Combined oral contraceptive use and obesity in women with polycystic ovary syndrome. A meta-analysis of randomized clinical trials.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogenous endocrine condition and combined oral contraceptives (COCs) have been demonstrated to be the first-line treatment to women who do not intend to become pregnant. The combination of COCs and PCOS may or may not amplify the risks of cardiovascular events. OBJECTIVE: To investigate whether surrogates for obesity may be influenced by the use of COCs containing different formulations in women with PCOS. METHOD: From January 2024 a literature search was conducted in Google Scholar and Pubmed databases using PCOS, COC, and obesity terms. Hand search of randomized clinical trials in the references of obtained manuscripts was also performed. After the exclusion of reviews and articles that did not fulfill eligibility criteria, compared the results obtained before and after the use of COCs in 13 randomized clinical trials (RCTs). Random-effects model was used to estimate the standardized mean differences (SMD) and standard errors (SE). Risk of bias was examined using the Rob2 tool. RESULT: Thirteen heterogeneous RCTs reported no difference in waist circumference with the use of different COC formulations (p = 0.714). On the contrary, body fat mass increased with the use of pill (p = 0.013). Waist triglyceride index and lipid accumulation product tended to be higher after the use of COCs (p = 0.073 and p = 0.064, respectively). CONCLUSION: Combined oral contraceptives with different formulations might increase fat mass accumulation in women with PCOS. Lipids may also be increased in PCOS users. Because some concerns about the quality and heterogeneity identified in various RCTs, caution should be taken before a definitive conclusion regarding the use of COCs and obesity.

Effects of vitamin D supplementation on oxidative stress biomarkers of Iranian women with polycystic ovary syndrome: a meta-analysis study.

Objective: To identify the impact of redox imbalance on the clinical evolution of patients with polycystic ovary syndrome and carry out a qualitative and quantitative projection of the benefits of vitamin D supplementation. Data sources: Combinations of the keywords polycystic ovary syndrome, vitamin D, oxidative stress, reactive oxygen species, antioxidant, and free radicals were used in PubMed, Cochrane Library, LILACS, EMBASE, and Web of Science databases. The last search was conducted on August 22, 2023.Selection of studies: Based on the inclusion and exclusion criteria, studies were selected considering a low risk of bias, published in the last 5 years in English, which investigated the effects of vitamin D supplementation in women with PCOS, focusing on oxidative stress markers. Of the 136 articles retrieved, 6 intervention studies (445 women) were included. Data collection: The risk of bias in included studies was assessed using the Jadad scale, and analysis and visualization of continuous data were performed using Review Manager 5.4.1, summarized as standardized mean differences (SMD) with confidence intervals (CI) of 95%. Data synthesis: Vitamin D effectively reduced malondialdehyde (P=0.002) and total testosterone (P=0.0004) levels and increased total antioxidant capacity levels (P=0.01). Although possible improvements in the modified Ferriman-Gallwey hirsutism score, levels of sex hormone-binding globulin, and free androgen index were identified and the results were not statistically significant. Conclusion: Vitamin D is a promising alternative for the treatment of PCOS with a positive influence on the oxidative, metabolic, and endocrine disorders of this syndrome.

Effects of melatonin and metformin on the ovaries of rats with polycystic ovary syndrome.

