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Medical treatment and comorbidity in polycystic ovary syndrome: An updated review

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Abstract

Polycystic ovary syndrome (PCOS) is defined by hyperandrogenism, irregular menses and polycystic ovaries when other etiologies are excluded. The risk of type 2 diabetes and cardiovascular disease is increased in PCOS. Furthermore, the immune function in PCOS is impaired with elevated circulating of autoantibodies and increased risk of thyroid disease. Especially obese women with PCOS are at increased risk of non-alcoholic fatty liver disease. Medical treatment of PCOS involves antiandrogen treatment in combination with insulin sensitising drugs. Oral contraceptives are often applied as anti-androgens, but spironolactone could have additional vascular benefits. New and upcoming treatments for PCOS involve GLP-1 agonists, DPP4 inhibitors, SGLT2 inhibitors, myoinositol, thyroid hormones, and vitamin supplements. Statins are rarely indicated for treatment of dyslipidemia in PCOS, but statins could improve PCOS phenotype. Use of antidepressants in PCOS could have adverse effects on PCOS metabolic phenotype. In the present article we give an update regarding established and upcoming medical treatment for PCOS and for comorbidities of PCOS.

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... Además, se ha visto una relación con el aborto, ya que existe una incidencia de 30-80% de SOP en pacientes que presentan abortos recurrentes (1). En el SOP se presenta un aumento del riesgo de padecer diabetes mellitus tipo 2, patología cardiovascular y tiroidea, enfermedad del hígado graso no alcohólico (en especial en pacientes con obesidad) y depresión (6). Esta enfermedad está asociada con factores ambientales y genéticos, aunque aún se desconocen los genes que están involucrados. ...
... Las primeras manifestaciones en presentar una respuesta al tratamiento son la seborrea y el acné, a los 3 meses de iniciado. Luego, el hirsutismo empieza a responder a los 6 meses (3,6,8,15). Al igual que con el tratamiento del HA, el tratamiento de la DO también se basa en la presencia o ausencia de deseo de concebir de la paciente. ...
... En conjunto con el tratamiento con metformina, mejoran los niveles glicémicos, de testosterona y regulan la ciclicidad menstrual, de forma superior que usados como monoterapia. La espironolactona es usada frecuentemente en el tratamiento del hirsutismo (6). Además, las alteraciones frecuentes que pueden acompañar al SOP, como el síndrome metabólico, la hipertensión, la dislipidemia, las alteraciones tiroideas y la depresión, deben ser tratadas con las medidas y los medicamentos respectivos, de forma individualizada para cada paciente. ...
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El síndrome de ovario poliquístico (SOP) es la patología endocrinometabólica más frecuente que afecta a mujeres en edad fértil, y es la principal causa de infertilidad por anovulación. Uno de los aspectos más importantes del síndrome es el exceso de andrógenos de origen ovárico, que se puede evidenciar en el análisis bioquímico o en las manifestaciones clínicas que induce. La fisiopatología aún no se conoce por completo, por lo que se deben excluir otras causas para realizar el diagnóstico, con 2 de los 3 siguientes criterios: a) hiperandrogenismo, b) oligoovulación, c) patrón polimicrofolicular de ovarios. Según sus manifestaciones, las pacientes se pueden clasificar en 4 diferentes fenotipos, los cuales también se diferencian por su severidad. Además, una evidente relación con la resistencia a la insulina y, por lo tanto, un aumento en el riesgo de enfermedad metabólica y cardiovascular. El tratamiento se basa principalmente en medidas higiénico - dietéticas y el uso de anticonceptivos orales, dependiendo de la clínica de cada paciente y de su deseo de concepción.
... On the other hand, bariatric surgery does promote excessive weight loss for obese individuals leading to improved ovulation and reduced risk of T2D. 204,205 Inositol. The most commonly described forms of inositol are myo-inositol and d-chiro-inositol. ...
... However, a Cochrane Systematic Review could not display any promising role of inositol when tested on 1472 sub-fertile PCOS females. 202,203,205 Vitamin D. Few studies are backing up the fact that vitamin D deficiency plays a role in insulin resistance, thereby being connected to the pathogenesis of PCOS. When a dosage was given, it did ameliorate insulin resistance; 195 nonetheless, its role remains contradictory based on many RCTs (randomized controlled trials) conducted previously. ...
Article
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Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age, which is still incurable. However, the symptoms can be successfully managed with proper medication and lifestyle interventions. Despite its prevalence, little is known about its etiology. In this review article, the up-to-date diagnostic features and parameters recommended on the grounds of evidence-based data and different guidelines are explored. The ambiguity and insufficiency of data when diagnosing adolescent women have been put under special focus. We look at some of the most recent research done to establish relationships between different gene polymorphisms with polycystic ovary syndrome in various populations along with the underestimated impact of environmental factors like endocrine-disrupting chemicals on the reproductive health of these women. Furthermore, the article concludes with existing treatments options and the scopes for advancement in the near future. Various therapies have been considered as potential treatment through multiple randomized controlled studies, and clinical trials conducted over the years are described in this article. Standard therapies ranging from metformin to newly found alternatives based on vitamin D and gut microbiota could shine some light and guidance toward a permanent cure for this female reproductive health issue in the future.
... PCOS is a life-long disease which currently, seems that can never be cured but the only way to manage this unpleasant and distressing disease, is to continue the medications for the rest of patients' life. But, if the medication is not taken properly or if it is misdiagnosed or dealt with a negligent attitude, it may cause some serious diseases, namely, endometrial cancer, diabetes type II, 18 heart disease, 18 sleep disorders, 19 moodanxiety disorders, 16 depression 18 and, the most common, infertility. 22 ...
... PCOS is a life-long disease which currently, seems that can never be cured but the only way to manage this unpleasant and distressing disease, is to continue the medications for the rest of patients' life. But, if the medication is not taken properly or if it is misdiagnosed or dealt with a negligent attitude, it may cause some serious diseases, namely, endometrial cancer, diabetes type II, 18 heart disease, 18 sleep disorders, 19 moodanxiety disorders, 16 depression 18 and, the most common, infertility. 22 ...
Article
BACKGROUND Poly cystic ovarian syndrome (PCOS) is a common endocrine ovarian disorder found to be affecting 6-26% of female respondents globally.1 Symptoms include hirsutism, anovulation and psychological factors like severe mood swings, depression etc. Stress, which is majorly caused by unhealthy lifestyle, especially in prolonged cases alters the metabolism of body and causes severe diseases like PCOS and decreases the efficiency of females. This study aims to evaluate as to whether stress is one of the major hidden reasons for PCOS in the females of Delhi-NCR (National Capital Region). METHODS 120 female students had given their consent to fill an online questionnaire made on Google forms and were distributed via WhatsApp. The form consisted of 31 questions distributed over stress and symptoms of PCOS. RESULTS Efficiency of 54.5 % of the respondents had decreased in the absence of sound sleep as they mostly experienced ‘situational stress’. Recurrence of sleeplessness had led to anger in 71 % of above respondents. It was also observed that 55 % of the respondents had a sign of early reproductive / late adolescence and they experienced irregular menstrual cycle along with facial hair, stretch marks, acne and severe hair fall. CONCLUSIONS 57 % of the respondents had both stress and symptoms of PCOS. Modifications in their lifestyles / dietary habits could control and improve the situation. Healthy lifestyle certainly helps in the treatment but is not a complete cure for PCOS. KEY WORDS Stress, PCOS, Lifestyle, Psychological Analysis
... Although statin drugs are rarely recommended for treating high cholesterol in PCOS, they may ameliorate the phenotype of the condition. Antidepressant use in PCOS patients may negatively impact their metabolic phenotype [30]. ...
... Incretin mimetics therapy has a profitable influence on non-alcoholic fatty liver disease (NAFLD) and neurodegenerative diseases like Alzheimer's disease or Parkinson's disease [75][76][77][78][79]. The GLP-1RAs also have positive effects in patients with PCOS decreasing IR and improving metabolic alterations [80][81][82][83]. ...
Article
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Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.
... These encompass single or combined therapies with oral contraception, antiandrogens and/or insulin sensitizers. The latter include, among others, thiazolidinediones, drugs acting through the PPAR-γ [125,[128][129][130][131][132]. ...
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Diabetes mellitus is a chronic metabolic disease characterized by disturbances in carbohydrate, protein, and lipid metabolism, often accompanied by oxidative stress. Diabetes treatment is a complicated process in which, in addition to the standard pharmacological action, it is necessary to append a comprehensive approach. Introducing the aspect of non-pharmacological treatment of diabetes allows one to alleviate its many adverse complications. Therefore, it seems important to look for substances that, when included in the daily diet, can improve diabetic parameters. Magnolol, a polyphenolic compound found in magnolia bark, is known for its health-promoting activities and multidirectional beneficial effects on the body. Accordingly, the goal of this review is to systematize the available scientific literature on its beneficial effects on type 2 diabetes and its complications. Taking the above into consideration, the article collects data on the favorable effects of magnolol on parameters related to glycemia, lipid metabolism, or oxidative stress in the course of diabetes. After careful analysis of many scientific articles, it can be concluded that this lignan is a promising agent supporting the conventional therapies with antidiabetic drugs in order to manage diabetes and diabetes-related diseases.
... However, due to the risk of thromboembolism and metabolic side effects (such as weight gain, development of type 2 diabetes, cardiovascular disease, and autoimmune disease), the use of OCPs should be balanced against the possible metabolic side effects in each patient. 52 Spironolactone is a nonselective mineralocorticoid receptor antagonist that suppresses testosterone levels. The antiandrogen effects of spironolactone are comparable with those of OCPs in the treatment of hirsutism; 53 however, spironolactone could have additional benefits with respect to the risk of cardiovascular disease. ...
Article
Polycystic ovary syndrome (PCOS) is a chronic multisystem endocrine disorder that affects women of reproductive age. In the ovary, the dynamic balance between dormant and growing follicles that culminates in ovulation becomes dysfunctional in the presence of excessive androgen production (ovarian/adrenal/peripheral). Moreover, hyperandrogenicity in pregnancy affects fetal development in utero and is linked to maternal pregnancy complications. Hormonal imbalance, ovarian dysfunction, and central obesity often emerge in these patients during adolescence. Once disordered physiological changes develop in PCOS, a vicious cycle ensues, leading to reproductive, metabolic, and psychological comorbidities. With the alarming increase in the number of young adults with a high degree of obesity in Korea, the prevalence of PCOS has also considerably increased. Timely and accurate screening, multicomponent healthy lifestyle modifications for both patients and family members, and comprehensive medical interventions based on international evidence-based guidelines are essential for curtailing PCOS and its comorbidities.
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Metformin has long been used in the treatment of polycystic ovarian syndrome (PCOS). Recently, sitagliptin has been reported to improve ovarian cycles and ovulation in PCOS. We suggest that a combination of sitagliptin and metformin can be more effective than either treatment alone in improving different aspects of PCOS.
