An Indian Expert Group Review of Acanthosis Nigricans with Recommendations for Early Detection and Timely Management.

INTRODUCTION: Acanthosis nigricans (AN) is a visible cutaneous manifestation of several underlying systemic conditions, such as prediabetes, diabetes mellitus (DM), polycystic ovarian syndrome (PCOS), metabolic syndrome (MS), and malignancy. AN is commonly seen in obese individuals and is a proven skin marker of insulin resistance (IR). Its typical clinical presentation and location, especially on the nape of the neck, allows for easy visual identification. Obesity, IR, and other noncommunicable diseases (NCD) are on the rise in India, with many cases being undiagnosed or missed. Every sixth diabetic in the world is Indian. AN can thus play a vital role in screening, early identification, and reduction of morbidity, especially of IR-related disorders. Currently, there are no national or international multidisciplinary guidelines or recommendations for AN. OBJECTIVE: To review published current literature and evidence on AN, its associations, and management. To recommend an approach to clinical identification of AN, associated/underlying disorders, investigations, and management, including lifestyle modifications. To sensitize and familiarize clinicians and healthcare workers across India with AN presentations. This will enable early detection of conditions such as IR, prediabetes, DM, PCOS, malignancy, etc., in practice and in the community. MATERIALS AND METHODS: The PCOS Society of India constituted a multispecialty Expert Working Group with representation from various national societies to review all published scientific evidence. Expert group meetings were conducted to provide recommendations. CONCLUSION: Acanthosis nigricans is a simple, non-invasive, cost-effective screening tool for early identification of IR. It is important to integrate and disseminate information and training on AN across medical specialties. The government of India has launched several National Health Programmes to help address the rising burden of NCD in the population. AN would provide a simple screening tool to pick up undiagnosed or missed cases.

Prevalence of non-communicable chronic diseases in rural India amongst peri- and post-menopausal women: Can artificial intelligence help in early identification?

AIMS: To identify peri- and post-menopausal women at risk of non-communicable diseases in rural India and to assess their prevalence amongst these groups via the use of artificial intelligence. SETTINGS AND DESIGN: An observational study conducted by the Indian Menopause Society in collaboration with the Government of Maharashtra. The study included rural women residents of three villages in the Latur district of Maharashtra, India. MATERIALS AND METHODS: Accredited social health activist workers identified 400 peri- and post-menopausal women aged 45-60 years. Specific symptoms able to predict the presence of a non-communicable disease were identified through the use of artificial intelligence. STATISTICAL ANALYSIS USED: Descriptive statistics and predictive network charts analysis. RESULTS: The mean age of 316 women included in the analysis was 50.4 years and the majority of them were illiterate (68 %). The prevalence of dyslipidaemia, osteopenia, diabetes mellitus, obesity and hypertension were 58 %, 50 %, 25 %, 25 %, and 20 % respectively. None of their symptoms or laboratory reports could be significantly correlated directly with any of these non-communicable diseases. Hence, we used a cluster of symptoms to suggest the presence of hypertension, diabetes mellitus, osteoporosis and hypothyroidism via predictive network analysis charts. CONCLUSIONS: Screening of at-risk women can be done using an artificial intelligence-based screening tool for early diagnosis, timely referral and treatment of non-communicable diseases with the support of community health workers.

Anti-Mullerian Hormone and Fertility Treatment Decisions in Polycystic Ovary Syndrome: A Literature Review.

Anti-Mullerian hormone is a robust marker of ovarian reserve and ovarian response in in vitro fertilisation (IVF). However, its role extends beyond improving the safety of IVF by aiding in choosing appropriate protocols and dosing. This review looks at the value of pre-treatment anti-Mullerian hormone (AMH) value in choosing the appropriate modality of treatment and its predictive ability for the outcomes of such treatment. It briefly addresses the factors that may modulate AMH levels and make clinical decision-making challenging.

Safety and effectiveness of intravenous iron sucrose versus standard oral iron therapy in pregnant women with moderate-to-severe anaemia in India: a multicentre, open-label, phase 3, randomised, controlled trial.