OBJECTIVE: To study the combined and isolated effects of melatonin and metformin in the ovarian tissue of rats with PCOS. DESIGN: Experimental study using a rat model of PCOS induced by continuous light exposure. INTERVENTION(S): Forty adult female rats were divided into 5 groups: physiological estrus phase (Sham); permanente estrus with PCOS induced by continuous lighting exposure for 60 consecutive days (control); with PCOS treated with melatonin; with PCOS treated with metformin; with PCOS treated with melatonin + metformin. After 60 days of treatments, all rats were killed, and ovaries were collected and processed for paraffin-embedding. Formalin-fixed paraffin-embedded sections were stained with hematoxylin and eosin or subjected to immunohistochemistry for proliferation (Ki-67) and apoptosis (cleaved caspase 3) detection markers. SETTING: Federal University of São Paulo, Brazil. ANIMALS: Forty adult female Wistar rats (Rattus norvegicus albinus). MAIN OUTCOME MEASURE(S): Number of corpus luteum and ovarian cysts, number of ovarian follicles (primary and antral follicles), number of interstitial cells, percentage of ovarian follicles (primary and antral follicles), and of interstitial cells immunostained to cleaved caspase-3 and Ki-67. RESULTS: Absence of corpus luteum, a higher number of cysts, and increased nuclear volume and area of interstitial cells, along with a decrease in primary and antral follicle numbers, were noticed in the control group compared with the Sham group. Melatonin and metformin treatments attenuated these effects, although the combined treatment did not mitigate the increased number of cysts and ovaries induced by PCOS. An increase in theca interna cell apoptosis was observed in the control group, whereas melatonina and metformin treatments reduced it significantly. A higher percentage of caspase-3-immunostained granulosa cells was noted in the Sham and all treated groups compared with the control group; no aditive effects on ovarian cell apoptosis were observed in the combined treatment. The percentage of Ki-67- immunostained granulosa cells was significantly higher in the control group compared with the Sham group. However, the combined treatment, not melatonin and metformin alone, mitigated this effect. A higher percentage of Ki-67-immunostained interstitial cells was observed in all treated groups compared with the Sham and control groups, whereas no additive effects in that immunoreactivity were observed in the combined treatment. CONCLUSIONS: Melatonin and metformin may improve ovarian function in rats with PCOS. The combined melatonin and metformin treatment is more effective in attenuating excessive granulosa cell proliferation, but it is not more effective in improving ovarian function than these drugs applied alone in rats with PCOS.

Effectiveness of metformin to pregnant women with PCOS to reduce spontaneous abortion and gestational diabetes mellitus: a protocol for an overview of reviews.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a globally prevalent endocrinological disorder and has been associated with poor pregnancy outcomes, including a higher rate of gestational diabetes and miscarriage. Metformin is among the drugs investigated to improve the prognosis of pregnant women with PCOS. OBJECTIVE: To conduct an overview of systematic reviews examining the effects of metformin versus placebo or no intervention throughout pregnancy among pregnant women with a preconception PCOS diagnosis to reduce the incidence of miscarriage and gestational diabetes. METHODS AND ANALYSIS: We will perform an overview of systematic reviews by searching Embase, PubMed, Virtual Health Library, Cochrane Central Register of Controlled Trials, Trip Database, Scopus, Web of Science and Cumulative Index to Nursing and Allied Health Literature from inception to 17 August 2023. Language, publication status and year indexed or published filters will not be applied. Two reviewers will independently screen and select papers, assess their quality, evaluate their risk of bias and collect the data. The included reviews will be summarised narratively. The quality and risk of bias of the systematic review and meta-analysis studies included will be assessed using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews, Second Version) and ROBIS (Risk of Bias in Systematic Reviews), respectively. ETHICS AND DISSEMINATION: This overview of reviews will analyse data from systematic reviews on the use of metformin for prepregnancy diagnosis of PCOS to reduce adverse outcomes. As there will be no primary data collection, a formal ethical analysis is unnecessary. The study outcomes will be submitted to a peer-reviewed journal and presented at conferences. PROSPERO REGISTRATION NUMBER: CRD42023441488.

Empty follicle syndrome following GnRH agonist stimulation, in a patient with PCOS treated with HCG rescue protocol, resulting in 3PN zygote formation: a case report.

