Insulin resistance is a prominent feature of polycystic ovarian syndrome (PCOS), and women with the disorder are at increased risk for the development of other diseases that have been linked to insulin resistance-namely, type 2 diabetes and cardiovascular disease. This association between insulin resistance and PCOS must guide the chronic management of the disorder, and accumulating evidence suggests that administration of insulin-sensitizing drugs to individuals at high risk for type 2 diabetes decreases the rate of conversion to overt disease. In contrast, limited evidence exists to suggest that oral contraceptive pills-the currently standard therapy for PCOS-may actually decrease insulin sensitivity and induce impaired glucose tolerance in women with PCOS. Hence, PCOS should be regarded as a general health issue and the use of insulin-sensitizing drugs such as metformin should be considered for the prevention of type 2 diabetes.
PMID 12151419 12151419 DOI 10.1093/humrep/17.8.1950 10.1093/humrep/17.8.1950 Nestler et al. 2002, Nestler 2002
Cite this article
Nestler, J. E. (2002). Should patients with polycystic ovarian syndrome be treated with metformin?: an enthusiastic endorsement. Human reproduction (Oxford, England), 17(8), 1950-1953. https://doi.org/10.1093/humrep/17.8.1950
Nestler JE. Should patients with polycystic ovarian syndrome be treated with metformin?: an enthusiastic endorsement. Hum Reprod. 2002;17(8):1950-1953. doi:10.1093/humrep/17.8.1950
Nestler, John E. "Should patients with polycystic ovarian syndrome be treated with metformin?: an enthusiastic endorsement." Human reproduction (Oxford, England), vol. 17, no. 8, 2002, pp. 1950-1953.
Polycystic ovary syndrome (PCOS) often coexists with a wide spectrum of dysglycemic conditions, ranging from impaired glucose tolerance to type 2 diabetes mellitus (T2D), which occur to a greater extent compared to healthy body mass index-matched women. This concurrence of disorders is mainly attributed to common pathogenetic pathways linking the two entities, such as insulin resistance. However, due to methodological flaws in the available studies and the multifaceted nature of the syndrome, there has been substantial controversy as to the exact association between T2D and PCOS which has not yet been elucidated. The aim of this review is to present the best available evidence regarding the epidemiology of dysglycemia in PCOS, the unique pathophysiological mechanisms underlying the progression of dysglycemia, the most appropriate methods for assessing glycemic status and the risk factors for T2D development in this population, as well as T2D risk after transition to menopause. Proposals for application of a holistic approach to enable optimal management of T2D risk in PCOS are also provided. Specifically, adoption of a healthy lifestyle with adherence to improved dietary patterns, such the Mediterranean diet, avoidance of consumption of endocrine-disrupting foods and beverages, regular exercise, and the effect of certain medications, such as metformin and glucagon-like peptide 1 receptor agonists, are discussed. Furthermore, the maintenance of a healthy weight is highlighted as a key factor in achievement of a significant reduction of T2D risk in women with PCOS.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients undergoing assisted reproduction was divided in two groups according to different ovarian stimulation protocols: (i) flare-up gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). During the ovarian stimulation regimen, the patients were submitted to hormonal (oestradiol and growth hormone), ultrasonographic (follicular number and diameter, endometrial thickness) and Doppler (uterine and perifollicular arteries) evaluations. Furthermore, the plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin-like growth factor-1 (IGF-1) were assayed. All 34 patients completed the study. In the L-arginine treated group a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group, increased plasma and follicular fluid concentrations of arginine, citrulline, NO2-/NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
A total of 17 women affected by polycystic ovarian disease (PCOD) were studied to evaluate the involvement of endogenous opioids in the pathophysiology of the hyperinsulinism in PCOD by administering naltrexone, an oral opioid antagonist. An oral glucose tolerance test (OGTT) was performed at baseline (on day 5 of the cycle) and repeated after 6 weeks of naltrexone administration. Plasma glucose, insulin and connecting peptide (c-peptide) concentrations were evaluated in all samples. Based on their insulinaemic response to OGTT, patients were classified as hyperinsulinaemic or normoinsulinaemic. Naltrexone treatment significantly (P < 0.007) reduced the insulin response to OGTT in the hyperinsulinaemic group without affecting the c-peptide incremental area; in the normoinsulinaemic group there was a slight, but not significant, increase in both c-peptide and insulin incremental areas. The two groups showed similar c-peptide incremental areas after naltrexone treatment. There was no significant difference in the c-peptide:insulin incremental areas molar ratio between the two groups; after treatment, a significant increase in this ratio was observed in both groups. When we considered the data as an expression of the fractional hepatic extraction of insulin, we found a lower value for hyperinsulinaemic in comparison with normoinsulinaemic patients (not significant), and a significant (P < 0.01) improvement of this parameter in the hyperinsulinaemic group after naltrexone administration. In conclusion, we suggest that the contribution to hyperinsulinaemia in PCOD patients may be at least in part due to both increased pancreatic secretion and reduced hepatic removal of insulin. Chronic pharmacological inhibition of opioid tone could improve the insulin plasma concentration by acting chiefly on the liver metabolism of insulin in hyperinsulinaemic patients.
Thyroid and Metabolic Function · Insulin and Metabolism
Polycystic ovary syndrome (PCOS) is a widespread and complex endocrine disorder affecting women of childbearing potential, characterized by reproductive dysfunction, hyperandrogenism, and metabolic disorders, including insulin resistance. Insulin resistance is a key pathogenetic factor contributing to ovarian dysfunction and reduced fertility. Myo-inositol (MI), a ubiquitous polyol, has earned a reputation as a promising dietary supplement due to its vital role in insulin signaling pathways. This scoping review aimed to map the available scientific literature on the effects of MI supplementation in women with PCOS, with particular emphasis on fertility and ovarian function, and to identify gaps in the current evidence base. This scoping review was conducted in accordance with the methodology developed by the Joanna Briggs Institute (JBI) and presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines. A literature search was conducted against six electronic databases: PubMed, Scopus, Web of Science, EBSCO (MEDLINE Complete), Cochrane Library and Google Scholar. Searches were conducted between 10 January and 20 February 2026. Eligibility sources included original articles (observational and randomized controlled trials), meta-analyses, systematic and narrative reviews, published in English with full text available, focusing on adult women with PCOS. Data extraction was performed independently by two reviewers using the Population-Concept-Context (PCC) framework. In accordance with the scope review methodology, no formal critical appraisal of study quality and no quantitative synthesis were performed. This is consistent with JBI methodology, which does not require critical appraisal for scoping reviews unless explicitly justified. Of the 77 records initially identified, 13 studies were included in the review, and no duplicates were found. These potential benefits should be interpreted cautiously, as the available evidence is heterogeneous and varies across study designs. Potential benefits were also reported for hormonal and metabolic parameters, including reductions in hyperandrogenism and the improvement of insulin sensitivity. Some studies suggest benefits for oocyte and embryo quality, but results remain inconsistent. MI supplementation may support PCOS management, particularly in fertility-related outcomes. Its ability to improve ovulation, increase pregnancy rates, optimize ART outcomes, and mitigate the risk of OHSS highlights its clinical utility. However, the evidence remains heterogeneous, and some outcomes, particularly oocyte and embryo quality, remain inconclusive.