BACKGROUND: Intravenous iron sucrose is a promising therapy for increasing haemoglobin concentration; however, its effect on clinical outcomes in pregnancy is not yet established. We aimed to assess the safety and clinical effectiveness of intravenous iron sucrose (intervention) versus standard oral iron (control) therapy in the treatment of women with moderate-to-severe iron deficiency anaemia in pregnancy. METHODS: We did a multicentre, open-label, phase 3, randomised, controlled trial at four government medical colleges in India. Pregnant women, aged 18 years or older, at 20-28 weeks of gestation with a haemoglobin concentration of 5-8 g/dL, or at 29-32 weeks of gestation with a haemoglobin concentration of 5-9 g/dL, were randomly assigned (1:1) to receive intravenous iron sucrose (dose was calculated using a formula based on bodyweight and haemoglobin deficit) or standard oral iron therapy (100 mg elemental iron twice daily). Logistic regression was used to compare the primary maternal composite outcome consisting of potentially life-threatening conditions during peripartum and postpartum periods (postpartum haemorrhage, the need for blood transfusion during and after delivery, puerperal sepsis, shock, prolonged hospital stay [>3 days following vaginal delivery and >7 days after lower segment caesarean section], and intensive care unit admission or referral to higher centres) adjusted for site and severity of anaemia. The primary outcome was analysed in a modified intention-to-treat population, which excluded participants who refused to participate after randomisation, those who were lost to follow-up, and those whose outcome data were missing. Safety was assessed in both modified intention-to-treat and as-treated populations. The data safety monitoring board recommended stopping the trial after the first interim analysis because of futility (conditional power 1·14% under the null effects, 3·0% under the continued effects, and 44·83% under hypothesised effects). This trial is registered with the Clinical Trial Registry of India, CTRI/2012/05/002626. FINDINGS: Between Jan 31, 2014, and July 31, 2017, 2018 women were enrolled, and 999 were randomly assigned to the intravenous iron sucrose group and 1019 to the standard therapy group. The primary maternal composite outcome was reported in 89 (9%) of 958 patients in the intravenous iron sucrose group and in 95 (10%) of 976 patients in the standard therapy group (adjusted odds ratio 0·95, 95% CI 0·70-1·29). 16 (2%) of 958 women in the intravenous iron sucrose group and 13 (1%) of 976 women in the standard therapy group had serious maternal adverse events. Serious fetal and neonatal adverse events were reported by 39 (4%) of 961 women in the intravenous iron sucrose group and 45 (5%) of 982 women in the standard therapy group. At 6 weeks post-randomisation, minor side-effects were reported by 117 (16%) of 737 women in the intravenous iron sucrose group versus 155 (21%) of 721 women in the standard therapy group. None of the serious adverse events was found to be related to the trial procedures or the interventions as per the causality assessment made by the trial investigators, ethics committees, and regulatory body. INTERPRETATION: The study was stopped due to futility. There is insufficient evidence to show the effectiveness of intravenous iron sucrose in reducing clinical outcomes compared with standard oral iron therapy in pregnant women with moderate-to-severe anaemia. FUNDING: WHO, India.

Anti-Müllerian Hormone in PCOS: A Review Informing International Guidelines.

Polycystic ovary syndrome (PCOS) affects 8-13% of women. The Rotterdam diagnostic criteria include polycystic ovarian morphology (PCOM) on ultrasound, but given recognized challenges, serum anti-Müllerian hormone (AMH) is proposed as an alternative. To inform international PCOS guidelines, a systematic review was completed. Key identified gaps include large international studies in well-defined populations across the lifespan, clustering of AMH with PCOS features, relationships to long-term health outcomes, and improved quality, assay standardization, and sample handling, all needed to determine cut offs. Here we identify research priorities to address these gaps and enhance AMH utility in PCOS. Once issues are addressed, AMH levels could replace more costly and less accessible ultrasound in PCOS diagnosis.

Consensus Statement on the Use of Oral Contraceptive Pills in Polycystic Ovarian Syndrome Women in India.