Empty follicle syndrome is a rare condition characterized by failure to retrieve oocytes despite repeated careful aspiration of mature precursor follicles during controlled ovarian stimulation. This report presents a case of empty follicle syndrome in a patient with polycystic ovary syndrome using a gonadotropin-releasing hormone agonist as a trigger for final oocyte maturation. No oocytes were retrieved from the right ovary and the procedure was discontinued. The patient was administered an injection with 10,000 units of HCG and 3 oocytes were obtained after 24 hours. All oocytes were mature (MII); fertilization was performed with sperm from the patient's husband resulting in 3PN zygotes. The formation of 3PN zygotes from ICSI might be due to oocyte cytoplasmic disorders caused by long-term exposure to gonadotropins and increased duration of stimulation. Although our patient had false empty follicle syndrome and the hCG rescue protocol led to the retrieval of oocytes, the oocytes were not of good quality. As previously described, empty follicle syndrome is not a predictor of success in subsequent cycles. Our patient's next cycle was uneventful.

Potassium levels in women with polycystic ovary syndrome using spironolactone for long-term.

OBJECTIVE: Spironolactone (SPL) has been used to manage hyperandrogenic manifestations in women with polycystic ovary syndrome (PCOS), but data on the risk of hyperkalemia in this population are scarce. The aim of this study was to evaluate the incidence of hyperkalemia in women with PCOS using SPL in the long term. DESIGN: Single-centre retrospective study. PATIENTS: Inclusion and analysis of 98 treatment periods in 78 women with PCOS (20 of whom were duplicates, returning after treatment interruption for a mean of 38 months) who received SPL for a minimum of 12 months and had at least three measurements of potassium levels over time. MEASUREMENTS: Clinical and hormonal profiles before and during SPL treatment. RESULTS: Mean age was 29.1 (SD: 9.6) years, and body mass index was 32.2 (SD: 8.1) kg/m². Nine patients had diabetes, and 22 had prediabetes. SPL was used in combination with combined oral contraceptive pills in 55 participants and progestin-only pills/long-acting reversible contraception in 28; metformin was added in 35, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in 15. Median SPL dose was 100 (range: 50-150) mg. A total of 327 serum potassium measurements were obtained (84 pre-exposure and 243 postexposure). Four potassium measurements were above the reference range before exposure and 19 during exposure. All potassium measurements above the reference range during follow-up were classified as mild hyperkalemia (5.1-5.5 mEq/L). CONCLUSIONS: The present findings suggest that women with PCOS, without kidney or heart disease, using SPL combined with hormonal contraception for managing clinical hyperandrogenism have a low incidence of hyperkalemia and well-tolerated minor adverse effects.

Anti-Müllerian Hormone levels after metformin treatment in polycystic ovary syndrome: A systematic review and meta-analysis.

This systematic review and meta-analysis aim to evaluate whether treatment with metformin would reduce Anti-Müllerian Hormone levels in patients with polycystic ovary syndrome. A search was performed in Medline, Embase, Web of Science, and Cochrane Library databases and grey literature (Google Scholar). The following keywords were used in the search strategy: "Polycystic Ovary Syndrome", "Anti-Mullerian Hormone", "Metformin". The search was limited to human studies, with no language restriction. 328 studies were found, 45 studies were selected for full-text reading and 16 of those studies, six randomized controlled trial and 10 non-randomized studies were included. The synthesis of randomized controlled trials, metformin showed a reduction in serum levels of Anti-Müllerian Hormone compared to control groups (SMD - 0.53, 95 %CI - 0.84 to - 0.22, p < 0.001, I2 = 0 %, four studies, 171 participants, high quality of evidence). Six non-randomized studies evaluated data before and after the metformin intervention. The synthesis showed that using metformin reduced serum Anti-Müllerian Hormone values (SMD - 0.79, 95 %CI - 1.03 to - 0.56, p < 0.001, I2 = 0 %, six studies, 299 participants, low quality of evidence). Metformin administration in women with polycystic ovary syndrome is associated significantly with reduced Anti-Müllerian Hormone serum levels.

Adding a ketogenic dietary intervention to IVF treatment in patients with polycystic ovary syndrome improves implantation and pregnancy.

