Insulin Sensitivity In Polycystic Ovary Syndrome Research Articles

Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis

BackgroundMultiple oral insulin-sensitizing agents, such as metformin, thiazolidinediones, inositols, and berberine, have been proven safe and efficacious in improving the endocrine, metabolic, and reproductive abnormalities seen in polycystic ovary syndrome (PCOS), providing more options for healthcare providers and patients. These oral insulin sensitizers are more convenient, practical, and economic than agents that need to be injected. A comparison of the clinical effectiveness of the four different classes of oral insulin sensitizers in PCOS has not been explored, leading to clinical uncertainty about the optimal treatment pathway. The present study aims to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with PCOS.MethodsWe identified randomized controlled trials for PCOS from a variety of databases, published from January 2005 to October 2020. Outcomes included changes in menstrual frequency, improvements in hyperandrogenism and glucolipid metabolism and adverse side effects. A random-effects network meta-analysis was performed.ResultsTwenty-two trials comprising 1079 patients with PCOS were included in this study. Compared with metformin, treatment with myo-inositol + d-chiro-inositol was associated with a greater improvement in menstrual frequency (odds ratio 14.70 [95% confidence interval (CI) 2.31–93.58]). Myo-inositol + d-chiro-inositol and metformin + thiazolidinediones combination therapies were superior to respective monotherapies in reducing total testosterone levels. Thiazolidinediones, metformin + thiazolidinediones, and myo-inositol + d-chiro-inositol were associated with a lower insulin resistance index (HOMA-IR) compared with that in metformin alone (mean differences: − 0.72 [95% CI (− 1.11)–(− 0.34)] to − 0.89 [95% CI (− 1.460)–(− 0.32)]). Metformin + thiazolidinediones treatment was associated with lower triglyceride levels compared with that in metformin and thiazolidinediones monotherapy, while thiazolidinediones was superior to metformin in increasing high-density lipoprotein cholesterol and decreasing fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, and gastrointestinal adverse events.ConclusionsOurs is the first study to report that for women with PCOS, myo-inositol combined with d-chiro-inositol and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone. Myo-inositol combined with d-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than metformin alone.Trial registration PROSPERO CRD42020211524

Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome.

Oxidative stress (OS) and inflammation are often present in polycystic ovary syndrome (PCOS). We examined the effects of salsalate treatment on nutrient-induced OS and inflammation, ovarian androgen secretion, ovulation, and insulin sensitivity in PCOS. Eight lean insulin-sensitive women with PCOS and eight age- and body composition-matched ovulatory controls for baseline comparison participated in the study. The women with PCOS underwent a 12-wk treatment of salsalate, a nonsteroidal anti-inflammatory drug, at a dose of 3 g daily. Markers of OS and inflammation were quantified in mononuclear cells (MNC) and plasma from blood drawn fasting and 2 h after saturated fat ingestion before and after treatment. Ovarian androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration before and after treatment. Ovulation was documented based on biphasic basal body temperatures and luteal range progesterone elevations. A two-step pancreatic clamp was performed pre- and posttreatment to measure basal endogenous glucose production (EGP) and the steady-state glucose disposal rate (GDR) during the euglycemic phase and markers of OS and inflammation in MNC and plasma during the hyperglycemic phase. Salsalate administration suppressed lipid- and glucose-stimulated reactive oxygen species generation, activated nuclear factor-κB and circulating tumor necrosis factor-α, normalized basal androgen levels, and lowered HCG-stimulated androgen secretion without altering EGP or GDR. Four salsalate-treated subjects responded with two consecutive ovulations. We conclude that in PCOS, salsalate-induced suppression of OS and inflammation ameliorates ovarian androgen hypersecretion and may induce ovulation while maintaining insulin action.