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Aim: To investigate risk of thyroid disease in Danish women with PCOS. Design: National register-based study on women with PCOS in Denmark. 18,476 women had a diagnosis of PCOS in the Danish National Patient Register. PCOS Odense University Hospital (PCOS OUH, N=1,146) was an embedded cohort of women with PCOS and clinical and biochemical examination. Three age-matched controls were included for each woman with PCOS (N=54,757). The main outcome measures were thyroid disease (hypothyroidism, Graves’ disease, goitre, thyroiditis) according to diagnosis codes and/or inferred from filled medicine prescriptions. Associations between baseline TSH and development of cardio-metabolic disease was examined in PCOS OUH. Results: The median (quartiles) age at inclusion was 29 (23-35) years and follow up duration was 11.1 (6.9–16.0) years. The Hazard ratio (95% CI) for thyroid disease development was 2.5 (2.3; 2.7) (p<0.001). The event rate of thyroid disease was 6.0 per 1000 patient years in PCOS Denmark versus 2.4 per 1000 patient years in controls (p<0.001). Women in PCOS OUH with TSH ≥2.5 mIU/L (n=133) had higher BMI (median 29 vs. 27 kg/m2), wider waist, higher triglycerides and free testosterone by the time of PCOS diagnosis compared to women in PCOS OUH with TSH <2.5 mIU/L (n=588). Baseline TSH did not predict later development of cardio-metabolic diseases in PCOS OUH. Conclusions: The event rate of thyroid disease was significantly and substantially higher in women with PCOS compared to controls.
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Background Polycystic ovary syndrome (PCOS) is a complex condition with high risk for dyslipidemia, dysglycemia, venous thromboembolism, cardiovascular disease and metabolic syndrome. Because the combined oral contraceptive (COC) use has also been associated with impaired fasting glucose, insulin resistance and increased risk of thromboembolism disease, it is rationale to think that the combination of oral contraceptive and PCOS could make it worse or increase the risks. Objective To examine the current data regarding potential additional risks and benefits of contraceptive use, highlights the major gap in knowledge for designing future studies and, when possible, suggests an adequate COC formulation for a determined PCOS phenotype. Methods English-language publications reporting on the influence of COCS in the development of venous thromboembolism in PCOS patients published until 2017 were searched using PubMed, Cochrane database, and hand search of references found in consulted articles. Ranges of collected data are given; the pooled data are presented as median and first and third quartiles. Wilcoxon signed-ranks test for paired samples was used to compare before-after original data. P value was set at 0.05. ResultsMost of COCs preparations significantly decrease androgens, and increase sex-hormone binding globulin. Therefore, the benefits of COCs are clear in patients with proved hyperandrogenemia. Regarding the impact of COCs on carbohydrate metabolism of PCOS subjects, the data were inconsistent but they tended to show no additional risk. Regarding lipids, most COCs consistently increased high-density lipoprotein cholesterol, triglycerides and total cholesterol concentrations but the clinical implications of these changes need additional studies. Conclusion The review showed consistent beneficial effect of COCs, particularly for hyperandrogenemic PCOS patients. The benefit size of COC’s use by normoandrogenemic PCOS patients is uncertain and need more investigation. The effects of COC use on carbohydrate metabolism of women with PCOS are still unresolved since most studies are observational but the current results demonstrated that COCs do not make their levels worse and may improve insulin sensitivity. The impact of COCs on lipids of PCOS patients seems to be clearer and most preparations increase total cholesterol, high-density lipoprotein cholesterol and triglycerides. In summary, it is important to balance the potential benefits and risks of the COCs individually before prescribing them for PCOS women.
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Metformin (MET), the most commonly used insulin sensitizer, is the reference off-label drug for the treatment of polycystic ovary syndrome (PCOS), worldwide. However, its use may be limited mainly by gastro-intestinal adverse effects. Myo-inositol (MI), a well-recognized food supplement, also represents an evidence-based treatment for PCOS women, popular in many countries. Our aim is to provide a systematic review of the literature and a meta-analysis which compares these two treatments, for their short-term efficacy and safety in PCOS patients. Systematic review and meta-analysis of randomized clinical trials (RCTs). RCTs were identified from 1994 through 2017 using MEDLINE, Cochrane Library, PubMed, and ResearchGate. Included studies were limited to those one directly comparing MET to MI on several hormones changes. Standardized mean difference (SMD) or risk ratios (RRs) with 95% CIs were calculated. Changes in fasting insulin was the main outcome of measure. Six trials with a total of 355 patients were included. At the end of treatment, no difference between MET and MI was found on fasting insulin (SMD ¼ 0.08 mU/ml, 95% CI: À0.31-0.46, p ¼ .697), HOMA index (SMD ¼ 0.17, 95% CI: À0.53-0.88, p ¼ .635), testosterone (SMD ¼ À0.01, 95% CI: À0.24-0.21, p ¼ .922), SHBG levels (SMD ¼ À0.50 nmol/l, 95% CI: À1.39-0.38, p ¼ .263) and body mass index (BMI) (SMD ¼ À0.22, 95% CI: À0.60-0.16, p ¼ .265). There was strong evidence of an increased risk of adverse events among women receiving MET compared to those receiving MI (RR ¼ 5.17, 95% CI: 2.91-9.17, p < .001). No differences were found in the effect of MET and MI on short-term hormone changes. The better tolerability of MI makes it more acceptable for the recovery of androgenic and metabolic profile in PCOS women. ARTICLE HISTORY
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Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20–30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role in pathogenic mechanisms of NAFLD. Many drugs have been tested but no medications have yet been approved. Antidiabetic drugs could have a role in the progression reduction of the disease. The aim of this review is to summarize evidence on efficacy and safety of antidiabetic drugs in patients with NAFLD. Metformin, a biguanide, is the most frequently used drug in the treatment of T2DM. To date 15 randomized controlled trials (RCTs) and four meta-analysis on the use of metformin in NAFLD are available. No significant improvement in histological liver fibrosis was shown, but it can be useful in the treatment of co-factors of NAFLD, like body weight, transaminase or cholesterol levels, and HbA1c levels. A possible protective role in various types of cancer has been reported for Metformin. Thiazolidinediones modulate insulin sensitivity by the activation of PPAR-γ. The RCTs and the meta-analysis available about the role of these drugs in NAFLD show an improvement in ballooning, lobular inflammation, and perhaps fibrosis, but some side effects, in particular cardiovascular, were showed. GLP-1 analogues stimulate insulin secretion by pancreatic beta cell and inhibit glucagon release; Liraglutide is the most used drug in this class and significantly improves steatosis, hepatocyte ballooning and transaminase levels. Scanty data about the role of DPP-4 and SGLT inhibitors were published. No data about insulin effects on NAFLD are available but it was showed a possible association between insulin use and the development of solid neoplasms, in particular HCC. In conclusion, antidiabetic drugs seem to be promising drugs, because they are able to treat both NAFLD manifestations and diabetes, preventing worsening of hepatic damage, but data are still conflicting. All antidiabetic drugs can be safely used in patients with compensated cirrhosis, while insulin is the preferred drug in decompensated Child C cirrhosis.
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Objective: To evaluate the effect of vitamin D supplementation (alone or with co-supplementation) on insulin resistance in patients with polycystic ovary syndrome (PCOS). Methods: We performed a literature search of databases (Medline, Scopus, Web of Knowledge, Cochrane Library) and identified all reports of randomized controlled trials (RCTs) published prior to April 2018. We compared the effects of supplementation with vitamin D alone (dose from 1000 IU/d to 60,000 IU/week) or with co-supplements to the administration of placebos in women diagnosed with PCOS. The systematic review and meta-analysis protocol was registered in the International Prospective Register of Systematic Reviews (Prospero) as number CRD42018090572. Main results: Eleven of 345 identified studies were included in the analysis; these involved 601women diagnosed with PCOS. Vitamin D as a co-supplement was found to significantly decrease fasting glucose concentrations and the HOMA-IR value. HOMA-IR also declined significantly when vitamin D was supplemented with a dose lower than 4000 IU/d. Conclusions: Evidence from RCTs suggests that the supplementation of PCOS patients with continuous low doses of vitamin D (<4000 IU/d) or supplementation with vitamin D as a co-supplement may improve insulin sensitivity in terms of the fasting glucose concentration (supplementation with vitamin D in combination with other micronutrients) and HOMA-IR (supplementation with vitamin D in continuous low daily doses or as co-supplement).
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Study question: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference? Summary answer: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. What is known already: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. Study design, size, duration: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Participants/materials, setting, methods: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. Main results and the role of chance: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. Limitations, reasons for caution: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. Wider implications of the findings: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. Study funding/competing interest(s): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.
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Background Polycystic ovary syndrome (PCOS) affects up to 13% women and is associated with significant complications. The quality of evidence supporting the recommendations on treatment of non‐reproductive outcomes in PCOS is unknown. Objective To summarise and appraise the methodological quality of systematic reviews and meta‐analyses evaluating pharmacological and surgical treatments for non‐reproductive outcomes in PCOS. Methods A literature search from MEDLINE, EMBASE, CINAHL PLUS, and PROSPERO was performed from inception until 15th of September 2017. Article selection, data extraction, and quality appraisal of included reviews were performed in duplicate. A narrative synthesis of the findings was conducted. Results This overview included 31 reviews. The quality was low for seven (23%), moderate for sixteen (52%), and high for eight reviews (26%). Two reviews assessed psychological outcomes. Metformin improved anthropometric (seven of ten reviews), metabolic (four of fourteen reviews), and endocrine outcomes (three of twelve reviews). Thiazolidinediones improved metabolic (two of five reviews) and endocrine outcomes (one of five reviews) but worsened weight gain (five of five reviews). Combined oral contraceptive pill (COCP) improved clinical hyperandrogenism (two of two reviews). Statins improved lipid profile (three of three reviews) and testosterone level (two of three reviews). There was no conclusive evidence from included systematic reviews regarding the use of other interventions. Conclusions There is reliable evidence regarding the use of metformin for anthropometric outcomes and COCPs for hyperandrogenism in women with PCOS but not for other interventions. There is significant gap in knowledge regarding the management of psychological outcomes in women with PCOS which needs further evaluation. This article is protected by copyright. All rights reserved.
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Background: Epidemiological literature regarding the effect of polycystic ovary syndrome (PCOS) as a risk factor for non-alcoholic fatty liver disease (NAFLD) remains inconsistent. Furthermore, it remains debatable whether NAFLD is associated with PCOS as a consequence of shared risk factors or whether PCOS contributes to NAFLD in an independent fashion. Therefore, this meta-analysis was conducted. Methods: This meta-analysis was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Relevant studies published before May 2017 were identified and retrieved from PubMed and Web of Science databases. The data were extracted, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results: A total of 17 studies were included into the present analysis. Compared to the control group, the risk of NAFLD in the PCOS group was higher (OR = 2.25, 95% CI = 1.95-2.60). When stratified by BMI and geographic location, the results indicated that the frequency of NAFLD risk was significantly higher in obese subjects (OR = 3.01, 95% CI = 1.88-4.82), non-obese subjects (OR = 2.07, 95% CI = 1.12-3.85), subjects from Europe (OR = 2.00, 95% CI = 1.58-2.52), subjects from the Asia-Pacific Region, (OR = 2.32, 95% CI = 1.89-2.84) and subjects from America (OR = 2.96, 95% CI = 1.93-4.55). In addition, PCOS patients with hyperandrogenism (HA) had a significantly higher risk of NAFLD, compared with controls (OR = 3.31, 95% CI = 2.58-4.24). However, there was no association between PCOS patients without HA and higher risk of NAFLD (OR = 1.46; 95% CI =0.55-3.87). The results of this meta-analysis should be interpreted with caution due to the small number of observational studies and possible confounding factors. Conclusion: The meta-analysis results suggest that PCOS is significantly associated with high risk of NAFLD. Although this association was independent of obesity and geographic region, it might be correlated with HA.