Patients with polycystic ovary syndrome (PCOS) on a high-carbohydrate diet intrinsically suffer from exacerbated glucotoxicity, insulin resistance (IR), and infertility. Lowering the carbohydrate content has improved fertility in patients with IR and PCOS; however, the effects of a well-controlled ketogenic diet on IR and fertility in PCOS patients undergoing in vitro fertilization (IVF) have not been reported. Twelve PCOS patients with a previous failed IVF cycle and positive for IR (HOMA1-IR>1.96) were retrospectively evaluated. Patients followed a ketogenic diet (50 g of total carbohydrates/1800 calories/day). Ketosis was considered when urinary concentrations were > 40 mg/dL. Once ketosis was achieved, and IR diminished, patients underwent another IVF cycle. The nutritional intervention lasted for 14 ± 11 weeks. Carbohydrate consumption decreased from 208 ± 50.5 g/day to 41.71 ± 10.1 g/day, which resulted in significant weight loss (-7.9 ± 1.1 kg). Urine ketones appeared in most patients within 13.4 ± 8.1 days. In addition, there was a decrease in fasting glucose (-11.4 ± 3.5 mg/dl), triglycerides (-43.8 ± 11.6 mg/dl), fasting insulin (-11.6 ± 3.7 mIU/mL), and HOMA-IR (-3.28 ± 1.27). All patients underwent ovarian stimulation, and compared to the previous cycle, there was no difference in oocyte number, fertilization rate, and viable embryos produced. However, there was a significant improvement in the implantation (83.3 vs. 8.3 %), clinical pregnancy (66.7 vs. 0 %), and ongoing pregnancy/live birth rates (66.7 vs. 0 %). Here, restriction in carbohydrate consumption in PCOS patients induced ketosis, improved key metabolic parameters, and decreased IR. Even though this did not affect oocyte or embryo quality or quantity, the subsequent IVF cycle significantly improved embryo implantation and pregnancy rates.

The Effect of Metformin and Carbohydrate-Controlled Diet on DNA Methylation and Gene Expression in the Endometrium of Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine disease associated with infertility and metabolic disorders in reproductive-aged women. In this study, we evaluated the expression of eight genes related to endometrial function and their DNA methylation levels in the endometrium of PCOS patients and women without the disease (control group). In addition, eight of the PCOS patients underwent intervention with metformin (1500 mg/day) and a carbohydrate-controlled diet (type and quantity) for three months. Clinical and metabolic parameters were determined, and RT-qPCR and MeDIP-qPCR were used to evaluate gene expression and DNA methylation levels, respectively. Decreased expression levels of HOXA10, GAB1, and SLC2A4 genes and increased DNA methylation levels of the HOXA10 promoter were found in the endometrium of PCOS patients compared to controls. After metformin and nutritional intervention, some metabolic and clinical variables improved in PCOS patients. This intervention was associated with increased expression of HOXA10, ESR1, GAB1, and SLC2A4 genes and reduced DNA methylation levels of the HOXA10 promoter in the endometrium of PCOS women. Our preliminary findings suggest that metformin and a carbohydrate-controlled diet improve endometrial function in PCOS patients, partly by modulating DNA methylation of the HOXA10 gene promoter and the expression of genes implicated in endometrial receptivity and insulin signaling.

Influence of metformin on hyperandrogenism in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized clinical trials.

PURPOSE: To summarize the effects of metformin treatment on markers of hyperandrogenism in patients diagnosed with polycystic ovary syndrome (PCOS). METHODS: A systematic review, with meta-analysis, of randomized placebo-controlled clinical trials that evaluated the effects of metformin treatment in adult patients with PCOS on the levels of hyperandrogenism markers was conducted. The literature search, data extraction, risk of bias, and the assessment of certainty of evidence were performed independently by two reviewers using a structured form. The results were combined by applying the random effect, and the effect measure presented as a standardized mean difference (SMD). Significant values were considered as p < 0.05 with 95% CI. Furthermore, sensitivity analyses were performed in order to explore possible heterogeneity between studies. RESULTS: Were included 18 studies in the quantitative evaluation and 17 studies (23 reports) in the quantitative evaluation. A significant reduction in total testosterone levels was seen in the metformin-treated group when compared to the control group after combining the results by the sensitivity analysis [SMD: - 0.46 (95% CI: - 0.89 to - 0.02)]. Therefore, FAI values were also regulated by metformin treatment. CONCLUSION: We showed that metformin proved to be effective in reducing total testosterone levels, and the same was observed for free androgen index (FAI) values-a measure influenced by testosterone levels. The protocol of this study was registered at Prospero (CRD42021235761).

Histological and molecular evaluation of Mentha arvensis extract on a polycystic ovary syndrome rat model.

OBJECTIVE: This study aimed to investigate the impact of Mentha arvensis on a rat model of polycystic ovary syndrome (PCOS). METHODS: The PCOS rat model was made by the daily subcutaneous injection of testosterone enanthate (250mg/kg) for 21 days. Thirty rats were divided into five groups, including a healthy control group and four PCOS groups treated with various concentrations of hydroalcoholic extract of Mentha arvensis (0, 50, 100 and 200mg/kg). LH and FSH were measured in the blood. The ovaries were used for histological investigation, Cyp17 and Ptgs2 genes expression and total antioxidant capacity. RESULTS: Our results indicated that the level of LH and FSH hormones in treated PCOS rats with various concentrations of M. arvensis were reduced in comparison with the untreated PCOS group (p>0.01). Mentha arvensis in the highest concentration (200mg/kg) decreased the number of cysts in this group in comparison with the untreated PCOS group (p<0.01). The expression of Cyp17 and Ptgs2 genes in the treated group with the highest concentration of hydroalcoholic extract were decreased in comparison with the untreated PCOS group (p<0.05). Moreover, the antioxidant capacity in the rats receiving Mentha arvensis hydroalcoholic extract was significantly increased in comparison with that from the untreated PCOS rats (p<0.05). CONCLUSIONS: For the first time, Mentha arvensis hydroalcoholic extract proved to reduce some polycystic ovary syndrome symptoms. In the present experiment, a dose of 200mg/kg of Mentha arvensis hydroalcoholic extract was regarded as the most efficient dose.

Polycystic ovary syndrome and the new antiepileptic drugs: A systematic review.

OBJECTIVE: To evaluate the presence of polycystic ovary syndrome (PCOS) in women of reproductive age with the use of antiepileptic drugs. METHODS: A systematic literature review of observational analytical studies (cohort, cross-sectional and case-control), from January 1966 to January 2021 on PCOS in women of reproductive age with the use of the antiepileptics. The search covered the Cochrane, MEDLINE, Embase and LILACS databases. INCLUSION CRITERIA: Studies reporting the frequency of PCOS with the antiepileptic drugs in women of reproductive age. EXCLUSION CRITERIA: studies that did not have categorically relevant measurements, those published as abstracts only, and studies of investigational treatment. Data extraction was performed based on the PECOT strategy, considering the method of intervention, methodological quality, and presence of PCOS with the antiepileptic drugs. RESULTS: A total of 2043 references were obtained from which 22 articles were selected by title and abstract. Four articles met the inclusion criteria. No articles were found describing the risk of PCOS upon exposure to levetiracetam, felbamate, gabapentin, lacosamide, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or zonisamide. Only articles related to oxcarbazepine and lamotrigine were found, in which the frequency of PCOS was like that found in women without epilepsy. CONCLUSIONS: The anticonvulsants are probably safer, but the risk of developing PCOS associated with the antiepileptics cannot be established, since there are insufficient studies.

Vitamin E supplementation improves testosterone, glucose- and lipid-related metabolism in women with polycystic ovary syndrome: a meta-analysis of randomized clinical trials.

AIM: This systematic review and meta-analysis assessed the effect of vitamin E supplementation on testosterone, glucose, lipid profile, pregnancy rate, hirsutism, and body mass index (BMI) in women with polycystic ovary syndrome (PCOS). METHODS: A multi-database search was performed from inception to January 2022 for randomized controlled trials (RCTs) reporting the effects of vitamin E supplementation with or without another nutritional supplement on women with PCOS. A random-effects model was used to obtain mean differences (MDs) and its 95% confidence intervals (95%CI). Evidence certainty was assessed with GRADE methodology. RESULTS: We meta-analyzed eight RCTs reporting vitamin E supplementation alone or combined with other individual substances like omega-3, vitamin D3, or magnesium oxide in adult women ≤40 years old with PCOS. Vitamin E supplementation reduced fasting glucose (MD: -1.92 mg/dL, 95%CI: -3.80 to -0.05), fasting insulin (MD: -2.24 µIU/mL, 95%CI: -3.34 to -1.14), HOMA-IR (MD: -0.42, 95%CI: -0.65 to -0.19), total cholesterol (MD: -18.12 mg/dL, 95%CI: -34.37 to -1.86), LDL-cholesterol (MD: -15.92 mg/dL, 95%CI: -29.93 to -1.90), triglycerides (MD: -20.95 mg/dL, 95%CI: -37.31 to -4.58), total testosterone (MD: -0.42 ng/mL, 95%CI: -0.55 to -0.29), and increased sex hormone-binding globulin (MD: 7.44 nmol/L, 95%CI: 2.68 to 12.20). However, it had no impact on female sex hormones, HDL-cholesterol, BMI, and hirsutism. Two RCTs assessed pregnancy and implantation rates with inconsistent results. The certainty of the evidence was very low to moderate. CONCLUSION: Vitamin E supplementation improves glucose, lipid, and androgenic-related biomarkers in women with PCOS.

Polycystic Ovary Syndrome in Adolescence: Challenges in Diagnosis and Management.

Diagnosing polycystic ovary syndrome (PCOS) during adolescence is challenging since normal pubertal development overlap typical features of this syndrome. The authors aim to summarize the existing evidence concerning PCOS in adolescence, particularly its diagnostic criteria and therapeutic options. A search throughout medical databases such as PubMed and MedScape was performed. Diagnostic criteria include irregular menstrual cycles according to time postmenarche and evidence of clinical hyperandrogenism and/or biochemical hyperandrogenism, provided other causes have been excluded. Polycystic ovarian morphology ought not to be used as a diagnostic criterion. Treatment should target manifestations and/or comorbidities, even in the absence of a definite diagnosis. Lifestyle interventions are the first-line treatment. Combined oral contraceptives, metformin or antiandrogens may also be considered as adjuvants. Screening for PCOS in adolescence is crucial as it allows an early intervention on the symptoms and comorbidities presented leading to better long-term reproductive and metabolic outcomes.

Diagnosticar a síndrome do ovário policístico (SOP) durante a adolescência é um desafio, uma vez que o desenvolvimento puberal normal se sobrepõe às características típicas desta síndrome. Os autores têm por objetivo resumir as evidências existentes sobre a SOP na adolescência, particularmente seus critérios diagnósticos e opções terapêuticas. Uma pesquisa em bases de dados médicas como PubMed e MedScape foi realizada. Os critérios de diagnóstico incluem ciclos menstruais irregulares de acordo com o tempo pós-menarca e evidência de hiperandrogenismo clínico e/ou hiperandrogenismo bioquímico, após exclusão de outras causas. A morfologia policística dos ovários não deve ser usada como um critério diagnóstico. O tratamento deve ser direcionado às manifestações e/ou comorbilidades, mesmo na ausência de um diagnóstico definitivo. As intervenções no estilo de vida são o tratamento de primeira linha. Contraceptivos orais combinados, metformina ou antiandrogênios também podem ser considerados como adjuvantes. O rastreamento da SOP na adolescência é fundamental, pois permite uma intervenção precoce ao nível dos sintomas e comorbilidades presentes levando a melhores resultados reprodutivos e metabólicos a longo prazo.

The effect of pomegranate seed oil on human health, especially epidemiology of polycystic ovary syndrome; a systematic review.

Polycystic ovary syndrome is the most common endocrine disorder in women. Today, medicinal plants have been considered by women, especially in the reproductive and pregnancy ages. Multiple drug treatments and the length of the treatment period often lead to incomplete treatment by patients. Therefore, due to the side effects of chemical drugs, this study was conducted to assess investigate the effect of pomegranate seed oil on polycystic ovary syndrome. The prevalence of polycystic ovary syndrome is increasing by 15 to 20% and clinically includes oligomenorrhea or amenorrhea, hirsutism, and often infertility. Databases such as Cochran library, Medline, PubMed, SID, and Science Direct were used to access the related articles. To collect the required information, first, the articles that had one of the keywords of medicinal plants, polycystic ovary syndrome, plant, pomegranate extract, and menstrual irregularities in their text were searched in databases. All studies from 1985 to 2021 are included in the study. Conjugated linolenic acid (CLN) is a group of geometric and positional isomers of linolenic acid in which double bonds are conjugated. CLN has been reported to have a very strong cytotoxic effect on tissue tumor cells in the body, preventing cancer, reducing the accumulation of triacylglycerol in the liver, polycystic ovary syndrome, and LDL cholesterol in the blood. So far, seven CLN isomers have been identified, including ponic acid in pomegranate seed oil. Conjugated linoleic acid (CLA) is a group of situational and geometric isomers of linoleic acid in which double bonds are conjugated. The positive effects of the two main CLA isomers (cis-9, trans-11, and trans-10, cis-12) include inhibiting the growth of cancer, reducing the risk of atherosclerosis, and reducing body fat.

Omega-3 supplementation in the treatment of polycystic ovary syndrome (PCOS) - a review of clinical trials and cohort.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women associated with cardiovascular disease and obesity. The possible benefits of omega-3 supplementation in this syndrome have been discussed much. This study is aimed to verify, based on the scientific data published, if there are any benefits in the omega-3 supplementation in the treatment of PCOS and to indicate its possible dosages for the treatment of polycystic ovary. The work consists of a systematic review of clinical trials and cohort of the MEDLINE/PubMed database from 2009 to October 2019. All studies that analyzed the omega-3 supplementation in women with PCOS were included. Cross-sectional studies, review articles, systematic reviews, meta-analysis, duplicates, studies in animals or cell culture, studies with omega-3 supplementation via food or associated with other supplementations were not included, except those involving vitamin E. In total, 21 articles were selected. Despite the heterogeneity of the studies selected, indirect benefits were observed mainly regarding the glycemic profile, such as insulin resistance reduction, lipid profile modulation (i.e. decrease in total cholesterol, triglycerides, and elevation of high-density lipoprotein), and the regulation of the androgenic profile. As for the anthropometric profile, the studies were scarce and most of them had no significant meaning. Regarding the antioxidant profile and inflammatory biomarkers, the findings differ among studies, but promising results were observed with different doses over 12 weeks of use, such as C-reactive protein (CRP) reduction. Thus, omega-3 fatty acids promote indirect benefits in the treating of women with PCOS. However, to reveal well-defined standards for dosage and supplementation time, further studies are needed.

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

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

Respuesta a metformina en el síndrome de ovario poliquístico (SOP): rol de las variantes genéticas / Response to metformin in polycystic ovary syndrome (PCOS): role of genetic variants