Heat Therapy Decreases Adipose Tissue Inflammation and Improves Insulin Signaling in Polycystic Ovary Syndrome

Passive hot water immersion promotes improvements in glucose control in humans, potentially by enhancing insulin sensitivity. In animal models, this improvement is mediated by increased heat shock protein (HSP) abundance, which inhibits production of inflammatory compounds that interfere with intracellular insulin signaling. The impact of repeated passive hot water immersion (termed ‘heat therapy’) on inflammation, HSP abundance, and insulin signaling in human adipose tissue have not been explored in an insulin‐resistant population such as obese women with Polycystic Ovary Syndrome (PCOS). While exercise training can improve insulin sensitivity in PCOS, novel treatments such as heat therapy are warranted as many individuals are unable to fully benefit from a traditional exercise program due to poor exercise tolerance or capacity. Therefore, the objective of this study was to examine changes in insulin signaling, inflammatory proteins, and HSPs in subcutaneous adipose tissue of obese women with PCOS undergoing an 8–10 week heat therapy intervention. Six obese women with PCOS (Age: 26±3y, BMI 42±2 kg·m2) underwent heat therapy, consisting of 30 × 1‐hr hot tub sessions over 8–10 weeks (3–4 per week) in 40.5°C water. Subcutaneous adipose tissue biopsies were collected from the periumbilical region at the start (Pre) and end (Post) of the chronic heat intervention. Tissue samples were analyzed using immunoblotting for HSP27, HSP70, and inflammatory proteins known to be impacted by HSPs and interfere with insulin signaling, including c‐Jun‐NH2‐terminal Kinase (JNK; inhibited by HSP70) and Inhibitor of Kappa B Kinase β (IKKβ; inhibited by HSP27). Additionally, a sub‐set of primary adipocytes in n=4 subjects were serum starved for 2 hours, then exposed to 1.2 nM insulin for 5 minutes for insulin signaling (p‐AKT) analysis using immunoblotting. All targets were quantified relative to loading control and expressed as a fold change from Pre to Post. Following heat therapy, insulin signaling (p‐AKT) increased in all subjects (4.1±2.0‐fold increase, p=0.19) despite no change in BMI (p=0.42). IKKβ significantly decreased (0.50 ± 0.06‐fold decrease, p=0.02) and JNK tended to decrease (0.48 ± 0.17‐fold decrease, p=0.09) after heat therapy. Abundance of HSP27 increased in all subjects (1.27 ± 0.14‐fold increase, p=0.18), while, conversely, HSP70 abundance significantly decreased (0.42±0.12‐fold decrease; p=0.03). In these preliminary data, heat therapy appears to promote improved insulin signaling in obese women with PCOS. This improvement is likely due to observed decreases in adipose tissue inflammation, potentially mediated in part by increased HSP27 abundance. Regular heat exposure has promise as a novel treatment in insulin‐resistant individuals to improve metabolic function. Heat can potentially be implemented as a complement or as a transition to exercise training to improve metabolic health, particularly in patient populations with severe metabolic dysfunction, mobility limitations, or low exercise tolerance.Support or Funding InformationSupported by American Heart Association Predoctoral Fellowship 16PRE27780085, Eugene & Clarissa Evonuk Memorial Fellowship, and the Ken and Kenda Singer Endowment Fund.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acupuncture treatment for insulin sensitivity of women with polycystic ovary syndrome and insulin resistance: a study protocol for a randomized controlled trial