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Background: Our prior meta-analyses demonstrated an increased prevalence of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) with polycystic ovary syndrome (PCOS), but with substantial clinical heterogeneity. Objective and rationale: We aimed to update our previous review to quantify the prevalence of IGT and T2DM in PCOS with only quality studies (good and fair quality). We also aimed to examine the contribution of parameters including ethnicity, obesity and method of diagnosing T2DM in explaining the observed heterogeneity in IGT and T2DM prevalence in PCOS. Search methods: We conducted a literature search (MEDLINE, CINAHL, EMBASE, clinical trial registries and hand-searching) up to June 2016 to identify studies reporting the prevalence of dysglycemia (IGT and T2DM) in women with and without PCOS. We included studies where women with PCOS (defined according to original National Institute of Health) were compared to women without PCOS for the end-points of the prevalence of IGT or T2DM. We excluded case reports, case series, editorials, and narrative reviews. Studies where PCOS was diagnosed by self-report, or where IGT or T2DM were measured by fasting glucose, only were excluded. We assessed the methodological quality of the included studies using a priori criteria based on the Newcastle-Ottawa Scaling (NOS) for non-randomized studies. Data are presented as odds ratio (OR) (95% CI) with random-effects meta-analysis by Mantel-Haenszel methods. We assessed the contribution of demographic and clinical factors to heterogeneity using subgroup and meta-regression analysis. Outcomes: We reviewed 4530 studies and included 40 eligible studies in the final analysis. On meta-analysis of quality studies, women with PCOS had an increased prevalence of IGT (OR = 3.26, 95% CI: 2.17-4.90) and T2DM (OR = 2.87, 95% CI: 1.44-5.72), which differed by ethnicity (for IGT, Asia: 5-fold, the Americas: 4-fold and Europe: 3-fold), was higher with obesity, and doubled among studies using self-report or administrative data for diagnosing diabetes. The ethnicity-related difference retained its significance for Asia and Europe in BMI-matched subgroups. Clear contributors to heterogeneity did not emerge in meta-regression. Wider implications: Our findings underscore the importance of PCOS as a cause of dysglycemia with a higher prevalence of IGT and T2DM. They support the relevance of ethnicity and obesity and emphasize the need for accurate diagnostic methods for diabetes. Prospero registration number: CRD42017056524.
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Background Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and represents a lifelong metabolic disorder, with increased risk of type 2 diabetes, hypertension, and cardiovascular events. Previous studies have suggested an increased risk of nonalcoholic fatty liver disease (NAFLD) in individuals with PCOS and implicated androgen excess as a potential driver. Methods and findings We carried out a retrospective longitudinal cohort study utilizing a large primary care database in the United Kingdom, evaluating NAFLD rates in 63,120 women with PCOS and 121,064 age-, body mass index (BMI)-, and location-matched control women registered from January 2000 to May 2016. In 2 independent cohorts, we also determined the rate of NAFLD in women with a measurement of serum testosterone (n = 71,061) and sex hormone-binding globulin (SHBG; n = 49,625). We used multivariate Cox models to estimate the hazard ratio (HR) for NAFLD and found that women with PCOS had an increased rate of NAFLD (HR = 2.23, 95% CI 1.86–2.66, p < 0.001), also after adjusting for BMI or dysglycemia. Serum testosterone >3.0 nmol/L was associated with an increase in NAFLD (HR = 2.30, 95% CI 1.16–4.53, p = 0.017 for 3–3.49 nmol/L and HR = 2.40, 95% CI 1.24–4.66, p = 0.009 for >3.5 nmol/L). Mirroring this finding, SHBG <30 nmol/L was associated with increased NAFLD hazard (HR = 4.75, 95% CI 2.44–9.25, p < 0.001 for 20–29.99 nmol/L and HR = 4.98, 95% CI 2.45–10.11, p < 0.001 for <20 nmol/L). Limitations of this study include its retrospective nature, absence of detailed information on criteria used to diagnosis PCOS and NAFLD, and absence of data on laboratory assays used to measure serum androgens. Conclusions We found that women with PCOS have an increased rate of NAFLD. In addition to increased BMI and dysglycemia, androgen excess contributes to the development of NAFLD in women with PCOS. In women with PCOS-related androgen excess, systematic NAFLD screening should be considered.
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Background: Polycystic ovary syndrome (PCOS) is associated with obesity and low grade inflammation and the risk for cardiovascular disease (CVD) could be increased in PCOS. Methods: National register-based study including women with PCOS and no previous diagnosis of CVD, hypertension, or dyslipidemia. PCOS Denmark (N = 18,112) included women with PCOS in the Danish National Patient Register. PCOS Odense University Hospital (OUH, N = 1165) was an embedded cohort including premenopausal women with PCOS and clinical and biochemical examination. Three age-matched controls were included per patient in PCOS Denmark (N = 52,769). The main study outcome was CVD events including hypertension and dyslipidemia defined according to nationwide in- and outpatient hospital contact diagnosis codes and/or inferred from filled medicine prescriptions. Results: The age at inclusion was median (quartiles) 29 (23-35) years and follow up was 11.1 (6.9-16.0) years. The Hazard ratio (95% CI) for development of CVD in PCOS Denmark was 1.7 (1.7; 1.8) (P < 0.001) and the total event rate of CVD was 22.6 per 1000 patient years in PCOS Denmark vs. 13.2 per 1000 patient years in controls (P < 0.001). The median age at diagnosis of CVD was 35 (28-42) years in PCOS Denmark vs. 36 (30-43) years in controls (P < 0.001). Obesity, diabetes, and infertility, and previous use of oral contraceptives were associated with increased risk of development of CVD in PCOS Denmark (P < 0.001). Women in PCOS OUH resembled women in PCOS Denmark regarding risk of CVD. Age, BMI, blood pressure, lipid status, and glycemic status predicted development of CVD in PCOS OUH. Conclusion: The event rate of CVD including hypertension and dyslipidemia was higher in PCOS compared to controls. The risk of developing CVD must be considered even in young women with PCOS.
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Background Several pharmacologic treatments for hirsutism are used in practice; however, their relative efficacy is unclear. Methods We searched MEDLINE, EMBASE, and CENTRAL through January 2017 for randomized controlled trials (RCTs) with follow-up of at least 6 months that evaluated antiandrogens, insulin sensitizers, and oral contraceptives in women with hirsutism. Independent pairs of reviewers selected and appraised trials. Random-effects network meta-analysis was used to compare individual drugs and classes. Results We included 43 trials. Estrogen-progestin oral contraceptives pills (OCPs), antiandrogens, and insulin sensitizers were superior to placebo, with standardized mean reductions (95% confidence intervals) of −0.94 (−1.49 to −0.38), −1.29 (−1.80 to −0.79), and −0.62 (−1.00 to −0.23), respectively. Antiandrogen monotherapy, the combination of OCP and antiandrogen, the combination of OCPs and insulin sensitizer, and the combination of antiandrogen and insulin sensitizer were superior to insulin sensitizer monotherapy. The combination of OCPs and antiandrogen was superior to OCPs. Antiandrogen monotherapy with flutamide, finasteride, and spironolactone were each superior to placebo but similar to each other in efficacy. OCPs containing levonorgestrel, cyproterone acetate, or drospirenone were similar in effectiveness to other OCPs or had trivial differences. The certainty in comparisons with placebo was moderate and for head-to-head comparisons was low. Conclusions Estrogen-progestin OCPs, antiandrogens, and insulin sensitizers are superior to placebo for the treatment of hirsutism.
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Background/aims: Polycystic ovary syndrome (PCOS) is associated with insulin resistance, adrenal hyperactivity and decreased mental health. We aimed to investigate changes in adrenal activity, metabolic status, and mental health in PCOS during treatment with escitalopram or placebo. Methods: Forty-two overweight premenopausal women with PCOS and no clinical depression were randomized to 12-weeks SSRI (20 mg escitalopram/day, n=21) or placebo (n=21). Patients underwent clinical examination, fasting blood samples, adrenocorticotroph hormone (ACTH) test, 3 hours oral glucose tolerance test (OGTT) and filled in questionnaires regarding mental health and health related quality of life (HRQoL): WHO Well Being Index (WHO-5), Major Depression Inventory (MDI), Short Form 36 (SF-36), and PCOS questionnaire. Results: Included women were aged 31 (6) years (mean (SD)) and had BMI 35.8 (6.5) kg/m2 and waist 102 (12) cm. Escitalopram was associated with increased waist (median(quartiles) change 1 (0; 3) cm), p= 0.005 vs. change during placebo and increased cortisol levels (cortisol 0, cortisol 60, peak cortisol, and area under the curve for cortisol during ACTH test), all p< 0.05 vs. changes during placebo. Escitalopram had no significant effect on measures of insulin sensitivity, insulin secretion, fasting lipids, mental health or HRQoL. Conclusion: Waist circumference and cortisol levels increased during treatment with escitalopram in women with PCOS and no clinical depression, whereas metabolic risk markers, mental health and HRQol were unchanged.
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Objective: Metformin has an established role in the management of polycystic ovary syndrome (PCOS). Some patients cannot tolerate it due to associated gastrointestinal adverse events. The present study evaluated the dipeptidyl peptidase 4 inhibitor sitagliptin as a potential treatment option in metformin-intolerant PCOS. Methods: We conducted a 12-week, prospective, randomized, open-label study with 30 obese metformin-intolerant women with PCOS (age 35.0 ± 7.2 years; body mass index, 36.9 ± 5.5 kg/m2). After metformin withdrawal, they were randomized to lifestyle intervention and sitagliptin 100 mg daily (SITA) or lifestyle intervention alone as controls (CON). All participants underwent anthropometric and endocrine measurements and oral glucose tolerance testing. Model-derived indexes of insulin resistance and beta-cell function were calculated. Results: SITA improved beta-cell function as assessed by the homeostasis model assessment for beta-cell function index (HOMA-B) of 45.9 ± 35.8 ( P = .001), modified beta-cell function index (MBCI) of 7.9 ± 7 ( P = .002), and quantitative insulin-sensitivity check index (QUICKI) of -0.03 ± 0.03 ( P = .002). By contrast, beta-cell function decreased in CON. The between-group differences were significant for HOMA-B ( P = 0.001), MBCI ( P = .010), and QUICKI ( P = .025). The conversion rate to impaired glucose homeostasis was prevented in SITA: 3 of 15 subjects had impaired glucose tolerance (IGT) before and after the study. In CON, none had type 2 diabetes (T2D), and 4 had IGT at the beginning. After 12 weeks, IGT was observed in 2 and T2D in 3 subjects. Conclusion: SITA improved beta-cell function and prevented a conversion to IGT and T2D in metformin-intolerant obese PCOS patients. Abbreviations: BMI = body mass index; DPP-4 = dipeptidyl peptidase-4; DXA = dual energy X-ray absorptiometry; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1; HOMA-B = homeostasis model assessment for beta-cell function; HOMA-IR = homeostasis model assessment of insulin resistance; IAI = insulin action index; IGT = impaired glucose tolerance; IR = insulin resistance; MBCI = modified beta-cell function index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index; PCOS = polycystic ovary syndrome; SHBG = sex hormone-binding globulin; T2D = type 2 diabetes.