OBJECTIVE: To provide consensus recommendations for health-care providers on the use of oral contraceptive pills (OCPs) in polycystic ovarian syndrome (PCOS) women in India. PARTICIPANTS: Extensive deliberations, discussions, and brainstorming were done with different fraternities (specialists) being involved. These included endocrinologists, gynecologists, reproductive endocrinologists, dermatologists, public health experts, researchers, and a project manager with a team to develop the guideline. EVIDENCE: Published literature was retrieved through searches of Medline and The Cochrane Database from January 2003 to December 2017 using appropriate-controlled vocabulary (e.g., oral contraceptive pills, polycystic ovarian syndrome, long term outcomes, infertility). Clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies' publications and data were also reviewed to suggest the recommendations. PROCESS: The working group for guideline committee included members from the PCOS Society (India), Indian Society for Assisted Reproduction, The Mumbai Obstetric and Gynecological Society, The Endocrine Society of India, Indian Association of Dermatologists, Venereologists and Leprologists, Cosmetic Dermatology Society (India), Academicians from Medical Colleges, National Institute for Research in Reproductive Health, and a Research Associate. The core team included five reproductive endocrinologists, five gynecologists, five dermatologists, three endocrinologists, two public health experts and one research associate. CONCLUSIONS: This consensus statement provides the guidance/recommendations for Indian practitioners regarding the use of OCP in women with PCOS. PCOS is one of the common endocrinopathies encountered in gynecological/endocrine practice. The spectrum of this disorder may range from prepubertal girls with premature pubarche, young girls with hirsutism, acne and anovulatory cycles, married women with infertility, and elderly women. Although obesity is a common feature for most PCOS patients, 'lean PCOS' also exists. For several years, OCPs have played an important role in the symptom management of PCOS women. This is due to the fact that OCPs decrease the luteinizing hormone, reduce androgen production, and increase sex hormone-binding globulin, which binds androgens. Several new formulations of OCPs have been developed to decrease the side effects. This includes use of less androgenic progestins and lower doses of ethinyl estradiol. These consensus recommendations help the health provider to choose the right type of OCPs, which will alleviate the symptoms with least side effects. It also gives insight into the indications, contraindications, and concerns regarding its short, intermediate and long-term use.

Androgen Excess- Polycystic Ovary Syndrome Society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome.

OBJECTIVE: To formulate clinical consensus recommendations for screening depression, anxiety, health-related quality of life (HRQoL), and disordered eating symptoms in women with polycystic ovary syndrome (PCOS) and review prevalence based on phenotypes and ethnicity, changes over time, etiology, and impact of treatment. DESIGN: Systematic reviews and preparation of position statement. SETTING: Not applicable. PATIENT(S): Women with PCOS and controls screened using validated tools. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Depressive symptoms, anxiety symptoms, disordered eating, and HRQoL scores. RESULT(S): Several studies demonstrate that women with PCOS have an increased prevalence of higher depression and anxiety scores and higher odds of moderate and severe depressive and anxiety symptoms compared with controls. Obesity, hyperandrogenism, and fertility have a weak association with these symptoms. HRQoL scores are consistently reduced in PCOS, with infertility and weight concerns having the most significant impact. Some studies suggest an increased prevalence of disordered eating in women with PCOS compared with controls. The few studies that have evaluated the impact of PCOS-related treatments (lifestyle interventions and pharmacotherapy) show no detrimental effect or some improvement in depressive and anxiety symptoms and HRQoL scores. CONCLUSION(S): In women with PCOS, screening for depressive and anxiety symptoms should be offered at the time of diagnosis and screening for disordered eating should be considered. Further research is required across PCOS phenotypes, in longitudinal cohorts and on impact of therapy on depressive and anxiety syptoms, HRQOL, and disordered eating.

Fertility with early reduction of ovarian reserve: the last straw that breaks the Camel's back.

Diminished fertility and poor ovarian response pose a conundrum to the experts in the field of reproductive medicine. There is limited knowledge about the risk factors of diminished ovarian reserve other than the iatrogenic ones. One of the leading causes of infertility in women today is diminished ovarian reserve (DOR). DOR is characterized by a low number of eggs in a woman's ovaries and/or with poor quality of the remaining eggs, which boils down to impaired development of the existing eggs, even with assisted reproductive techniques. A good number of such women with low ovarian reserve may conceive with their own eggs, if they are given individualized treatment that is tailored for their profile. Such patients should be counseled appropriately for an aggressive approach towards achieving fertility. The sooner the treatment is started, the better the chances of pregnancy.