BackgroundOur prospective pilot study of acupuncture affecting insulin sensitivity on polycystic ovary syndrome (PCOS) combined with insulin resistance (IR) showed that acupuncture had a significant effect on improving the insulin sensitivity of PCOS. But there is still no randomized controlled trial to determine the effect of acupuncture on the insulin sensitivity in women with PCOS and IR. In this article, we present the protocol of a randomized controlled trial to compare the effect of true acupuncture on the insulin sensitivity of these patients compared with metformin and sham acupuncture. Acupuncture may be an effective therapeutic alternative that is superior to metformin and sham acupuncture in improving the insulin sensitivity of PCOS combined with IR.MethodsThis study is a multi-center, controlled, double-blind, and randomized clinical trial aiming to evaluate the effect of acupuncture on the insulin sensitivity in PCOS combined with IR. In total 342 patients diagnosed with PCOS and IR will be enrolled. Participants will be randomized to one of the three groups: (1) true acupuncture + metformin placebo; (2) sham acupuncture + metformin, and (3) sham acupuncture + metformin placebo. Participants and assessors will be blinded. The acupuncture intervention will be given 3 days per week for a total of 48 treatment sessions during 4 months. Metformin (0.5 g per pill) or placebo will be given, three times per day, and for 4 months.Primary outcome measures are changes in homeostasis model assessment of insulin resistance (HOMA-IR) and improvement rate of HOMA-IR by oral glucose tolerance test (OGTT) and insulin releasing test (Ins). Secondary outcome measures are homeostasis model assessment-β (HOMA-β), area under the curve for glucose and insulin, frequency of regular menstrual cycles and ovulation, body composition, metabolic profile, hormonal profile, questionnaires, side effect profile, and expectation and credibility of treatment.Outcome measures are collected at baseline, at the end of treatments, and 3 months after the last acupuncture treatment. On completion of the screening visit, randomization will be conducted using a central randomization system.DiscussionThis study will investigate the effects of acupuncture on the insulin sensitivity of PCOS and IR women compared with metformin and sham acupuncture. We will test whether true acupuncture with needles placed in skeletal muscles and stimulated manually and by electrical stimulation is more effective than metformin and sham acupuncture with superficial needle placement with no manual or electrical stimulation in improving the insulin sensitivity in PCOS women with IR.Trial registrationClinicalTrials.gov, NCT02491333; Chinese Clinical Trial Registry, ChiCTR-ICR-15006639. Registered on 24 June 2015.

Comparison of Insulin Sensitivity Levels in Women with PCOS and Women with Regular Menses

Amac: Polikistik over sendromu (PKOS)’un patofizyolojisi tam olarak anlasilamamistir. Bununla beraber insulin direncinin sendromun gelismesinde merkezi bir rolu oldugu dusunulmektedir. Bu calismada insulin duyarliligi durumunu yansitan non-invaziv kantitatif insulin duyarliligi hesaplama indeksi’ nin (quantitative insulin sensitivity check index-QUICKI) degerlerini PKOS’u olan ve adet duzeni normal olan kadinlar arasinda karsilastirildi. Ayrica bu indeksin klinik pratikte PKOS daki insulin duyarligi/direnci durumundaki kullanilabilirliginin incelenmesi amaclandi. Materyal ve Metot: Retrospektif olarak 50 PKOS’lu kadin ile adet duzeni normal olan, 50 saglikli kadin yas ve vucut kitle indeksi kiyaslamali incelendi. Serum aclik glukoz, insulin ve testosteron konsantrasyonlari degerlendirildi. QUICKI ve insulin direncinin homeostasis model degerlendirmesi (homeostasis model assessment of insulin resistance-HOMA-IR) indeksleri hesaplandi. Bulgular: Her iki grup arasinda QUICKI (PKOS grubu=0,329±0,022 ve kontrol grubu=0,333±0,019; p=0,39) ve HOMA-IR (PKOS grubu= 3,057±1,468 ve kontrol grubu=2,717±1,037; p=0,184) yonunden anlamli fark bulunmadi. QUICKI ile serum aclik glukoz konsantrasyonlari (p=0,136) ve serum testosteron konsantrasyonlari (p=0. 227), arasinda anlamli korelasyon saptanmaz iken; hem serum aclik insulin konsantrasyonlari (r=-0,925, p<0,001), hem de HOMA-IR (r=-0,95, p<0,001), arasinda anlamli negatif korelasyon saptandi. Sonuc: PKOS’lu kadinlarda insulin duyarliligi degerlendirilmesi gereken bir klinik durumdur. PKOS’da ulkemize ait insulin duyarliligi/ direnci durumlarini yansitan guvenilir esik degerleri halen mevcut degildir. Bundan oturu ilerideki calismalarin PKOS’daki insulin duyarliligini prospektif olarak ortaya koymasi onerilmektedir.

Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies.