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Purpose: To assess the effectiveness and safety of myoinositol for patients with PCOS. Methods: In this meta-analysis, data from randomized controlled trials are obtained to assess the effects of myoinositol vs. placebo or western medicine in women with PCOS. The study's registration number is CRD42017064563. The primary outcomes included total testosterone, estradiol (E2) and the homeostatic model assessment (HOMA) of insulin resistance. Result: Ten trials involving 573 patients were included. The meta-analysis results show that: compared with the control group, myoinositol may improve HOMA index (WMD -0.65; 95% CI -1.02, -0.28; P = 0. 0005) and increase the E2 level (WMD 16.16; 95% CI 2.01, 30.31; P = 0. 03); while there is no enough strong evidence that the myoinositol has an effect on the total testosterone level (WMD -16.11; 95% CI -46.08, 13.86; P = 0. 29). Conclusion: Based on current evidence, myoinositol may be recommended for the treatment of PCOS with insulin resistance, as well as for improving symptoms caused by decreased estrogen in PCOS.
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Yi-Wei Wang,1,* Si-Jia He,1,* Xiao Feng,1 Jin Cheng,1 Yun-Tao Luo,1 Ling Tian,2 Qian Huang1 1The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Metformin is the most commonly prescribed drug for type 2 diabetes mellitus. In recent years, in addition to glucose lowering, several studies have presented evidence suggesting some potential role for metformin, such as antitumor effect, antiaging effect, cardiovascular protective effect, neuroprotective effect or an optional treatment for polycystic ovary syndrome. This paper will critically review the role of metformin to provide reference for doctors and researchers. Keywords: metformin, antitumor effect, antiaging effect, cardiovascular protective effect, neuroprotective effect, PCOS
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Objective: To review the potential role and specific impact of statin drugs in women with PCOS. The evidence for this use of statins in PCOS is limited and still under further investigation. Materials and methods: A search was conducted using PubMed, DynaMed and PubMedHealth databases through October 16, 2016 using the terms polycystic ovary syndrome, PCOS, hydroxymethylglutaryl-CoA reductase inhibitors, hydroxymethylglutaryl-CoA, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. English-language trials evaluating statins in PCOS were obtained and incorporated if they provided relevant data for providers. Results: We summarize twelve trials involving statins in PCOS. The trials were predominantly 12 weeks to 3 months in length (8 of the 12 trials) and low to moderate dose of statin drugs were used. The majority (10 of 12) of the trials show that statins reduce testosterone levels or other androgen hormones (DHEA-S and androstenedione), half of the trials evaluating LH/FSH ratio show an improvement, and all had positive effects on lipid profiles. Conclusion: Statins show promising improvements in serum levels of androgens and LH/FSH ratios translating to improved cardiovascular risk factors above and beyond simply lowering LDL levels. More investigation is needed to determine if statins can clinically impact women with PCOS long term, particularly those who are young and are not yet candidates for traditional preventative treatment with a statin medication.
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Context: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined. Setting: Outpatient clinic. Patients and interventions: Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol), metformin (2 g/day) or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT) measuring fasting and area under the curve (AUC) for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls. Main outcome measures: Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT. Results: Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P < 0.01) and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P = 0.01). Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI. Conclusions: AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion.
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Despite the significance placed on lifestyle interventions for obesity management, most weight loss is followed by weight regain. Psychological concepts of habitual behaviour and automaticity have been suggested as plausible explanations for this overwhelming lack of long-term weight loss success. Interventions that focus on changing an individual's behaviour are not usually successful at changing an individual's habits because they do not incorporate the strategies required to break unhealthy habits and/or form new healthy habits. A narrative review was conducted and describes the theory behind habit formation in relation to weight regain. The review evaluated the effectiveness of using habits as tools to maintain weight loss. Three specific habit-based weight loss programmes are described: ‘10 Top Tips’, ‘Do Something Different’ and ‘Transforming Your Life’. Participants in these interventions achieved significant weight loss compared to a control group or other conventional interventions. Habit-based interventions show promising results in sustaining behaviour change. Weight loss maintenance may benefit from incorporating habit-focused strategies and should be investigated further.
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Background Liraglutide 3 mg was recently approved as an anti-obesity drug. Metformin is weight neutral, yet it could enhance the therapeutic index of GLP-1 agonist. We compared weight-lowering potential of liraglutide 1.2 mg in combination with metformin to liraglutide 3 mg monotherapy in obese PCOS. Methods Thirty obese women with PCOS (aged 33.1 ± 6.1 years, BMI 38.3 ± 5.4 kg/m2) were randomized to combination (COMBO) of metformin (MET) 1000 mg BID and liraglutide 1.2 mg QD (N = 15) or liraglutide 3 mg (LIRA3) QD alone (N = 15) for 12 weeks. The primary outcome was change in anthropometric measures of obesity. ResultsBoth treatments led to significant weight loss (−3.6 ± 2.5 kg, p = 0.002 in COMBO vs −6.3 ± 3.7 kg, p = 0.001 in LIRA3). BMI and waist circumference reduction in LIRA3 was greater than in COMBO (−2.2 ± 1.3 vs −1.3 ± 0.9 kg/m2,p = 0.05 and −4.2 ± 3.4 vs −2.2 ± 6.2 cm, p = 0.014, respectively). Both interventions resulted in a significant decrease of post-OGTT glucose levels. COMBO significantly reduced total testosterone and was associated with less nausea. Conclusions Short-term interventions with COMBO and LIRA3 both led to significant improvement of measures of obesity in obese PCOS, LIRA3 being superior to COMBO. However, COMBO further improved androgen profile beyond weight reduction and was associated with better tolerability. Trial registrationThe study was retrospectively registered with ClinicalTrials.gov (NCT02909933) on 16th of September 2016.
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Polycystic ovary syndrome (PCOS) is associated with increased risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) in later life. We aimed to study the effect of liraglutide intervention on markers of VTE and CVD risk, in PCOS. In a double-blind, placebo-controlled, randomized trial, 72 overweight and/or insulinresistant women with PCOS were randomized, in a 2:1 ratio, to liraglutide or placebo 1.8 mg/day. Endpoints included between-group difference in change (baseline to follow-up) in plasminogen activator inhibitor-1 levels and in thrombin generation test parameters: endogenous thrombin potential, peak thrombin concentration, lag time and time to peak. Mean weight loss was 5.2 kg (95% CI 3.0?7.5 kg, P < 0.001) in the liraglutide group compared with placebo. We detected no effect on endogenous thrombin potential in either group. In the liraglutide group, peak thrombin concentration decreased by 16.71 nmol/L (95% CI 2.32?31.11, P < 0.05) and lag time and time to peak increased by 0.13 min (95% CI 0.01?0.25, P < 0.05) and 0.38 min (95% CI 0.09?0.68, P < 0.05), respectively, but there were no between-group differences. There was a trend toward 12% (95% CI 0?23, P = 0.05) decreased plasminogen activator inhibitor-1 in the liraglutide group, and there was a trend toward 16% (95% CI ?4 to 32, P = 0.10) reduction, compared with placebo. In overweight women with PCOS, liraglutide intervention caused an approximate 5% weight loss. In addition, liraglutide affected thrombin generation, although not significantly differently from placebo. A concomitant trend toward improved fibrinolysis indicates a possible reduction of the baseline thrombogenic potential. The findings point toward beneficial effects of liraglutide on markers of VTE and CVD risk, which should be further pursued in larger studies.
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In the last decades several studies suggested that vitamin D is involved in the modulation of the reproductive process in women due to the expression of VDR and 1α-hydroxylase in reproductive tissues such as ovary, uterus, placenta, pituitary and hypothalamus. Vitamin D has also a role in the regulation of sex hormone steroidogenesis. Increasing evidence suggests that vitamin D might have a regulatory role in polycystic ovary syndrome (PCOS)-associated symptoms, including ovulatory dysfunction, insulin resistance and hyperandrogenism. Vitamin D deficiency also has been reported to contribute to the pathogenesis of endometriosis due to its immunomodulatory and anti-inflammatory properties. Although most of the studies supported a role of vitamin D in the onset of these diseases, randomized controlled trials to assess the efficacy of vitamin D supplementation have never been performed. In this review we critically discuss the role of vitamin D in female fertility, starting from in vitro and in vivo studies, focusing our attention on the two most frequent causes of female infertility: PCOS and endometriosis.
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Irene González,1 Albert Lecube,2 Miguel Ángel Rubio,3 Pedro Pablo García-Luna4 1Endocrinology and Nutrition Department, Complejo Hospitalario Universitario de Huelva, Huelva, Spain; 2Endocrinology and Nutrition Department, Arnau de Vilanova University Hospital, Lleida Biomedicine Research Institute (IRB-Lleida), CIBER in Diabetes and Associated Metabolic Disorders (CIBERDEM), Lleida University, Lleida, Spain; 3Endocrinology and Nutrition Department, Hospital Clínico San Carlos, IDISSC, Madrid, Spain; 4Endocrinology and Nutrition Department, Hospitales Universitarios Virgen del Rocío, Seville, Spain Abstract: The significant increase in the prevalence of obesity has led to an increase in the number of obese women who become pregnant. In this setting, in recent years, there has been an exponential rise in the number of bariatric procedures, with approximately half of them performed in women of childbearing age, and a remarkable surge in the number of women who become pregnant after having undergone bariatric surgery (BS). These procedures entail the risk of nutritional deficiencies, and nutrition is a crucial aspect during pregnancy. Therefore, knowledge and awareness of the consequences of these techniques on maternal and fetal outcomes is essential. Current evidence suggests a better overall obstetric outcome after BS, in comparison to morbid obese women managed conservatively, with a reduction in the prevalence of gestational diabetes mellitus, pregnancy-associated hypertensive disorders, macrosomia, and congenital defects. However, the risk of potential maternal nutritional deficiencies and newborns small for gestational age cannot be overlooked. Results concerning the incidence of preterm delivery and the number of C-sections are less consistent. In this paper, we review the updated evidence regarding the impact of BS on pregnancy. Keywords: bariatric surgery, pregnancy, maternal and fetal outcomes, gestational diabetes mellitus, small for gestational age
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AimTo investigate the therapeutical effect of vitamin D supplementation on the metabolism and endocrine parameters of PCOS patients. Materials and methodsClinical studies investigating the therapeutic effect of vitamin D supplementation on PCOS patients were selected by searching PubMed, Embase, The Cochrane library and Web of Science until April 2016. The included articles were selected according to the inclusion criteria. Serum HOMA-IR, QUICKI, LDL, DHEAS, free testosterone (FT), total testosterone (TT), PTH, 25-hydroxy-vitamin D, and triglyceride of PCOS patients were enrolled for evaluating the therapeutic effects of vitamin D. Results16 studies were included in this study. There was no significant difference between the placebo group and vitamin D group in the concentration of serum 25-hydroxy-vitamin D in patients with PCOS (P = 0.06). After treated with vitamin D, the serum 25-hydroxy-vitamin D in PCOS patients was increased (P < 0.00001), while the serum PTH (P = 0.003) and triglyceride (P = 0.006) were decreased. In addition, the serum HOMA-IR, QUICKI, LDL, DHEAS, FT, and TT in PCOS patients did not change. Subgroup analysis showed that the serum triglyceride of PCOS patients was decreased by low dose of vitamin D supplementation (<50,000 IU) (P = 0.03), but no significantly changed by high-dose vitamin D supplementation (≥50,000 IU) (P = 0.17). Conclusion Vitamin D supplementation significantly attenuates serum PTH and triglyceride in PCOS patients except for serum HOMA-IR, QUICKI, LDL, DHEAS, FT, and TT. Furthermore, less than 50,000 IU vitamin D supplementation is sufficient for decreasing serum triglyceride.
