Cochrane Central Register of Controlled Trials (Cochrane Library, third Quarter 2008), CINAHL (searched September 2008), MEDLINE (January 1966 to September 2008), and EMBASE (January 1985 to September 2008). All searches were rerun 13 August 2009 17 RCTs were located and await classification. SELECTION CRITERIA: Randomised controlled trials which investigated the effect of insulin sensitising drugs compared with either placebo or no treatment, or compared with an ovulation induction agent. DATA COLLECTION AND ANALYSIS: Thirty one trials (2537 women) were included for analysis, 27 of them using metformin and involving 2150 women. MAIN RESULTS: There is no evidence that metformin improves live birth rates whether it is used alone (Pooled OR = 1.00, 95% CI 0.16 to 6.39) or in combination with clomiphene (Pooled OR = 1.48, 95% CI 1.12 to 1.95). However, clinical pregnancy rates are improved for metformin versus placebo (Pooled OR = OR 3.86, 95% C.I. 2.18 to 6.84) and for metformin and clomiphene versus clomiphene alone (Pooled OR =1.48, 95% C.I. 1.12 to 1.95) ). In the studies that compared metformin and clomiphene alone, there was no evidence of an improved live birth rate (OR= 0.67, 95% CI 0.44 to 1.02) but the pooled OR resulted in improved clinical pregnancy rate in in the clomiphene group (OR = 0.63 , 95% 0.43 to 0.92), although there was significant heterogeneity.There is also evidence that ovulation rates are improved with metformin in women with PCOS for metformin versus placebo (Pooled OR 2.12, 95% CI 1.50 to 3.0) and for metformin and clomiphene versus clomiphene alone (Pooled OR = 3.46, 95% CI 1.97 to 6.07).Metformin was also associated with a significantly higher incidence of gastrointestinal disturbance, but no serious adverse effects were reported. AUTHORS' CONCLUSIONS: In agreement with the previous review, metformin is still of benefit in improving clinical pregnancy and ovulation rates. However, there is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited.

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by anovulation, hyperandrogaenemia and insulin resistance. Hyperinsulinaemia is associated with an increase in cardiovascular risk and the development of diabetes mellitus. If insulin sensitising agents such as metformin are effective in treating features of PCOS, then they could have wider health benefits than just treating the symptoms of the syndrome. OBJECTIVES: To assess the effectiveness of insulin sensitising drugs in improving reproductive outcomes and metabolic parameters for women with PCOS and menstrual disturbance. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched September 2008), the Cochrane Central Register of Controlled Trials (Cochrane Library, third Quarter 2008), CINAHL (searched September 2008), MEDLINE (January 1966 to September 2008), and EMBASE (January 1985 to September 2008). All searches were rerun 13 August 2009 17 RCTs were located and await classification. SELECTION CRITERIA: Randomised controlled trials which investigated the effect of insulin sensitising drugs compared with either placebo or no treatment, or compared with an ovulation induction agent. DATA COLLECTION AND ANALYSIS: Thirty one trials (2537 women) were included for analysis, 27 of them using metformin and involving 2150 women. MAIN RESULTS: There is no evidence that metformin improves live birth rates whether it is used alone (Pooled OR = 1.00, 95% CI 0.16 to 6.39) or in combination with clomiphene (Pooled OR = 1.48, 95% CI 1.12 to 1.95). However, clinical pregnancy rates are improved for metformin versus placebo (Pooled OR = OR 3.86, 95% C.I. 2.18 to 6.84) and for metformin and clomiphene versus clomiphene alone (Pooled OR =1.48, 95% C.I. 1.12 to 1.95) ). In the studies that compared metformin and clomiphene alone, there was no evidence of an improved live birth rate (OR= 0.67, 95% CI 0.44 to 1.02) but the pooled OR resulted in improved clinical pregnancy rate in in the clomiphene group (OR = 0.63 , 95% 0.43 to 0.92), although there was significant heterogeneity.There is also evidence that ovulation rates are improved with metformin in women with PCOS for metformin versus placebo (Pooled OR 2.12, 95% CI 1.50 to 3.0) and for metformin and clomiphene versus clomiphene alone (Pooled OR = 3.46, 95% CI 1.97 to 6.07).Metformin was also associated with a significantly higher incidence of gastrointestinal disturbance, but no serious adverse effects were reported. AUTHORS' CONCLUSIONS: In agreement with the previous review, metformin is still of benefit in improving clinical pregnancy and ovulation rates. However, there is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited.