This finding may be explained by the lower levels of testosterone in women older than 35 years, which may reduce the strength of the association between the two parameters.

The data on the relationship between adiposity and total testosterone in PCOS from other studies are scarce and controversial Metformin use in PCOS is not consistently associated with improvements in menstrual regularity.

In a Cohrane review that included a meta-analysis of 38 RCT of women with PCOS, metformin therapy only marginally improved menstrual pattern In our cohort menstrual frequency increased after first year and normalized in the majority of patients in the following years.

In the month study conducted with prospective cohort, metformin was also associated with improvements in the menstrual cycle in overweight and normal weight women with PCOS Our patients in whom menstrual regularity improved after first year had less frequent bleedings at baseline when compared with those with no improvement in menstrual frequencies.

Importantly, the potential effect of aging that results in improvement of hyperandogenism as well as the well-known methodological difficulties related to RIA assays should be taken into account when interpreting the observed impact on the androgen status.

In comparison with the women in whom androgens remained unchanged or increased, women in whom androgens decreased had worst androgen profile at baseline. It is believed that metformin lowered testosterone levels by reducing hyperinsulinemia 32 , In addition, it might have a direct inhibitory effect on ovarian steroidogenesis 34 , 35 , 36 through inhibition of mitochondrial complex I Given that an androgen excess plays an important role in favoring the expansion of visceral fat and development of metabolic syndrome and T2D 37 , the improved androgen profile observed throughout long-term metformin treatment should be considered as an independent cardiometabolic risk reduction outcome in these population.

Few studies aimed to clarify the relationship between PCOS and T2D independent of obesity in longitudinal population-based cohorts.

There have been very limited studies of the natural history of glucose homeostasis in this population. In an elegant study by Legro et al.

Prospective studies investigating the impact of metformin on T2D risk specifically in women with PCOS are lacking 6. Nonetheless, considering that these women are at high risk for developing T2D 39 , 40 , it has been suggested that they will benefit from metformin therapy in case of glucose intolerance 7.

One of the longest retrospective study with 50 patients followed by a mean treatment period of In our cohort the mean fasting glucose was within normal range throughout the longitudinal follow-up.

Conversion to IGT and T2D was low, yet OGTT was not performed annually, but as recommended by national guidelines rescreened periodically at 2—3 years, meaning that this conversion risk could be underestimated. We acknowledge that our study has several limitations.

The major one is its retrospective nature. It is clear that prospective randomized design represents the gold standard, but such a study would be extremely long lasting and laborious to achieve.

Lack of randomization with placebo represents another possible bias, yet placebo arm in this group would have hardly been a realistic or possible approach. Moreover, the possible bias might be related to the process of ageing, in particular when interpreting the improvements of menstrual irregularity and hyperandrogenism as both improve by age.

Furthermore, lifestyle measures that had been promoted by the lifestyle advice might contribute to at least some of the benefits including low rates of conversion to IGT and T2DM. Another point of concern is the high rate of drop-outs and the effects that may have on the study outcome.

However, this attrition rate was similar to that from other studies on PCOS 16 , The main strength of this study is the long-term longitudinal follow-up assessing the effectiveness of treatment with metformin in real life setting that is insufficiently studied in PCOS.

Attempts were made to achieve clinical homogeneity of the included patients by reviewing the medical records of all patients that had been referred to our clinics from to All patients were managed in the single center using a standardized treatment protocol with mg metformin that had been introduced in all overweight-obese women regardless of their glycemic status unless contraindicated since , and thus any possible selection bias had been eliminated.

This offers very important and rarely available insight into the long-term longitudinal follow-up in this subset of patients that have not been, in general, characterized as candidates for metformin treatment until the latest recommendations update 7.

We conclude that, in agreement with the latest recommendations 7 , metformin should not be withheld from treatment of PCOS in overweight-obese women with normal fasting glucose and normal glucose tolerance.

We suggest that treatment decisions for metformin are based on BMI, oligomenorrhea and biochemical hyperandrogenism regardless of the glycemic status. The overweight-obese and oligomenorrheic women should be prioritized treatment candidates. The high rate of drop outs not related to intolerance and side effects could be decreased in clinical practice by discussing the realistic treatment goals and potential benefits of long-term intervention.

We encourage future designs to investigate the stabilization of BM through the years as one of the main treatment benefits of long-term treatment with metformin in overweight-obese PCOS.

The separate impact of metformin on visceral and s. fat depots is another topic that deserves further attention. The protective effect of the long-term use of metformin in reducing the risk of unopposed endometrial proliferation and endometrium cancer should also be evaluated.

The next important question is for how long metformin should be applied to reach the homeostasis that can sustain weight and glucose metabolism after metformin withdrawal.

We suggest to compare the consequences of metformin withdrawal after long-term therapy as opposed to the consequences of metformin withdrawal immediately after the maximum treatment effect is achieved, usually after the first year.

Intermittent regimens vs continuing long-term interventions with metformin represent another issue to be addressed. The heterogeneity in response to metformin represents another exciting research field. Traditional as well as nontraditional risk cardiometabolic markers including chronic inflammation, oxidative stress, homeostasis and fibrinolysis imbalance, gut microbiota dysbiosis and epigenetic alterations sympathetic nervous system dysfunction 41 should be considered as potential predictors for responders and non-responders.

Furthermore, large-scale genome wide studies are also imperative to identify the best responders. The further research needs to firstly identify and then prioritize those groups who will benefit most from being treated with metformin. The treatment goals and duration of therapy should be clearly defined, in particular, in overweight-obese women with PCOS and normal initial glucose homeostasis where its long-term use is currently more difficult to advocate.

Individually tailored approaches might lead to better adherence that would provide better insights into a long-term cost—benefit profile. Continuing follow-ups in randomized prospective trials and in real life settings would provide further information on putative long-term benefits of metformin and whether they are homogeneous across subgroups.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This research did not receive any specific grant from any funding agency in the public, commercial, or not-for profit sector.

Bates GW , Legro RS. Long-term management of polycystic ovarian syndrome PCOS. Molecular and Cellular Endocrinology 91 — Kakoly NS , Earnest A , Teede HJ , Moran LJ , Joham AE.

The impact of obesity on the incidence of Type 2 diabetes among women with polycystic ovary syndrome. Diabetes Care — Velazquez EM , Mendoza S , Hamer T , Sosa F , Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.

Metabolism: Clinical and Experimental — Tang T , Glanville J , Hayden CJ , White D , Barth JH , Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome.

A randomized, placebo-controlled, double-blind multicentre study. Human Reproduction 80 — McCartney CR , Marshall JC. CLINICAL PRACTICE.

Polycystic ovary syndrome. New England Journal of Medicine 54 — Sam S , Ehrmann DA. Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome. Diabetologia — Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.

Human Reproduction — Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism — American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome — Part 1.

Endocrine Practice — Aroda VR , Knowler WC , Crandall JP , Perreault L , Edelstein SL , Jeffries SL , Molitch ME , Pi-Sunyer X , Darwin C , Heckman-Stoddard BM , et al. Diabetes Prevention Program Research Group. Long-term effects of metformin on diabetes prevention: identification of subgroups that benefited most in the diabetes prevention program and diabetes prevention program outcomes study.

Lentferink YE , Knibbe CAJ , van der Vorst MMJ. Efficacy of metformin treatment with respect to weight reduction in children and adults with obesity: a systematic review. Drugs — Azziz R.

Introduction: determinants of polycystic ovary syndrome. Fertility and Sterility 4 — 5. Jayasena CN , Franks S.

The management of patients with polycystic ovary syndrome. Nature Reviews: Endocrinology — Tang T , Lord JM , Norman RJ , Yasmin E , Balen AH. Insulin-sensitising drugs metformin, rosiglitazone, pioglitazone, D-chiro-inositol for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

Cochrane Database of Systematic Reviews CD Hoeger KM , Kochman L , Wixom N , Craig K , Miller RK , Guzick DS. Fertility and Sterility — Naderpoor N , Shorakae S , de Courten B , Misso ML , Moran LJ , Teede HJ. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis.

Human Reproduction Update — Teede H , Tassone EC , Piltonen T , Malhotra J , Mol BW , Peña A , Witchel SF , Joham A , McAllister V , Romualdi D , et al. Clinical Endocrinology — Glueck CJ , Aregawi D , Agloria M , Winiarska M , Sieve L , Wang P.

Franks S. When should an insulin sensitizing agent be used in the treatment of polycystic ovary syndrome? Norman RJ , Davies MJ , Lord J , Moran LJ. The role of lifestyle modification in polycystic ovary syndrome. Trends in Endocrinology and Metabolism — Velázquez E , Acosta A , Mendoza SG.

Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstetrics and Gynecology — Kiddy DS , Hamilton-Fairley D , Bush A , Short F , Anyaoku V , Reed MJ , Franks S.

Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Look AHEAD Research Group , Wing RR , Bolin P , Brancati FL , Bray GA , Clark JM , Coday M , Crow RS , Curtis JM , Egan CM , et al. Cardiovascular effects of intensive lifestyle intervention in Type 2 diabetes.

New England Journal of Medicine — Glueck CJ , Dharashivkar S , Wang P , Zhu B , Gartside PS , Tracy T , Sieve L. Obesity and extreme obesity, manifest by ages 20—24 years, continuing through 32—41 years in women, should alert physicians to the diagnostic likelihood of polycystic ovary syndrome as a reversible underlying endocrinopathy.

European Journal of Obstetrics, Gynecology, and Reproductive Biology — Glueck CJ , Wang P , Fontaine R , Tracy T , Sieve-Smith L. Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome PCOS. Journal of Adolescent Health — Ollila MM , Piltonen T , Puukka K , Ruokonen A , Järvelin MR , Tapanainen JS , Franks S , Morin-Papunen L.

Weight gain and dyslipidemia in early adulthood associate with polycystic ovary syndrome: prospective cohort study. Seifarth C , Schehler B , Schneider HJ. Effectiveness of metformin on weight loss in non-diabetic individuals with obesity.

Experimental and Clinical Endocrinology and Diabetes 27 — Tosi F , Di Sarra D , Kaufman JM , Bonin C , Moretta R , Bonora E , Zanolin E , Moghetti P. Total body fat and central fat mass independently predict insulin resistance but not hyperandrogenemia in women with polycystic ovary syndrome.

The efficacy of month metformin for improving menses, hormones, and metabolic profiles in polycystic ovary syndrome. Van Anders SM , Watson NV. Menstrual cycle irregularities are associated with testosterone levels in healthy premenopausal women.

American Journal of Human Biology — Nestler JE , Jakubowicz DJ. Decreases in ovarian cytochrome Pc17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian Pc17 alpha activity and serum androgens.

Hirsch A , Hahn D , Kempná P , Hofer G , Nuoffer JM , Mullis PE , Flück CE. Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain.

Endocrinology — Mansfield R , Galea R , Brincat M , Hole D , Mason H. Metformin has direct effects on human ovarian steroidogenesis. Attia GR , Rainey WE , Carr BR.

Metformin directly inhibits androgen production in human thecal cells. Pasquali R , Oriolo C. Obesity and androgens in women. Frontiers of Hormone Research — Legro RS , Gnatuk CL , Kunselman AR , Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study.

Ehrmann DA , Barnes RB , Rosenfield RL , Cavaghan MK , Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Sharma ST , Wickham EP 3rd , Nestler JE.

Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Chiu WL , Boyle J , Vincent A , Teede H , Moran LJ. Cardiometabolic risks in polycystic ovary syndrome: non-traditional risk factors and the impact of obesity.

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Advanced Search Help. Long-term efficacy of metformin in overweight-obese PCOS: longitudinal follow-up of retrospective cohort in Endocrine Connections. Authors: Mojca Jensterle Mojca Jensterle Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Slovenia University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia Search for other papers by Mojca Jensterle in Current site Google Scholar PubMed Close.

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Simona Ferjan Simona Ferjan Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Slovenia University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia Search for other papers by Simona Ferjan in Current site Google Scholar PubMed Close.

Their ovaries contain multiple small cystic structures, usually about mm in diameter. Many women with PCOS produce higher levels of insulin to control their blood sugar level, which is called insulin resistance. Metformin is a drug used to treat insulin resistance.

These side effects can be minimized by increasing the dose of metformin slowly and allowing your body to get used to the medication. Metformin treatment of PCOS will start as a single tablet with an evening meal. After a few days, once your body has adjusted to the medication, you may add second pill daily with your morning meal and then a third pill daily with your evening meal; this is the usual dose needed for ovulation.

If you experience significant side effects, please call our office so that we may help you adjust the dose.

People with severe liver or kidney damage are at a high risk of developing a rare side effect of metformin called lactic acidosis. This means, if you suffer from kidney damage or severe liver disease, unfortunately, metformin will not be suitable for you 8.

If you have been diagnosed with PCOS, or have been experiencing symptoms that suggest you may have the condition, our experts are here to help you get the answers you deserve.

Our at-home PCOS hormone tests have been developed to help you understand or reach a diagnosis, and our experts can guide you through your next steps to manage your symptoms and make plans for the future. Metformin and PCOS: A treatment right for you?

Home Conditions Fertility and Treatment Metformin and PCOS: A treatment right for you? Check your fertility. PCOS pcos treatment. Hertility Posts that Hertility has created for the Hertility Blog. Prev Post Structural Infertility: What Are the Causes?

Next Post Alcohol and Hormones: What is the link? Follow Us. Popular Category. LATEST POSTS. There is no such important impact of higher BMI in attenuating the response to clomiphene therapy 6. It is feasible that the additional insulin resistance affecting women with obesity, on top of the insulin resistance that is a fundamental part of the pathophysiology of PCOS, may be too much for metformin recognized as an insulin sensitizer of only moderate potency compared to, say, the glitazones to overcome.

It is logical to use monotherapy as first line treatment with either metformin alone or clomiphene alone. In spite of many RCTs examining the potential benefit of combined therapy, no clear benefit has been found in RCTs of dual therapy over monotherapy 4.

The live birth rate was not improved amongst women in a meta-analysis who were randomised to clomiphene plus metformin versus clomiphene alone Peto OR 1. Although the clinical pregnancy rate was significantly higher in women receiving dual therapy versus clomiphene alone Peto OR 1.

Whilst there is emerging evidence that letrozole may be superior to clomiphene in terms of live births 26 , there are few RCT data comparing metformin with aromatase inhibitors.

There are no consistent data comparing effectiveness of metformin versus either laparoscopic ovarian drilling or gonadotrophin injection therapy for women with anovulatory PCOS.

Logically metformin should be considered prior to laparoscopic ovarian drilling or gonadotrophin injection therapy and whether synchronous administration of metformin improves outcomes from these treatments is meritworthy of further research.

A systematic review of five RCTs of a total of randomised women with PCOS found no evidence that metformin treatment before or during assisted reproductive technique ART cycles could improve live birth or clinical pregnancy rates The Peto OR live birth rate 3 RCTs was 0.

The risk of OHSS in women with PCOS and undergoing IVF or ICSI cycles was reduced with metformin pooled OR 0. Evidence is emerging that abruptly stopping metformin once pregnancy is diagnosed might predispose to pregnancy loss It has long been debated whether PCOS is an independent risk factor in its own right that contributes to risk of recurrent pregnancy loss, or whether it is purely the association of PCOS with obesity that sees recurrent miscarriage over-represented in women with PCOS, with most authorities now favouring the latter theory of obesity as the cause for this association.

The logical extension of the use of metformin beyond reproductive indications was that for the other symptoms of PCOS. A systematic review of six RCTs, that assessed hyperandrogenic symptoms and other non-fertility symptoms, compared metformin versus the combined oral contraceptive pill OCP participants and two RCTs compared OCP combined with metformin versus OCP alone 70 participants Limited data demonstrated no evidence of difference in effect between metformin and the OCP on hirsutism and acne Metformin was less effective than OCP in reducing serum androgen levels [total testosterone: weighted mean difference WMD 0.

Metformin was less effective than OCP in improving menstrual pattern Peto OR 0. Metformin resulted in a higher incidence of gastrointestinal Peto OR 7.

Lifestyle intervention, through dietary improvement and exercise yielding weight loss, remains the cornerstone of effective long term health improvement for women with PCOS who are overweight or obese Metformin was more effective than OCP in reducing fasting insulin WMD —3.

There was either insufficient or no data on the relative efficacy of metformin or OCP alone or in combination for preventing the development of diabetes, cardiovascular disease, or endometrial cancer Nonetheless if metformin restores cyclicity and ovulation for women with PCOS who would otherwise be anovulatory, this would be expected to have a protective effect from the increased risk of endometrial cancer amongst these women, and may be a very suitable treatment for women who are unable to use OCP.

The absence of evidence of superiority of either agent, metformin versus clomiphene, from available RCT data combined with the other advantages of metformin over clomiphene, means that metformin should be seriously considered as the most suitable first line treatment for anovulatory infertility for non-obese women with PCOS.

View Topic. Font Size Small Normal Large. Metformin for treatment of the polycystic ovary syndrome. Formulary drug information for this topic.

No drug references linked in this topic. Find in topic Formulary Print Share. View in. Language Chinese English. Authors: Robert L Barbieri, MD David A Ehrmann, MD Section Editors: Peter J Snyder, MD William F Crowley, Jr, MD Deputy Editor: Kathryn A Martin, MD Literature review current through: Jan This topic last updated: Dec 01, When fully expressed, the manifestations include irregular menstrual cycles, hirsutism, obesity, and a constellation of cardiometabolic disturbances.

It is a common endocrinopathy, occurring in 5 to 7 percent of reproductive age women [ ]. OVERVIEW Interest in the use of metformin, an insulin-lowering drug, in PCOS increased when it was appreciated that insulin resistance played an important role in the pathophysiology of the disorder.