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Context Women with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can increase visceral adiposity (VAT) and impair vascular function. GH releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion. Objective We tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS. Methods Eighteen women with PCOS participated in a double-blinded, cross-over study. They received sitagliptin 100 mg vs. placebo daily for one month separated by an eight-week washout. During each treatment, women underwent a 75-gram oral glucose tolerance test (OGTT), assessment of vascular function and body composition. Overnight GH secretion was assessed via venous sampling every 10 minutes for 12 hours and analyzed using an automated deconvolution algorithm. Results During OGTT, sitagliptin increased GLP-1 (p<0.001), early insulin secretion (from mean insulinogenic index 1.9±1.2 (SD) to 3.2±3.1; p=0.02) and decreased peak glucose (mean -17.2 mg/dL [95% CI -27.7, -6.6]; p<0.01). At one month, sitagliptin decreased VAT (from 1141.9±700.7 to 1055.1±710.1 g; p=0.02) but did not affect vascular function. Sitagliptin increased GH half-life (from 13.9±3.6 to 17.0±6.8 min, N=16; p=0.04) and interpulse interval (from 53.2±20.0 to 77.3±38.2 min, N=16; p<0.05) but did not increase mean overnight GH (p=0.92 vs. placebo). Conclusions Sitagliptin decreased the maximal glucose response to OGTT and VAT. Sitagliptin did not increase overnight GH but increased GH half-life and the interpulse interval. Precis Sitagliptin decreases visceral fat and blood glucoses following oral glucose load in women with PCOS. Sitagliptin potentiated GH half-life but did not increase overnight GH levels.
Article
Polycystic ovary syndrome (PCOS) is common endocrine disease in women during reproductive age. It was shown that PCOS women are with high risk for dyslipidemia, glucose intolerance, type 2 diabetes and metabolic syndrome. These factors are considered to represent traditional risk factors for the occurrence of cardiovascular disease. Observed increased risk for hypertension in PCOS women seems was associated with insulin resistance and hyperinsulinemia. Both conditions are interfering with the endothelium-dependent vasodilatation mechanisms causing vascular muscle wall hypertrophy. Obesity and insulin resistance are considered key factors for the alteration of blood pressure in PCOS women. Higher cardiovascular risk was implicated in PCOS with aging and its consequent association with both systolic and diastolic blood pressure. The elements of renin–angiotensin–aldosterone system (RAAS) have an impact on endothelial dysfunction as a marker of cardiovascular damage that could be modified is women with PCOS. Androgens and components of RAAS are involved in the process of atherogenesis in PCOS women. Therefore, it is hypothesized that spironolactone treatment could ameliorate endothelial dysfunction in PCOS women. Recently it was shown that telmisartan, angiotensin II receptor antagonist poses insulin-sensitizing capacity to activate PPAR gamma and mediate favorable metabolic and reproductive effects in hypertensive PCOS women.
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Background Polycystic ovary syndrome (PCOS) has a prevalence of 8‐13%. Given the prevalence, diverse health impacts and variation in care, rigorous evidence‐based guidelines are needed in PCOS management. This systematic review with meta‐analyses aims to investigate the effect of the combined oral contraceptive pill (COCP) and/or metformin in the management of hormonal and clinical features of PCOS, to inform international guidelines. Methods Electronic databases were searched systematically from inception until 11 January 2017 to inform the guideline process. Eligible studies were randomized controlled trials (RCTs) which investigated the effect of COCPs and/or metformin alone or combined on hormonal and clinical features in women with PCOS. Outcomes were prioritised as critical for informing a decision about an intervention or important or not important, according to GRADE. Articles were assessed by one author against selection criteria, in consultation with a second author. Data were double extracted independently by four authors, and data quality appraisal completed. Meta‐analyses were conducted, where appropriate. Results Fifty‐six studies were eligible for inclusion. Outcomes prioritised by women and health professionals included: irregular cycles, insulin resistance, weight, BMI, thromboembolic events and gastrointestinal effects. In low quality evidence in adolescents, meta‐analyses demonstrated that metformin was better than COCP for BMI (mean difference (MD) −4.02 [−5.23, −2.81], p <0.001); and COCP was better than metformin for menstrual regulation (MD ‐0.19 [‐0.25, ‐0.13], p <0.00001). In low quality evidence in adults, meta‐analyses demonstrated that metformin was better than placebo for BMI (MD ‐0.48 [‐0.94, ‐0.02], p= 0.04); metformin was better than COCP for fasting insulin (MD 4.00 [2.59, 5.41], p= 0.00001), whereas COCP was better than metformin for irregular cycles (MD 12.49 [1.34, 116.62], p= 0.03). COCP alone was better than the combination with an anti‐androgen for BMI (MD ‐3.04 [‐5.45, ‐0.64], p= 0.01). Metformin was associated with generally mild gastrointestinal adverse events. Differences in statistical significance were observed when outcomes were sub‐grouped by BMI. Conclusions This review identified that COCP therapy has benefits for management of hyperandrogenism and menstrual regulation. Metformin combined with the COCP may be useful for management of metabolic features. There is minimal evidence of benefits of adding an anti‐androgen to COCP therapy. Metformin alone has benefits for adult women for management of weight, hormonal, and metabolic outcomes, especially for women with BMI≥25 kg/m². There is inadequate evidence to suggest the optimal COCP formulation, or dosing regimen and formulation of metformin. This article is protected by copyright. All rights reserved.
Article
This meta-analysis aimed to evaluate the efficacy and safety of glucagon-like peptide 1 (GLP-1) receptor agonists for women with polycystic ovary syndrome (PCOS) by comparing their effect with that of metformin. Electronic databases (PubMed, EMBASE, Cochrane Library, WanFang Database, CNKI) dating from their establishment to June 2018 were searched to find all randomized controlled trials (RCTs) reporting the efficacy of GLP-1 receptor agonists versus metformin for patients with PCOS. Therapeutic variables included menstrual cycle, sex hormone and clinical manifestations, glucose metabolism and other metabolic indexes. Eight RCTs among 462 related articles were included in the meta-analysis. Compared with metformin, GLP-1 receptor agonists were more effective in improving insulin sensitivity (standard mean difference [SMD] -0.40, 95% confidence interval [CI] -0.74 to -0.06, P = 0.02) and reducing body mass index (SMD -1.02, 95% CI -1.85 to -0.19, P = 0.02) and abdominal girth (SMD -0.45, 95% CI -0.89 to -0.00, P = 0.05). GLP-1 receptor agonists were associated with a higher incidence of nausea and headache than metformin, but there were no significant differences in other data. Therefore, compared with metformin, GLP-1 receptor agonists might be a good choice for obese patients with PCOS, especially those with insulin resistance. The available evidence is, however, inconclusive given its moderate to low quality. More high-quality research is needed to assess the efficacy of a GLP-1 receptor agonist on women with PCOS.
Article
Introduction: High levels of anti-Mullerian hormone and a high antral follicle count in women with polycystic ovary syndrome, reflecting increased ovarian antral follicles, predisposes them to have a high number of retrieved oocytes with in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) and an increased risk of ovarian hyperstimulation syndrome. Inositols, which act as insulin sensitizers, have the potential to alter folliculogenesis and the functional ovarian reserve, with subsequent benefits to reproductive outcomes following IVF/ICSI treatment. Published literature is, however, unable to provide definitive evidence of its efficacy. The objective of our review was to evaluate the effect of inositols on anti-Mullerian hormone, antral follicle count and reproductive outcomes in women with polycystic ovary syndrome undergoing IVF/ICSI. Material and methods: We performed a literature search using standard methodology recommended by Cochrane. Randomized controlled trials and non-randomized studies comparing inositols with no treatment, placebo or other treatment were included in the review. Using standard methodology recommended by Cochrane we pooled results using the random effects model; our findings were reported as relative risk or mean differences. PROSPERO registration: CRD42017082275. Results: We included 18 trials. The primary outcome was a change in anti-Mullerian hormone and antral follicle count before and after treatment, for which data were unsuitable for meta-analysis. A narrative review showed no consistent direction or size of effect. A meta-analysis for the secondary outcomes showed no evidence of a significant difference between inositol and control groups for any outcome: number of oocytes (mean difference -0.39, 95% confidence interval [CI] -1.11 to 0.33), number of metaphase II oocytes (mean difference 0.29, 95% CI -0.83 to 1.40), number of top grade embryos (risk ratio [RR] 1.02, 95% CI 0.93-1.12), clinical pregnancy rate (RR 1.16, 95% CI 0.87-1.53), and risk of ovarian hyperstimulation syndrome (RR 0.73, 95% CI 0.39-1.37). The quality of evidence was assessed as very low. Conclusions: There is insufficient evidence for an effect of inositols on ovarian reserve markers and to support their use as pretreatment before IVF/ICSI in women with polycystic ovary syndrome.
Article
Background: Bariatric surgery has been widely used for the treatment of obesity and its related metabolic diseases, such as type 2 diabetes (T2D), hypertension, and sleep apnea syndrome. Polycystic ovary syndrome (PCOS) is a common reproductive endocrine metabolic disease; however, little attention has been paid to the efficacy of bariatric surgery on PCOS. Objective: To evaluate the efficacy of bariatric surgery on obese PCOS patients. Setting: A systematic review and meta-analysis at a university hospital. Methods: Online databases were searched for all studies reporting the efficacy of bariatric surgery for obese patients with PCOS up to October 2018. Results: A total of 9 studies with 234 obese PCOS patients were included in this article. The results of meta-analysis showed that after bariatric surgery, there was a significant reduction of the incidence of abnormal menstruation (relative risk [RR] .23; 95% confidence interval [CI] .13-.43; P < .00001) and hirsutism (RR .47; 95% CI .28-.79; P = .004). Bariatric surgery can also cause a decrease in the serum total testosterone level (mean difference [MD] = -25.82; 95% CI -30.06 to -21.58; P < .00001), serum free testosterone level (MD = -4.10; 95% CI -6.97 to -1.23; P = .005), and body mass index (MD = -14.51; 95% CI -17.88 to -11.14; P < .00001). It also showed a significant effect on T2D (RR .09; 95% CI .03-.32; P = .0002) and hypertension (RR .21; 95% CI .05-.98; P = .05) in obese patients with PCOS. Conclusions: Bariatric surgery can reduce the incidence of abnormal menstruation, improve hyperandrogenism and its clinical manifestations, and decrease the body mass index, prevalence of T2D, and hypertension in obese patients with PCOS.