La metformina es un hipoglicemiante ampliamente utilizado en el tratamiento de mujeres con síndrome de ovario poliquístico (SOP) por su acción como sensibilizante a la insulina, demostrando tener múltiples efectos favorables en parámetros clínicos y bioquímicos. Especial interés ha causado la variabilidad interindividual en el tratamiento con metformina, que se manifiesta con una respuesta subóptima en diversos grados o con la presencia de efectos adversos, principalmente gastrointestinales. Hasta ahora, pocos estudios han caracterizado este fenómeno en el SOP, así como los mecanismos que le subyacen. Se ha propuesto que variantes de genes envueltos en el transporte y acción de metformina podrían contribuir a la heterogeneidad de su respuesta. En este sentido, se han identificado polimorfismos de nucleótidos únicos (SNPs) en los transportadores de cationes orgánicos, en las proteínas de extrusión de múltiples fármacos y toxinas, y en proteínas quinasas; cuyas principales acciones son a nivel intestinal, hepático y renal, afectando la absorción, distribución y excreción de metformina, probablemente por modificaciones en su farmacocinética. Hasta ahora los escasos estudios disponibles en el SOP han identificado SNPs que estarían afectando la eficacia del tratamiento, sin embargo, no se ha profundizado en los efectos adversos asociados a las variantes genéticas. Es evidente que dichas variantes tienen relevancia clínica y que debieran ser consideradas al diseñar un tratamiento farmacológico, para optimizar su efectividad y minimizar reacciones adversas. El objetivo de este artículo es revisar la información sobre las variantes genéticas asociadas a la variabilidad en la respuesta del tratamiento con metformina en el SOP.

Metformin is a hypoglycemic agent widely used in the treatment of women with Polycystic Ovary Syndrome (PCOS) due to its action as an insulin sensitizer and its multiple favorable effects on clinical and biochemical parameters. There is great concern regarding the inter-individual variability in the response to metformin treatment, which may manifest as a suboptimal effect to varying degrees or by the presence of adverse effects, mainly gastrointestinal. Until now, scarce studies have characterized this phenomenon in PCOS, as well as the mechanisms that underlie it. It has been proposed that genetic variants involved in metformin transport and action could contribute to the heterogeneity of its response. In this sense, single nucleotide polymorphisms (SNPs) have been identified in organic cation transporters, in multidrug and toxin extrusion proteins, and in protein kinases; whose main actions are at the intestinal, hepatic and renal levels, affecting the absorption, distribution and excretion of metformin, probably due to modifications in the pharmacokinetics of the drug. Until now, the few studies available on PCOS have identified SNPs that may be affecting the efficacy of the treatment. However, the adverse effects associated with genetic variants have not been studied in depth. These variants may have clinical relevance and should be considered when designing a pharmacological treatment, to optimize its effectiveness and minimize adverse reactions. The objective of this article is to review the information on genetic variants associated with variability in the response to metformin treatment in PCOS.

A multicenter clinical study with myo-inositol and alpha-lactalbumin in Mexican and Italian PCOS patients.

OBJECTIVE: This open-label non-randomized clinical study aimed at evaluating the effects of myo-inositol plus alpha-lactalbumin in two groups of PCOS women, treated in Mexico and Italy. Alpha-lactalbumin was used being effective in increasing myo-inositol intestinal absorption. This effect is very useful in greatly reducing the therapeutic failure of myo-inositol in some patients (inositol resistant subjects). PATIENTS AND METHODS: The study involved 34 normal weight or overweight patients (14 in Mexico and 20 in Italy), aged 18 to 40 years, with anovulation and infertility > 1 year and insulin resistance diagnosed by HOMA-Index. Patients were administered orally with 2 g myo-inositol, 50 mg alpha-lactalbumin, and 200 µg of folic acid twice a day for 6 months. Controls were the same patients at t0 (baseline). The primary outcome was HOMA-index decrease after 3 and 6 months of treatment. Other parameters monitored were BMI, progesterone, LH, FSH, total testosterone, free testosterone, androstenedione, total cholesterol, HDL, LDL, triglycerides. RESULTS: Recovery was general, and its relevance was higher when the starting point was further away from the normal range. The most important results were obtained with insulin, HOMA-index, LH, and androstenedione. No significant adverse effects were detected in both groups of patients. CONCLUSIONS: This clinical trial demonstrated for the first time that myo-inositol and alpha-lactalbumin improve important parameters in PCOS patients characterized by different metabolic profiles.