What is the degree of intrinsic insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) and the relative contribution of BMI to overall IR based on meta-analysis of gold standard insulin clamp studies? We report an inherent reduction (-27%) of insulin sensitivity (IS) in PCOS patients, which was independent of BMI. PCOS is prevalent, complex and underpinned by IR but controversies surround the degree of intrinsic IR in PCOS, the effect of BMI and the impact of the different diagnostic criteria (NIH versus Rotterdam) in PCOS. A systematic review and meta-analysis of Medline and All EBM databases was undertaken of studies published up to 30 May2015. Studies were included if premenopausal women diagnosed with PCOS were compared with a control group for IS, measured by the gold standard euglycaemic-hyperinsulinaemic clamp. The systematic review adheres to the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analyses were performed using mixed modelling and magnitude-based inferences expressed as mean effect ±99% CI. We inferred the effect was small, moderate or large relative to a smallest important change of -3.7% or 3.8% derived by standardisation. Effects were deemed unclear when the CI overlapped smallest important positive and negative values. Effects were qualified with probabilities reflecting uncertainty in the magnitude of the true value (likely, 75-95%; very likely, 95-99.5%; most likely, >99.5%). A total of 4881 articles were returned from the search. Of these, 28 articles were included in the meta-analysis. Overall IS was lower in women with PCOS compared with controls (mean effect -27%, 99% CI ±6%; large, most likely lower). A higher BMI exacerbated the reduction in IS by -15% (±8%; moderate, most likely lower) in PCOS compared with control women. There was no clear difference in IS between women diagnosed by the original National Institutes of Health (NIH) criteria alone compared with those diagnosed by the Rotterdam criteria. Low levels of sex hormone-binding globulin (SHBG) were associated with reduced levels of IS (-10%, ±10%; small, very likely negative), which was not confounded by BMI. This systematic review and meta-analysis inherited the confounding problems of small sample sizes, missing data (e.g. some hormones, waist and hip girths) and the lack of Rotterdam criteria phenotype reporting, limiting the evidence synthesis and meta-analysis. BMI has a greater impact on IS in PCOS than in controls. SHBG appears a potentially valuable marker of IR in PCOS, whereas testosterone after adjustment for BMI demonstrated an unexpected interplay with IS which warrants further investigation. This work was supported by grants from the National Health & Medical Research Council (NHMRC), grant number 606553 (H.J.T., N.K.S.), as well as Monash University. H.J.T. is an NHMRC Research Fellow. N.K.S. is supported through the Australian Government's Collaborative Research Networks (CRN) programme. The funding bodies played no role in the design, methods, data management or analysis or in the decision to publish. All authors declare no conflict of interests. N/A.

Common genetic variation in the 3′-untranslated region of gonadotropin-releasing hormone receptor regulates gene expression in cella and is associated with thyroid function, insulin secretion as well as insulin sensitivity in polycystic ovary syndrome patients

Gonadotropin-releasing hormone receptor (GNRHR) is a member of the G protein-coupled Ca(2+)-dependent family of receptors. It interacts with GnRH, whose signaling plays an important role in thyroid-stimulating hormone (TSH) secretion and insulin activity. There has been no study on the genetic effect of GNRHR on TSH secretion and insulin action in polycystic ovary syndrome (PCOS). We decided to investigate whether naturally occurring genetic variation at the human GNRHR locus is associated with thyroid function, insulin secretion and insulin sensitivity in PCOS. We undertook a systematic search for polymorphisms in GNRHR by resequencing the gene and then genotyped common single-nucleotide polymorphisms across the locus in 261 PCOS patients well-phenotyped for several metabolic traits to determine associations. A test for association of common genetic variants with susceptibility to PCOS was carried out in a large cohort of 948 subjects. Finally, we experimentally validated the marker-on-trait associations using GNRHR 3'-UTR region/reporter analysis in 293T cells. The 3'-UTR variant rs1038426 was associated with serum thyroid concentration (P=0.007), change of insulin levels during oral glucose tolerance test (P=0.004) and insulin sensitivity index (P=0.014). In a functional study, 3'-UTR variant T allele increased reporter expression by a transfected luciferase reporter/GNRHR 3'-UTR expression plasmid. In conclusion, our results strongly suggest that common genetic variant in GNRHR contributes to the phenotypic expression of PCOS. The findings suggest novel pathophysiological links between the GNRHR locus and thyroid function and insulin secretion in PCOS.