Article
Background: Polycystic ovary syndrome (PCOS) affects 8% to 13% of reproductive-aged women and is associated with reproductive and metabolic dysfunction. Obesity worsens the presentation of PCOS and weight management (weight loss, maintenance or prevention of excess weight gain) is proposed as an initial treatment strategy, best achieved through lifestyle changes incorporating diet, exercise and behavioural interventions. Objectives: To assess the effectiveness of lifestyle treatment in improving reproductive, anthropometric (weight and body composition), metabolic and quality of life factors in PCOS. Search methods: We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, CINAHL and AMED (date of last search March 2018). We also searched controlled trials registries, conference abstracts, relevant journals, reference lists of relevant papers and reviews, and grey literature databases, with no language restrictions applied. Selection criteria: Randomised controlled trials (RCTs) comparing lifestyle treatment (diet, exercise, behavioural or combined treatments) to minimal or no treatment in women with PCOS. Data collection and analysis: Two authors independently selected trials, assessed evidence quality and risk of bias, and extracted data. Our primary outcomes were live birth, miscarriage and pregnancy. We used inverse variance and fixed-effect models in the meta-analyses. We reported dichotomous outcomes as an odds ratio and continuous outcomes as a mean difference (MD) or standardised mean difference (SMD). Main results: We included 15 studies with 498 participants. Ten studies compared physical activity to minimal dietary and behavioural intervention or no intervention. Five studies compared combined dietary, exercise and behavioural intervention to minimal intervention. One study compared behavioural intervention to minimal intervention. Risk of bias varied: eight studies had adequate sequence generation, seven had adequate clinician or outcome assessor blinding, seven had adequate allocation concealment, six had complete outcome data and six were free of selective reporting. No studies assessed the fertility primary outcomes of live birth or miscarriage. No studies reported the secondary reproductive outcome of menstrual regularity, as defined in this review.Lifestyle intervention may improve a secondary (endocrine) reproductive outcome, the free androgen index (FAI) (MD -1.11, 95% confidence interval (CI) -1.96 to -0.26, 6 RCTs, N = 204, I2 = 71%, low-quality evidence). Lifestyle intervention may reduce weight (kg) (MD -1.68 kg, 95% CI -2.66 to -0.70, 9 RCTs, N = 353, I2 = 47%, low-quality evidence). Lifestyle intervention may reduce body mass index (BMI) (kg/m2) (-0.34 kg/m2, 95% CI -0.68 to -0.01, 12 RCTs, N = 434, I2= 0%, low-quality evidence). We are uncertain of the effect of lifestyle intervention on glucose tolerance (glucose outcomes in oral glucose tolerance test) (mmol/L/minute) (SMD -0.02, 95% CI -0.38 to 0.33, 3 RCTs, N = 121, I2 = 0%, low-quality evidence). Authors' conclusions: Lifestyle intervention may improve the free androgen index (FAI), weight and BMI in women with PCOS. We are uncertain of the effect of lifestyle intervention on glucose tolerance. There were no studies that looked at the effect of lifestyle intervention on live birth, miscarriage or menstrual regularity. Most studies in this review were of low quality mainly due to high or unclear risk of bias across most domains and high heterogeneity for the FAI outcome.
Article
Background Empagliflozin is a sodium‐glucose‐cotransporter‐2 inhibitor that improves cardiovascular risk and promotes weight loss in patients with type 2 diabetes. Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular risk; therefore, empagliflozin may be of benefit for these women. The aim of this study was to compare the effects of empagliflozin vs. metformin on anthropometric and body composition, hormonal and metabolic parameters in women with PCOS. Materials and methods A randomized open‐label study was conducted in women with PCOS who were randomised to either empagliflozin 25mg (n=19) or metformin 1500mg (n=20) daily for 12 weeks. The main outcomes assessed were changes in anthropometric and body composition, hormonal and metabolic parameters. Results Univariate analysis showed significant differences in weight (empagliflozin: ‐1.4±3.2% vs. metformin: 1.2±2.3%; p=0.006), body mass index (empagliflozin: ‐1.4±3.2% vs. metformin: 1.1±2.2%; p=0.006), waist circumference (empagliflozin: ‐1.6±2.8% vs. metformin: 0.2±2.1%; p=0.029) and hip circumference (empagliflozin: ‐2.0±3.0% vs. metformin: 1.1±1.9%; p=0.001), basal metabolic rate (empagliflozin: ‐1.8±2.9% vs. metformin: 0.1±1.9%, p=0.024) and fat mass (empagliflozin: ‐0.7±4.9% vs. metformin, 3.2±5.0%; p=0.023) between the empagliflozin and the metformin groups. These differences were confirmed in linear regression analysis after adjustment for relevant covariates. There were no significant changes in hormonal or metabolic parameters between both groups. Conclusion There was a significant improvement in anthropometric parameters and body composition, in overweight and obese women with PCOS after 12 weeks of treatment with empagliflozin compared to metformin, although no changes were seen in hormonal or metabolic parameters. This article is protected by copyright. All rights reserved.
Article
Background: Polycystic ovary syndrome (PCOS) is a major contributor to subfertility, diabetes and cardiovascular disease in women. The role of non-pharmacological interventions to prevent these outcomes has been reported in many systematic reviews, but robust conclusions have not been made due to variations in the scope, quality and findings of these reviews. Objective and rationale: Our aim was to provide an overview of existing evidence on the effects of non-pharmacological interventions in women with PCOS on fertility and non-fertility outcomes by a review of existing systematic reviews. Search methods: We reviewed systematic reviews of randomized trials that have evaluated the effects of non-pharmacological interventions, such as lifestyle interventions, nutritional supplements or alternative medicine therapies in women with PCOS on fertility, endocrine, glycaemic and weight-related outcomes. We assessed the quality of systematic reviews with the AMSTAR tool, and reported the outcomes with regard to: fertility (live birth, clinical pregnancy, ovulation and menstrual cycle regularization); endocrine outcomes (Ferriman-Gallwey score, free androgen index, free testosterone and total testosterone levels); and glycaemic (fasting blood insulin, fasting blood glucose, homoeostatic model assessment) and weight-related (BMI) outcomes. We assessed the strength of evidence for significant outcomes as per the grading of recommendations assessment, development and evaluation (GRADE) system. Outcomes: We found twelve eligible systematic reviews which included between three (143 women) and 27 randomized trials (2093 women). Four reviews assessed the effects of lifestyle interventions (diet, physical activity and/or behavioural interventions); four evaluated nutritional supplements (one each on n-acetylcysteine, omega-3 fatty acids, inositol and vitamin D); and four studied alternative medical therapies (Chinese herbal medicine and acupuncture). All of the included reviews were of high quality and scored between 8 and 11 with the AMSTAR tool (with a maximum score of 11).Randomized evidence is lacking for live birth rate. N-acetylcysteine, inositol and the addition of alternative medicine to ovulation induction agents show preliminary potential to improve fertility (odds ratios (OR) for clinical pregnancy rate range from 1.99 to 4.83). Lifestyle interventions show benefits in improving hirsutism (mean difference (MD): -1.01 to -1.19). Lifestyle interventions (MD: -1.10 to -2.02), inositol (MD: -2.1) and acupuncture (MD: -1.90 to -3.43) all show some evidence of improvement in glycaemic outcomes and there is some evidence of reduced BMI with lifestyle interventions (MD: -0.15 to -1.12). All of these outcomes scored either low or very low quality of evidence on the GRADE score. Wider implications: Lifestyle interventions in women with PCOS appear to improve glycaemic results, androgenic symptoms and anthropometric outcomes. The role of inositol and N-acetylcysteine in women with PCOS needs further evaluation. Large primary trials on all interventions are needed for an agreed set of core outcomes.
Article
Objective: The nature of the independent relationship between polycystic ovary syndrome (PCOS) and type 2 diabetes remains unclear. Few studies have aimed to clarify this relationship independent of obesity in longitudinal population-based cohorts. Research design and methods: We used the Australian Longitudinal Study on Women's Health (ALSWH) (2000-2015) database to estimate nationwide incidence rates and predictors of type 2 diabetes among women aged 18-42 using person-time and survival analysis. Results: Over a follow-up of 1,919 person-years (PYs), 186 women developed type 2 diabetes. The incidence rate was 4.19/1,000 PYs and 1.02/1,000 PYs (P < 0.001) in PCOS and control subjects. On subgroup analyses across healthy-weight, overweight, and obese categories of women, the incidence rates for type 2 diabetes were 3.21, 4.67, and 8.80, whereas incidence rate ratios were 4.68, 3.52, and 2.36 (P < 0.005) in PCOS versus age-matched control subjects. PCOS was one of the most influential predictors for type 2 diabetes in the entire cohort (hazard ratio 3.23, 95% CI 2.07-5.05, P < 0.001) adjusting for BMI, education, area of residence, and family history of type 2 diabetes. Conclusions: Women with PCOS are at an increased risk of type 2 diabetes, irrespective of age and BMI. The incidence of type 2 diabetes increases substantially with increasing obesity; yet, PCOS adds a greater relative risk in lean women. Based on the overall moderate absolute clinical risk demonstrated here, guideline recommendations suggest type 2 diabetes screening every 1-3 years in all women with PCOS, across BMI categories and age ranges, with frequency influenced by additional type 2 diabetes risk factors.
Article
Background: Subfertile women are highly motivated to try different adjunctive therapies to have a baby, and the widespread perception is that dietary supplements such as myo-inositol (MI) and D-chiro-insoitol (DCI) are associated with only benefit, and not with harm. Many fertility clinicians currently prescribe MI for subfertile women with polycystic ovary syndrome (PCOS) as pre-treatment to in vitro fertilisation (IVF) or for ovulation induction; however no high-quality evidence is available to support this practice. This review assessed the evidence for the effectiveness of inositol in subfertile women with a diagnosis of PCOS. Objectives: To evaluate the effectiveness and safety of oral supplementation of inositol for reproductive outcomes among subfertile women with PCOS who are trying to conceive. Search methods: We searched the following databases (to July 2018): Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and AMED. We also checked reference lists and searched the clinical trials registries. Selection criteria: We included randomised controlled trials (RCTs) that compared any type, dose, or combination of oral inositol versus placebo, no treatment/standard treatment, or treatment with another antioxidant, or with a fertility agent, or with another type of inositol, among subfertile women with PCOS. Data collection and analysis: Two review authors independently selected eligible studies, extracted data, and assessed risk of bias. The primary outcomes were live birth and adverse effects; secondary outcomes included clinical pregnancy rates and ovulation rates. We pooled studies using a fixed-effect model, and we calculated odds ratios (ORs) with 95% confidence intervals (CIs). We assessed the overall quality of the evidence by applying GRADE criteria. Main results: We included 13 trials involving 1472 subfertile women with PCOS who were receiving myo-inositol as pre-treatment to IVF (11 trials), or during ovulation induction (two trials). These studies compared MI versus placebo, no treatment/standard, melatonin, metformin, clomiphene citrate, or DCI. The evidence was of 'low' to 'very low' quality. The main limitations were serious risk of bias due to poor reporting of methods, inconsistency, and lack of reporting of clinically relevant outcomes such as live birth and adverse events.We are uncertain whether MI improves live birth rates when compared to standard treatment among women undergoing IVF (OR 2.42, 95% CI 0.75 to 7.83; P = 0.14; 2 RCTs; 84 women; I² = 0%). Very low-quality evidence suggests that for subfertile women with PCOS undergoing pre-treatment to IVF who have an expected live birth rate of 12%, the rate among women using MI would be between 9% and 51%.We are uncertain whether MI may be associated with a decrease in miscarriage rate when compared to standard treatment (OR 0.40, 95% CI 0.19 to 0.86; P = 0.02; 4 RCTs; 535 women; I² = 66%; very low-quality evidence). This suggests that among subfertile women with PCOS with an expected miscarriage rate of 9% who are undergoing pre-treatment to IVF, the rate among women using MI would be between 2% and 8%; however this meta-analysis is based primarily on one study, which reported an unusually high miscarriage rate in the control group, and this has resulted in very high heterogeneity. When we removed this trial from the sensitivity analysis, we no longer saw the effect, and we noted no conclusive differences between MI and standard treatment.Low-quality evidence suggests that MI may be associated with little or no difference in multiple pregnancy rates when compared with standard treatment (OR 1.04, 95% CI 0.63 to 1.71; P = 0.89; 2 RCTs; 425 women). This suggests that among subfertile women with PCOS who are undergoing pre-treatment to IVF, with an expected multiple pregnancy rate of 18%, the rate among women using inositol would be between 12% and 27%.We are uncertain whether MI may be associated with an increased clinical pregnancy rate when compared to standard treatment (OR 1.27, 95% CI 0.87 to 1.85; P = 0.22; 4 RCTs; 535 women; I² = 0%; very low-quality evidence). This suggests that among subfertile women with PCOS who are undergoing pre-treatment to IVF, with an expected clinical pregnancy rate of 26%, the rate among women using MI would be between 24% and 40%. Ovulation rates were not reported for this comparison.Other comparisons included only one trial in each, so for the comparisons MI versus antioxidant, MI versus an insulin-sensitising agent, MI versus an ovulation induction agent, and MI versus another DCI, meta-analysis was not possible.No pooled evidence was available for women with PCOS undergoing ovulation induction, as only single trials performed comparison of the insulin-sensitising agent and the ovulation induction agent. Authors' conclusions: In light of available evidence of very low quality, we are uncertain whether MI improves live birth rate or clinical pregnancy rate in subfertile women with PCOS undergoing IVF pre-treatment taking MI compared to standard treatment. We are also uncertain whether MI decreases miscarriage rates or multiple pregnancy rates for these same women taking MI compared to standard treatment. No pooled evidence is available for use of MI versus placebo, another antioxidant, insulin-sensitising agents, ovulation induction agents, or another type of inositol for women with PCOS undergoing pre-treatment to IVF. No pooled evidence is available for use of MI in women undergoing ovulation induction.
Article
Context PCOS is associated with many traditional cardiovascular disease risk factors, but it is unclear whether PCOS is an independent risk factor for hypertension. Objective To investigate in a population-based set-up whether PCOS associates with the risk of hypertension independently of body-mass-index (BMI), and with cardiovascular manifestations. Design Cross-sectional assessments in the Northern Finland Birth Cohort 1966 at ages 31 and 46. Setting General community. Participants Women who reported both oligo/amenorrhea and hirsutism at age 31 and/or diagnosis of PCOS by age 46 (self-reported PCOS [srPCOS], n=279) and women without PCOS symptoms or diagnosis (n=1577). Intervention None. Main Outcome Measures Blood pressure (BP), BMI, cardiovascular manifestations. Results Use of antihypertensive medication was significantly more common in women with srPCOS. At age 31, women with srPCOS had significantly higher systolic (SBP) and diastolic BP (DBP) than control women (SBP: normal-weight: 119.9±13.2 vs. 116.9±11.4mmHg, P=0.017; overweight/obese: 126.1±14.3 vs. 123.0±11.9mmHg, P=0.031; and DBP: normal-weight: 75.5±10.0 vs. 72.4±9.6mmHg, P=0.003; overweight/obese: 80.7±11.8 vs. 78.0±10.6mmHg, P=0.031). At age 46, srPCOS was significantly associated with hypertension (AOR=1.56 [1.14–2.13]) independently of BMI, and with higher cardiovascular morbidity (6.8% vs. 3.4%, P=0.011). Hypertensive srPCOS displayed consistent, unfavorable changes in cardiac structure and function compared with controls. Conclusion Women with srPCOS displayed higher BP compared with controls already at early age and srPCOS was associated with hypertension independently of overweight/obesity. srPCOS was associated with increased cardiovascular morbidity in premenopausal women, suggesting that cardiovascular disease risk factors should be screened and efficiently managed early enough in women with PCOS.
Article
Background Women with polycystic ovary syndrome (PCOS) are almost three times more likely to be obese than those without PCOS. However, we have no specific interventions to induce weight loss so far and rely on drugs used to treat other symptoms of the syndrome or obesity in the general population. Objective The objective of this study is to compare the effectiveness of metformin, inositol, liraglutide and orlistat to induce weight loss in women with PCOS and overweight/obesity. Methods A search was conducted using the MEDLINE, EMBASE, PubMed and CENTRAL databases. Individually randomized, parallel group trials that evaluated the effects of these pharmacological treatments among adults or adolescents with PCOS and overweight/obesity, compared with a placebo or metformin group, were considered eligible. Registration number: PROSPERO CRD 42017076625. Results Twenty‐three trials reporting on 941 women were included in the network meta‐analysis. The amount of weight lost differed significantly among the drugs (in descending order): liraglutide, orlistat and metformin. Liraglutide alone, liraglutide/metformin and metformin alone significantly reduced waist circumference, but no change was found with orlistat. Data for waist‐to‐hip ratio were only available for metformin, which had no significant effect. Conclusion Liraglutide appears superior to the other drugs in reducing weight and waist circumference.
Article
The aim of the current work was to investigate the value of the long term effects of combined use of simvastatin and metformin treatment for a year versus the effects of their individual treatment on the clinical, biochemical abnormalities, and ovulation dysfunction in young single women with polycystic ovary syndrome (PCOS). It was a randomized, double-blind controlled study. Where two hundreds (n = 200) single young women with PCOS were randomized into seventy (n = 70) women using simvastatin 20 mg daily combined with metformin 500 mg three times daily considered as group A (study group), and another 2 sixty five (n = 65) women groups using simvastatin and metformin individually as a single treatment use, and considered as groups (B & C), respectively. Medications period extended for twelve months treatment period. The primary outcome measures were the changes in serum androgen levels (testosterone, androstendione, and dehydro-epiandrostenion sulfate-DHEAS), LH, FSH, LH/FSH ratio, and insulin resistance (IR), in addition to menstrual regularity, hirsutism, BMI, and W/H ratio. Spontaneous ovulation, confirmed with both trans-abdominal sonography (TAS) and luteal serum progesterone as well had been also evaluated. After 12 months’ treatment, in group A serum testosterone showed significant decline by 37%, with significant drop in LH serum level (51%) and a marked decline of the LH/FSH ratio (53%). IR showed a significant improvement in groups A and C but still relatively higher in group B. There was also a clear decrease of total cholesterol (36%), low-density lipoprotein (LDL; 48%), and triglycerides (26%), and increased high-density lipoprotein (HDL) by 24% in groups A and B. Improved menstrual regularity and decreased hirsutism, acne, ovarian volume, and BMI had been significantly noticed in the study groups A and C, although still relatively higher in group C. Spontaneous ovulation had been confirmed in group A: songoraphically (TAS), and biochemically (progesterone >10 ng) in 10 women after the first six months treatment, and 26 at the end of 12 months treatment, compared to 5 & 8 in group B, and 2 & 5 in group C, respectively. Combined simvastatin and metformin treatment showed significant improvement of PCOS clinical and ovarian dysfunction abnormalities much better than their individual treatment.
Article
Polycystic ovary syndrome (PCOS) is common in premenopausal women. The majority of women with PCOS have insulin resistance and the risk of type 2 diabetes mellitus (T2D) is higher in women with PCOS compared to controls. In non-pregnant women with PCOS, glycemic status may be assessed by oral glucose tolerance test (OGTT), fasting plasma glucose (FPG), or HbA1c. OGTT has been reckoned gold standard test for diagnosing T2D, but OGTT is rarely used for diagnostic purpose in other non-pregnant individuals at risk of T2D, apart from PCOS. OGTT has questionable reproducibility, and the high sensitivity of the 2 hour glucose value is at the expense of relatively low specificity, especially regarding impaired glucose tolerance (IGT). Furthermore, lean women with PCOS are rarely diagnosed with T2D and only few percent of normal-weight women have prediabetes. Glycemic status is necessary at diagnosis and during follow-up of PCOS, especially in women with high risk of T2D (obesity, previous gestational diabetes (GDM)). We suggest that OGTT should be used in the same situations in PCOS as in other patient groups at risk of T2D. OGTT is indicated for diagnosing GDM, however, OGTT during pregnancy may not be indicated in lean women with PCOS without other risk factors for GDM.
Article
Health-related quality of life (HRQoL) is impaired in polycystic ovary syndrome (PCOS), but the effect of treatment with metformin (M) and/or oral contraceptives (OCP) is undetermined. To assess changes in HRQoL during 12-month randomized treatment with M, OCP or M + OCP in PCOS. Ninety women with PCOS were randomized to treatment with M, OCP or M + OCP. HRQoL was evaluated by a PCOS-specific visual analog scale (PCOS-VAS) regarding 1: Facial hair, 2: Body hair, 3: Acne, 4: Irregular menses, 5: Weight and 6: PCOS in general, and Short Form 36 (SF-36). PCOS-VAS1(facial hair) improved during treatment with OCP (n = 23) compared to M (n = 19), and during M + OCP (n = 23) compared to M treatment, whereas changes in PCOS-VAS2-6 and SF-36 scores were comparable between the three medical intervention groups. Pooled data (n = 65) showed improved PCOS-VAS scores during treatment (all p < .05), but changes in PCOS-VAS were unassociated with changes in BMI or FG-scores despite significant weight-loss during treatment with M (−3.0 kg (−10.3; 0.6)) and M + OCP (−1.9 kg (−4.9; 0.1)) and decreased FG-score during M + OCP treatment (median (quartiles)). PCOS-VAS scores improved significantly and to the same extent during treatment with M, OCP or M + OCP.
Article
Introduction: Currently available combined oral contraceptives (COC) reportedly increase the risk of venous thromboembolism (VTE). We aimed to quantify this risk considering both progestogen type and estrogen dose. Materials and methods: PubMed, Embase and LIVIVO were searched for relevant publications until April 2017. Case-control and cohort studies including healthy women taking COC and assessing incident VTE as outcome were selected. Adjusted relative risks (RR) with 95% confidence intervals (CI) derived from random effects model using a generic inverse-variance approach are reported. Results: Overall, 1,359 references were identified and 17 studies were included in the meta-analysis. The pooled RR of VTE was associated with various COC, with the association depending on their respective estrogen dose and progestogen type. Compared to the reference, levonorgestrel with 30-40 μg ethinylestradiol, the overall risk of VTE was higher for all other COC. Preparations with desogestrel with 30-40 μg estrogen showed the highest relative risk (RR: 1.46; 95% CI: 1.33-1.59), while RRs for drospirenone (30-40 μg ethinylestradiol) and desogestrel (30-40/20 μg ethinylestradiol) were lower. COC containing gestodene and cyproterone with 30-40 μg estrogen showed the lowest risk (RR: 1.27; 95% CI: 1.15-1.41 and RR: 1.29; 95% CI: 1.12-1.49, respectively). Conclusions: Compared to levonorgestrel with 30-40 μg ethinylestradiol, all COC showed a significantly increased VTE risk. The association varied depending on the progestogen type and the dose of estrogen. Our results suggest that the prescription of COC with the lowest possible dose of ethinylestradiol may help to avoid VTE cases among young, healthy women.