Diagnosis of hyperinsulinaemia in a normoglycaemic healthy Indian Population--developing ethnic reference ranges.

CONTEXT: Reference limits for diagnosing hyperinsulinaemia are currently derived from non-Indian cohorts and have not been validated in Indians even though it is acknowledged that different patterns of insulin secretion are seen across ethnicities. AIMS: To develop ethnicity specific reference limits for insulin levels in a normoglycaemic healthy Indian cohort in order to derive a clinical cut off for hyperinsulinaemia as an effective screening tool for predicting future risk of metabolic and cardiovascular disease. SETTINGS AND DESIGN: Prospective analysis of plasma insulin levels in healthy normoglycaemic volunteers availing diagnostic facilities at a central reference laboratory in Mumbai. METHODS AND MATERIAL: 122 normoglycaemic males between 19-73 years and 126 females between 19-55 years of age were selected based on a screening questionnaire as per the Clinical Laboratory and Standards Institute (CLSI) guidance document for deriving reference ranges. Fasting insulin levels were analysed using a Chemiluminescent Microparticle Immunoassay platform and derived results were analysed to determine reference limits for insulin. STATISTICAL ANALYSIS USED: A non-parametric method of statistical analysis was used to determine the 2.5 and 97.5% limits with 90% confidence intervals. RESULTS: Reference range for insulin in a normoglycemic Indian cohort was derived as 2.7-17 uIU/ml which established 17 uIU/ml as the clinical cut off for diagnosing hyperinsulinemia in healthy Indians. CONCLUSIONS: Reference limits for insulin in normoglycemic Indians needs to be revised to 2.7-17 uIU/ ml. Clinical cut off for hyperinsulinemia needs to be lowered to 17 uIU/ml from currently used cut offs which range from 25-31 ulU/ml. KEY MESSAGES: Reference limits currently used for diagnosing hyperinsulinemia in healthy normoglycemic adults need to be revised and made specific for different ethnicities. In Indians the upper limit of the normal reference range for insulin levels needs to be brought down to 17 uIU/ml from the existing 25-31 u IU/ml. This modified cut off would help clinicians identify apparently healthy individuals who may need to be screened for a future risk of metabolic and cardiovascular disorders.

Luteal insufficiency in first trimester.

Luteal phase insufficiency is one of the reasons for implantation failure and has been responsible for miscarriages and unsuccessful assisted reproduction. Luteal phase defect is seen in women with polycystic ovaries, thyroid and prolactin disorder. Low progesterone environment is created iatrogenically due to interventions in assisted reproduction. Use of gonadotrophin-releasing hormone analogs to prevent the LH surge and aspiration of granulosa cells during the oocyte retrieval may impair the ability of corpus luteum to produce progesterone. Treatment of the underlying disorder and use of progestational agents like progesterone/human chorionic gonadotrophin have been found to be effective in women with a history of recurrent miscarriage. There has been no proved beneficial effect of using additional agents like ascorbic acid, estrogen, prednisolone along with progesterone. Despite their widespread use, further studies are required to establish the optimal treatment. Literature review and analysis of published studies on luteal phase support.

Assisted reproductive technology in India: A 3 year retrospective data analysis.

Assisted reproductive technology (ART) has grown by leaps and bounds in the last few years. India has one of the highest growths in the ART centers and the number of ART cycles performed every year. Very soon India will be the leader in the world of ART in terms of a number of cycles. With the advances of technology and availability of techniques even in tier II and tier III cities our country, the results still vary dramatically. There is no standardization of protocols and reporting is very inadequate. Furthermore, there are only ART guidelines and no law still exists. Our first and the biggest challenge is to document the tremendous work being done in India and on the basis of analysis of this work, a proper registry can be made and guidance given to all on standardization and improvement. This is the 8(th) edition of National ART Registry of India being presented and analyzed.