Adipose Tissue Has Aberrant Morphology and Function in PCOS: Enlarged Adipocytes and Low Serum Adiponectin, but not Circulating Sex Steroids, Are Strongly Associated with Insulin Resistance

Context: Comprehensive characterization of the adipose tissue in women with polycystic ovary syndrome (PCOS), over a wide range of body mass indices (BMIs), is lacking. Mechanisms behind insulin resistance in PCOS are unclear. Objective: To characterize the adipose tissue of women with PCOS and controls matched pair-wise for age and BMI, and to identify factors, among adipose tissue characteristics and serum sex steroids, that are associated with insulin sensitivity in PCOS. Design/Outcome measures: Seventy-four PCOS women and 31 controls were included. BMI was 18-47 (PCOS) and 19-41 kg/m2 (controls). Anthropometric variables, volumes of subcutaneous/visceral adipose tissue (magnetic resonance imaging; MRI), and insulin sensitivity (clamp) were investigated. Adipose tissue biopsies were obtained to determine adipocyte size, lipoprotein lipase (LPL) activity, and macrophage density. Circulating testosterone, free testosterone, free 17β-estradiol, SHBG, glycerol, adiponectin, and serum amyloid A were measured/calculated. Results: Comparison of 31 pairs revealed lower insulin sensitivity, hyperandrogenemia, and higher free 17β-estradiol in PCOS. Adipose tissue volumes/distribution did not differ in the groups, but PCOS women had higher waist-to-hip ratio, enlarged adipocytes, reduced adiponectin, and lower LPL activity. In regression analysis, adipocyte size, adiponectin, and waist circumference were the factors most strongly associated with insulin sensitivity in PCOS (R2=0.681, P &amp;lt; 0.001). Conclusions: In PCOS, adipose tissue has aberrant morphology/function. Increased waist-to-hip ratio indicates abdominal/visceral fat accumulation, but this is not supported by MRI. Enlarged adipocytes and reduced serum adiponectin, together with a large waistline, rather than androgen excess, may be central factors in the pathogenesis/maintenance of insulin resistance in PCOS.

Insulin-sensitizing agents in the treatment of polycystic ovary syndrome: an update

Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in reproductive-aged women, mainly characterized by oligoanovulation and hyperandrogenism. Insulin resistance represents a major pathophysiological feature of the syndrome and, therefore, insulin-sensitizing agents (metformin and thiazolidinediones) have been applied in PCOS women. However, the clinical use of insulin sensitizers in PCOS has been debated. The aim of the current review was to update the knowledge regarding the role of metformin and thiazolidinediones in PCOS treatment, focusing on recently published studies. Several clinical trials examined metformin effectiveness on lipids, atherosclerosis and inflammatory markers, hormone levels, menstrual irregularities, ovulation induction, fertility, hirsutism, obesity parameters and quality of life in PCOS women. Metformin treatment was shown to improve these features, although conflicting results were also reported. Only one study investigated pioglitazone effect on PCOS, reporting an improved IVF outcome in clomiphene citrate-resistant PCOS patients. Finally, both metformin and pioglitazone, as a part of a low-dose polytherapy, exerted beneficial effects on lipids, androgen levels, hirsutism and markers of atherosclerosis in nonobese PCOS women. Further research, including larger randomized controlled trials and meta-analyses, is needed to clarify the role of metformin and thiazolidinediones in the treatment of clinical and biochemical PCOS characteristics.

Adipose Tissue Has Aberrant Morphology and Function in PCOS: Enlarged Adipocytes and Low Serum Adiponectin, But Not Circulating Sex Steroids, Are Strongly Associated with Insulin Resistance

Comprehensive characterization of the adipose tissue in women with polycystic ovary syndrome (PCOS), over a wide range of body mass indices (BMIs), is lacking. Mechanisms behind insulin resistance in PCOS are unclear. To characterize the adipose tissue of women with PCOS and controls matched pair-wise for age and BMI, and to identify factors, among adipose tissue characteristics and serum sex steroids, that are associated with insulin sensitivity in PCOS. Seventy-four PCOS women and 31 controls were included. BMI was 18-47 (PCOS) and 19-41 kg/m(2) (controls). Anthropometric variables, volumes of subcutaneous/visceral adipose tissue (magnetic resonance imaging; MRI), and insulin sensitivity (clamp) were investigated. Adipose tissue biopsies were obtained to determine adipocyte size, lipoprotein lipase (LPL) activity, and macrophage density. Circulating testosterone, free testosterone, free 17β-estradiol, SHBG, glycerol, adiponectin, and serum amyloid A were measured/calculated. Comparison of 31 pairs revealed lower insulin sensitivity, hyperandrogenemia, and higher free 17β-estradiol in PCOS. Abdominal adipose tissue volumes/distribution did not differ in the groups, but PCOS women had higher waist-to-hip ratio, enlarged adipocytes, reduced adiponectin, and lower LPL activity. In regression analysis, adipocyte size, adiponectin, and waist circumference were the factors most strongly associated with insulin sensitivity in PCOS (R(2)=0.681, P < 0.001). In PCOS, adipose tissue has aberrant morphology/function. Increased waist-to-hip ratio indicates abdominal/visceral fat accumulation, but this is not supported by MRI. Enlarged adipocytes and reduced serum adiponectin, together with a large waistline, rather than androgen excess, may be central factors in the pathogenesis/maintenance of insulin resistance in PCOS.

The FTO gene modifies weight, fat mass and insulin sensitivity in women with polycystic ovary syndrome, where its role may be larger than in other phenotypes

Aim Genome-wide association studies have shown that variation in the FTO gene predisposes to obesity and related traits that are common features of polycystic ovary syndrome (PCOS). The aim of the present study was to assess the effect of FTO variation on obesity, insulin sensitivity, and metabolic and hormonal profiles in PCOS. Methods We examined 136 PCOS women (mean body mass index [BMI]: 28.28 ± 6.95 kg/m 2, mean age: 25.36 ± 5.48 years). Anthropometric measurement, euglycaemic–hyperinsulinaemic clamp and oral glucose tolerance tests and sex hormone assessments were performed. The study group was genotyped for the FTO rs9939609 polymorphism. Results BMI (29.0 ± 6.9 kg/m 2 vs 26.1 ± 6.8 kg/m 2; P = 0.023), body weight (80.1 ± 20.7 kg vs 72.6 ± 20.2 kg; P = 0.048), fat mass (29.7 ± 1 6.6 kg vs 24.6 ± 17.7 kg; P = 0.045) and waist circumference (89.8 ± 16.7 cm vs 83.2 ± 17.1 cm; P = 0.028) were higher in carriers of at least one copy of the A allele. Differences in these parameters were more significant when comparing AA and TT homozygotes. Women with the AA genotype also had decreased insulin sensitivity ( P = 0.025) and follicle-stimulating hormone ( P = 0.036). In logistic-regression analyses, the association of the FTO gene polymorphism with insulin sensitivity was no longer significant when BMI was included in the model. Conclusion Variation in the FTO gene modifies weight, adiposity and other measures of obesity and insulin sensitivity in PCOS. The examined FTO gene variant appears to have a greater impact on obesity and related traits in PCOS than in other phenotypes. The effect on insulin sensitivity appears to be secondary to its influence on obesity and body fat.