Article
Background: Weight loss is often nonsustainable after liraglutide cessation. The present study is the first insight into the potential prevention of weight regain in obese subjects who have been withdrawn from liraglutide. We evaluated whether dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in adjunct to metformin prevents body weight regain more effectively than metformin alone in obese polycystic ovary syndrome (PCOS) previously treated with liraglutide. Methods: A 12-week prospective randomized open-label study was conducted with 24 obese women with PCOS who had been pretreated with liraglutide 3.0 mg due to antiobesity management (aged 34.3 ± 6.8 years, body mass index [BMI] 36.3 ± 5.2 kg/m(2), mean ± standard deviation). They were randomized to combined treatment (COMBO) with sitagliptin 100 mg per day (QD) and metformin (MET) 1000 mg twice daily (BID) (n = 12) or MET 1000 mg BID (n = 12). Lifestyle intervention was promoted in both groups. The primary outcome was change in anthropometric measures of obesity. Results: Women treated with MET regain 4.7 ± 2.7 kg (P = 0.002) compared with a 0.9 ± 2.5 kg in COMBO (P = 0.147). BMI increased for 1.7 ± 0.9 kg/m(2) in MET (P = 0.002) compared with 0.3 ± 0.8 kg/m(2) increase in COMBO (P = 0.136). MET group regain 4.5% ± 2.5% of body weight as opposed to 0.8% ± 2.6% in COMBO. The between-treatment differences were significant for weight change (P < 0.001), percentage of weight change (P < 0.001), and BMI change (P < 0.001). Greater ability to resist emotional eating was demonstrated in COMBO. Conclusion: Sitagliptin in adjunct to metformin prevented weight regain in obese women with PCOS previously treated with liraglutide.
Article
Purpose of review: Polycystic ovary syndrome (PCOS) is defined by hyperandrogenism, irregular menses and polycystic ovaries when other causes are excluded. The possible implication of increased morbidity in PCOS for screening and follow-up is uncertain and is reviewed in this article. Recent findings: The increased risk of type 2 diabetes and cardiovascular disease in PCOS is closely associated with BMI. Women with PCOS should be screened for the elements of the metabolic syndrome upon diagnosis. Measurement of HbA1c and the lipid accumulation product could be important tools to differentiate women with high metabolic risk. The immune function in PCOS is impaired with increased secretion of autoantibodies and increased risk of type 1 diabetes, asthma and thyroid disease. The occurrence of thyroid disease could be modified by BMI and D-vitamin status. Screening for diabetes and thyroid disease is part of routine evaluation for endocrine diseases at baseline in PCOS, whereas the necessity of prospective screening for thyroid disease awaits future studies. Especially obese women with PCOS are at an increased risk of nonalcoholic fatty liver disease, gall bladder disease and endometrial cancer. Summary: Recent data support that screening and follow-up in patients with PCOS should be stratified according to BMI.
Article
Objective Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Prospective population-based data regarding development and possible predictors of type 2 diabetes (T2D) in PCOS are limited. Design National Register-based study. Methods Patients with PCOS (PCOS Denmark and embedded cohort; PCOS OUH) and a control population with no previous diagnosis of T2D. PCOS OUH (N=1,162) included premenopausal women with PCOS and standardized clinical and biochemical examination. PCOS Denmark (N=18,477) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (N=54,680). Main outcome T2D events according to diagnosis codes and filled medicine prescriptions. Results The median (quartiles) follow up was 11.1 (6.9 - 16.0) years. The Hazard ratio (95% CI) for development of T2D in PCOS Denmark was 4.0 (3.7; 4.3) (p<0.001) and the total event rate of T2D was 8.0 per 1000 patient years in PCOS Denmark vs. 2.0 per 1000 patient years in controls (p<0.001). The median age at diagnosis of T2D was 31 (26-37) years in PCOS Denmark vs. 35 (27-44) years in controls (p<0.001). In multiple regression analyses, body mass index, HbA1c, fasting blood glucose, 2 hour blood glucose, homeostasis model assessment of insulin resistance, and triglycerides were positively associated with development of T2D, whereas higher number of births was negatively associated with development of T2D. Conclusion The event rate of T2D was higher in PCOS compared to controls and T2D was diagnosed at a younger age.
Article
Low plasma sex hormone-binding globulin (SHBG) levels are a hallmark in chronic metabolic diseases, including nonalcoholic fatty liver disease (NAFLD), which represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The functional link between altered SHBG production and NAFLD development and progression remains unclear. We investigated the effects of overexpressing human SHBG in 2 mouse models of NAFLD: a genetically induced double transgenic mouse and a diet-induced model. Remarkably, SHBG overexpression in both NAFLD models significantly reduced liver fat accumulation by reducing key lipogenic enzymes. These findings were corroborated by modulating SHBG expression and by adding exogenous SHBG in HepG2 cells, suggesting the cell autonomous nature of the mechanism. Mechanistically, exogenous SHBG treatment downregulated key lipogenic enzymes by reducing PPARγ messenger RNA and protein levels through activation of extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase pathway. Taking together, we found that SHBG modulates hepatic lipogenesis. This is of importance because reduction of SHBG plasma levels in obese and type 2 diabetic subjects could be directly associated with NAFLD development through an increase in hepatic lipogenesis. Our results point to SHBG as a therapeutic target for preventing or arresting NAFLD development.
Article
Study question: What are the respective roles of polycystic ovary syndrome (PCOS), long-term weight gain and obesity for the development of prediabetes or Type 2 diabetes mellitus (T2DM) by age 46 years? Summary answer: The risk of T2DM in women with PCOS is mainly due to overweight and obesity, although these two factors have a synergistic effect on the development of T2DM. What is known already: PCOS is associated with an increased risk of prediabetes and T2DM. However, the respective roles of PCOS per se and BMI for the development of T2DM have remained unclear. Study design, size, duration: In a prospective, general population-based follow-up birth cohort 1966 (n = 5889), postal questionnaires were sent at ages 14 (95% answered), 31 (80% answered) and 46 years (72% answered). Questions about oligoamenorrhoea and hirsutism were asked at age 31 years, and a question about PCOS diagnosis at 46 years. Clinical examination and blood sampling were performed at 31 years in 3127 women, and at 46 years in 3280 women. A 2-h oral glucose tolerance test (OGTT) was performed at 46 years of age in 2780 women. Participants/materials, setting, methods: Women reporting both oligoamenorrhoea and hirsutism at age 31 years and/or diagnosis of PCOS by 46 years were considered as women with PCOS (n = 279). Women without any symptoms at 31 years and without PCOS diagnosis by 46 years were considered as controls (n = 1577). The level of glucose metabolism was classified according to the results of the OGTT and previous information of glucose metabolism status from the national drug and hospital discharge registers. Main results and the role of chance: PCOS per se significantly increased the risk of T2DM in overweight/obese (BMI ≥ 25.0 kg/m(2)) women with PCOS when compared to overweight/obese controls (odds ratio: 2.45, 95% CI: 1.28-4.67). Normal weight women with PCOS did not present with an increased risk of prediabetes or T2DM. The increase in weight between ages 14, 31 and 46 years was significantly greater in women with PCOS developing T2DM than in women with PCOS and normal glucose tolerance, with the most significant increase occurring in early adulthood (between 14 and 31 years: median with [25%; 75% quartiles]: 27.25 kg [20.43; 34.78] versus 13.80 kg [8.55; 20.20], P < 0.001). Limitations, reasons for caution: The diagnosis of PCOS was based on self-reporting, and the questionnaire at 46 years did not distinguish between polycystic ovaries only in ultrasonography and the syndrome. Ovarian ultrasonography was not available to aid the diagnosis of PCOS. Wider implications of the findings: These results emphasize weight management already during adolescence and early adulthood to prevent the development of T2DM in women with PCOS, as the period between 14 and 31 years seems to be a crucial time-window during which the women with PCOS who are destined to develop T2DM by 46 years of age experience a dramatic weight gain. Furthermore, our results support the view that, particularly in times of limited sources of healthcare systems, OGTT screening should be targeted to overweight/obese women with PCOS rather than to all women with PCOS. Study funding/competing interests: Finnish Medical Foundation; North Ostrobothnia Regional Fund; Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE); Sigrid Juselius Foundation; Biocenter Oulu; University Hospital Oulu and University of Oulu (75617); Medical Research Center Oulu; National Institute for Health Research (UK); National Heart, Lung, and Blood Institute (grant 5R01HL087679-02) through the STAMPEED program (1RL1MH083268-01); National Institute of Health/National Institute of Mental Health (5R01MH63706:02); ENGAGE project and grant agreement HEALTH-F4-2007-201413; EU FP7 EurHEALTHAgeing-277849 European Commission and Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and Medical Research Center, Centenary Early Career Award. The authors have no conflicts of interests. Trial registration number: N/A.
Article
Objective: Subclinical hypothyroidism (SCH) is encountered in 10-25 % of women with PCOS. To date, it remains unclear whether this coexistence influences the severity of metabolic and hormonal profile of these patients. The purpose of our systematic review is to investigate this potential relation. Methods: We systematically searched Medline, Scopus, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials CENTRAL and Google Scholar databases together with reference lists from included studies. All prospective and retrospective observational cohort studies that investigated the impact of subclinical hypothyroidism on hormonal and metabolic parameters of PCOS patients were included. The methodological quality of studies was assessed with the Ottawa-Newcastle criteria. Statistical meta-analysis was performed with the RevMan 5.3 software. Results: Twelve studies were finally included in the present review which enrolled 2,341 PCOS patients. Among them 577 had subclinical hypothyroidism while the remaining 2,077 were PCOS women with normal thyroid function. The presence of SCH significantly affected HDL (MD -3.92 mg/dl 95% CI -6.56, -1.29) and triglycerides levels (26.91 mg/dl 95% CI -3.79, 50.02). HOMA-IR was also affected (MD 0.82 95% CI 0.15, 1.50). On the other hand, LDL, fasting glucose and 2-hour OGTT were not influenced. Similarly, prolactin, FSH, LH, LH/FSH ratio and sex hormone binding globulin remained unaffected. Conclusion: Subclinical hypothyroidism does not influence the hormonal profile of women with PCOS. On the other hand, it results in mild metabolic abnormalities which are not clinically important in a short-term setting.
Article
Objective: To evaluate the effect of vitamin D supplementation on patients with PCOS. Methods: We performed a literature search in database and identified all of the RCTs published before December 2015 that compared the effect of vitamin D supplementation with placebo or metformin in PCOS patients. Main results: Nine out of 463 identified studies were included, involving 502 women presenting with PCOS. Vitamin D supplementation had significant effect on the improvement of follicular development with a higher number of dominant follicles (OR, 2.34; 95% CI, 1.39 to 3.92). Differences in regular menstrual cycles were also observed when metformin plus vitamin D was compared with metformin alone (OR, 1.85; 95% CI, 1.01 to 3.39). Conclusions: Evidence from available RCTs suggests vitamin D supplementation may be beneficial for follicular development and menstrual cycle regulation in patients with PCOS. Additional high-quality RCTs are required to confirm the effectiveness of vitamin D on PCOS.