Insulin-sensitizing agents in polycystic ovary syndrome

Insulin-sensitizing agents have been recently proposed as the therapy of choice for polycystic ovary syndrome (PCOS), since insulin resistance and associated hyperinsulinemia are recognized as important pathogenetic factors of the syndrome. Moreover, since almost all obese PCOS women and more than half of those of normal weight are insulin resistant, and therefore present some degree of hyperinsulinemia, the use of insulin sensitizers should be suggested in most patients with PCOS. Insulin sensitizer treatment has been associated with a reduction in serum androgen levels and gonadotropins, and with an improvement in serum lipids and in prothrombotic factor plasminogen-activator inhibitor type 1, whatever the insulin sensitizer used. This therapy has also been associated with a decrease in hirsutism and acne, and with a regulation of menses and an improvement of ovulation and fertility. Notable improvements in all these parameters have also been described after a change in lifestyle approach, particularly in the presence of obesity. Lifestyle interventions should therefore be combined with insulin sensitizers in PCOS when obesity is present.

Assessment of Insulin Sensitivity from Measurements in the Fasting State and during an Oral Glucose Tolerance Test in Polycystic Ovary Syndrome and Menopausal Patients

Polycystic ovary syndrome (PCOS) and menopausal subjects are characterized by an increased cardiovascular and type 2 diabetes mellitus risk, at least partially related to insulin disturbances. The evaluation of insulin resistance in these patients could be useful as primary prevention. The aim of the study was to verify the validity of several indexes of insulin sensitivity in PCOS and menopausal subjects by comparing the data obtained by these indexes to those of euglycemic-hyperinsulinemic clamp studies. One hundred PCOS and 110 menopausal subjects were analyzed; all subjects underwent an oral glucose tolerance test (75 g) and euglycemic-hyperinsulinemic clamp study. Seven PCOS patients and 13 menopausal subjects had impaired glucose tolerance or type 2 diabetes mellitus and were excluded from the study. After analysis of correlation coefficients between the evaluated indexes and the clamp studies, the sensitivity and specificity of different cut-off values for each parameter were analyzed by receiver operating characteristic (ROC) curves. The best correlation coefficients with clamp studies were obtained with the Avignon insulin sensitivity index (SiM) (R(s) = 0.7812) in PCOS patients and the Matsuda and De Fronzo index (R(s) = 0.6178) in menopausal patients. The best predictive index of insulin resistance in PCOS was a Avignon insulin sensitivity basal index (SibB) value of 62 or less (78% sensitivity, 95% specificity) and an insulin area under the curve (AUC) of 7,000 microIU/ml or more (>/=50,225 pmol/liter) x 120 min (83% sensitivity, 90% specificity). In the menopausal population, the best predictive performance was obtained by an insulin AUC of 10,000 microIU/ml or more (>/=71,750 pmol/liter) x 240 min (70% sensitivity, 88% specificity). The presence of high correlation coefficients does not necessarily mean that the indexes of insulin resistance have an optimal predictive performance; this is probably due to the presence of many borderline values. The simple evaluation of insulin AUC seems to effectively replace the euglycemic-hyperinsulinemic clamp in routine clinical practice, allowing results superimposable to those obtained by minimal model analysis.

Is insulin resistance an essential component of PCOS?: The influence of confounding factors.

Insulin resistance is often considered a regular component of polycystic ovary syndrome (PCOS). Many interventional studies assume a state of insulin resistance in all patients. However, the evidence is based on small samples that are often insufficient to adjust for significant confounding factors. Moreover, several studies have not confirmed differences in insulin sensitivity between women with PCOS and healthy controls, especially in non-obese patients. This debate article provides an overview of the data published regarding the presence of abnormal or normal insulin sensitivity in PCOS. In conclusion, available data offer evidence that a substantial subgroup of women with PCOS have insulin sensitivity comparable with healthy controls if matched carefully for potential confounding factors.

We should avoid the indiscriminate use of insulin sensitizers in women with polycystic ovary syndrome

Insulin resistance and hyperinsulinemia, although not universal, represent a significant health risk for patients with polycystic ovary syndrome (PCOS) when present. A thorough search for metabolic abnormalities in patients with PCOS should always be performed, including determining whether there is a family history of diabetes and cardiovascular disease, or dermatologic (e.g., acanthosis nigricans and acrochordons) or biochemical evidence (e.g., 2-hour postprandial insulin and glucose measures) of hyperinsulinism. However, we should avoid the indiscriminate use of insulin sensitizers in PCOS.