Insulin-resistant Polycystic Ovary Syndrome Patients Research Articles

AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial β-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients.

Insulin resistance and dysglycaemia in polycystic ovary syndrome patients

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathy occurring during women reproductive age marked by a large range of metabolic disorders and abnormalities. This study was conducted in Bouaké Teaching Hospital. The diagnosis of PCOS was confirmed according to the revised Rotterdam criteria. Firstly, we established the diagnosis of PCOS through the measurement of different hormonal parameters and on the basis of ultrasonography and disease’s history. Secondly, we met patients to realize different tests aimed to explore glucose metabolism. The oral glucose tolerance test was performed each 30 minutes after administration of 75 g of oral glucose. We noted that 17% of PCOS patients had a HOMA Insulin Resistant in contrary to 83% of patients with a HOMA insulin sensitive state and obesity was significantly more prevalent in the IR group. PCOS patients HOMA IR group had a mean BMI significantly higher than those of IS group. Out of 12 insulin-resistant PCOS patients, 01 had normal BMI and 11 were overweight or obese (91.70%) contrary to those in IS group within 47.45% had normal BMI and 52.54% were overweight or obese. In the subgroup of IR with high BMI, we noticed the higher values of glycaemia. The rate of dysglycaemia was more prevalent in this subgroup following by IS with high BMI group. The rate of PCOS patients with HOMA-IR was important and was correlated to anthropometric disorders and high level of LH and testosterone. To successfully handling this important endocrinopathy, it’s strongly advised to early diagnosed PCOS.

Metformin doses and body mass index: clinical outcomes in insulin resistant polycystic ovary syndrome women.

PCOS is the most common endocrinopathy among reproductive age women. Approximately 60% of PCOS women have insulin resistance. While the efficacy of metformin in reducing insulin resistance and decreasing androgen level has been widely validated, there is no agreement on the dose of metformin to be used. Prospective non-randomized cohort study of 108 insulin resistant, overweight and obese PCOS women, aged between 22 and 35 years. All patients received 1500 mg of metformin (500 mg x 3 times/day) for the first 6 months. At the end of this period, the patients' HOMA index was evaluated. In subjects, who did not demonstrate normalization of the HOMA index, the dose was increased to 2500 mg/day (500 mg at breakfast and 1000 mg at lunch and dinner) for additional 6 months. The hormonal blood profile, fasting insulin and fasting glucose levels, HOMA index, anthropometric assessment, pelvic ultrasound, FAI index and cholesterol were evaluated. Overall results showed a good response to metformin therapy in insulin-resistant PCOS patients with BMI >25, while in patients with higher BMI (31.15 ± 0.40), no normalization of HOMA was found. At the higher dose of metformin, obese patients achieved a good response to therapy, with improvement in BMI, menstrual pattern, cholesterol levels and hyperandrogenism. Our results demonstrate a correlation between the required dose of metformin, BMI and hyperandrogenism. The dose of metformin should be adjusted to patients' BMI in order to obtain significant results in terms of clinical, metabolic and hormonal responses.

Inositols in Insulin Signaling and Glucose Metabolism.

In the past decades, both the importance of inositol for human health and the complex interaction between glucose and inositol have been the subject of increasing consideration. Glucose has been shown to interfere with cellular transmembrane transport of inositol, inhibiting, among others, its intestinal absorption. Moreover, intracellular glucose is required for de novo biosynthesis of inositol through the inositol-3-phosphate synthase 1 pathway, while a few glucose-related metabolites, like sorbitol, reduce intracellular levels of inositol. Furthermore, inositol, via its major isomers myo-inositol and D-chiro-inositol, and probably some of its phosphate intermediate metabolites and correlated enzymes (like inositol hexakisphosphate kinase) participate in both insulin signaling and glucose metabolism by influencing distinct pathways. Indeed, clinical data support the beneficial effects exerted by inositol by reducing glycaemia levels and hyperinsulinemia and buffering negative effects of sustained insulin stimulation upon the adipose tissue and the endocrine system. Due to these multiple effects, myoIns has become a reliable treatment option, as opposed to hormonal stimulation, for insulin-resistant PCOS patients.

Structural and functional profiles of the gut microbial community in polycystic ovary syndrome with insulin resistance (IR-PCOS): a pilot study

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder that affects 9–21% of reproductive-aged women. Affected women frequently display obesity, insulin resistance, and inflammation. Altered gut microbial community has been reported in PCOS and obese PCOS patients. However, the profile of the gut microbial community in insulin resistant PCOS (IR-PCOS) patients still remains unknown. In this study, next-generation sequencing based on the 16S rRNA gene was used to compare the gut microbial composition of women with IR-PCOS (n = 9, PCOS with insulin resistance), NIR-PCOS (n = 8, PCOS alone) and healthy controls (n = 8, HC). We assessed that the composition of the gut microbial communities in NIR-PCOS and IR-PCOS patients were significantly altered. The family Bacteroidaceae was prolific in the NIR-PCOS group and reached its highest level in the IR-PCOS group, while the Prevotellaceae dramatically decreased in PCOS patients, especially in the IR-PCOS group. Subsequent correlation analysis revealed that the increased clinical parameter levels, including insulin resistance, sex-hormones and inflammation, were positively associated with the abundance of Bacteroidaceae, but negatively associated with that of Prevotellaceae. In addition, IR-PCOS patients also displayed a significant difference in their amounts of Ruminococcaceae and Lachnospiraceae when compared to the NIR-PCOS group. Moreover, the functional prediction from PICRUSt revealed that 73 pathways are significantly changed in the gut microbial communities of PCOS patients. Specifically, 21 metabolism-associated pathways, including the steroid hormone biosynthesis and lipopolysaccharide biosynthesis pathways, are obviously changed in IR-PCOS when compared to NIR-PCOS and HC groups. Taking this into consideration, our present study suggests that the dysbiosis of gut microbial communities occurred most notably in IR-PCOS patients, and the difference in gut dysbiosis profile between the IR-PCOS and NIR-PCOS should be considered in clinical treatment for PCOS patients and future drugs development.

Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity

Polycystic ovary syndrome (PCOS) is associated with decreased fertility, insulin resistance and an increased risk of developing cardiovascular disease. Treating PCOS patients with metformin improves fertility and decreases cardiovascular complications. Given that platelet activation contributes to both infertility and cardiovascular disease development, we assessed platelet reactivity in PCOS patients and the consequences of metformin treatment. Compared to washed platelets from healthy donors, platelets from PCOS patients demonstrated enhanced reactivity and impaired activation of the AMP-activated kinase (AMPK). PCOS platelets also demonstrated enhanced expression of mitochondrial proteins such as the cytochrome c reductase, ATP synthase and the voltage-dependent anion channel-1. However, mitochondrial function was impaired as demonstrated by a decreased respiration rate. In parallel, the phosphorylation of dynamin-related protein-1 (Drp-1) on Ser616 was increased while that on Ser637 decreased. The latter changes were accompanied by decreased mitochondrial size. In insulin-resistant PCOS patients (HOMA-IR> 2) metformin treatment (1.7 g per day for 4 weeks to 6 months) improved insulin sensitivity, restored mitochondrial integrity and function and normalised platelet aggregation. Treatment was without effect in PCOS patients with HOMA-IR< 2. Moreover, treatment of megakaryocytes with metformin enhanced mitochondrial content and in the same cells metformin enhanced the phosphorylation of the Drp-1 on Ser637 via an AMPKα1-dependent mechanism. In conclusion, the improvement of mitochondrial integrity and platelet reactivity may contribute to the beneficial effects of metformin on cardiovascular disease.

Metabolic heterogeneity of follicular amino acids in polycystic ovary syndrome is affected by obesity and related to pregnancy outcome

BackgroundPolycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder frequently accompanied by obesity and by insulin resistance, and patients with this syndrome suffer from infertility and poor pregnancy outcome. Disturbances in plasma amino acid (AA) metabolism have been implicated in women with PCOS. However, direct evidence on follicular AA metabolic profiles in PCOS patients and their relationship with pregnancy outcome is sparse.MethodsWe conducted a prospective study in 63 PCOS patients and 48 controls in the Division of Reproductive Center, Peking University Third Hospital. Follicular AA levels were measured by the liquid chromatography-tandem mass spectrometric method, and the results were analyzed based on different grouping criteria.ResultsThe levels of aromatic amino acid (AAA) increased in PCOS patients independent of obesity (P < 0.05), whereas the levels of branched-chain amino acid (BCAA), glutamic acid, phenylalanine, alanine, and arginine increased with body mass index irrespective of the PCOS status (all P < 0.05). In addition, compared with non insulin resistant-PCOS patients and controls, insulin resistant-PCOS group had higher levels of leucine, valine and glutamic acid (all P < 0.05). In PCOS group, aspartic acid and serine levels were elevated in pregnant patients compared with the non-pregnant subjects (both P < 0.05). Moreover, the levels of BCAA and valine were higher in the non-pregnant group than in the pregnant group (both P < 0.05). The pregnancy rate (45.00%) of subjects with elevated BCAA level was significantly lower than that (66.67%) in control subjects (P = 0.036) at a BCAA cutoff value of 239.10 μM, while the abortion rate was much higher (33.33% versus 2.78%, P = 0.004).ConclusionsBoth PCOS and obesity were accompanied by follicular AA metabolic disturbances, with obesity exerting a more pronounced effect on AA metabolic profiles. The disruptions in specific AAs in the follicular fluid might account for the inferior pregnancy outcome in obese patients and increased risk of abortion in PCOS patients.

Alterations in thyroid function among the different polycystic ovary syndrome phenotypes

The study evaluates the prevalence of subclinical thyroid dysfunction in infertile PCOS patients, according to the different PCOS phenotypes and to examine whether insulin sensitizers in insulin resistant (IR) PCOS patients may improve thyroid function. The study population consisted of all PCOS patients, attending the infertility and IVF unit of Department of Pediatrics, Obstetrics and Reproductive Medicine of University of Siena, Italy, and compared them to regularly cycling, healthy, infertile controls. Upon admission, blood was drawn from all patients during the early follicular phase, for complete hormonal and metabolic profiles. In IR-PCOS patients treated with insulin sensitizers, blood was drawn again after 6 months. PCOS patients had a significantly higher prevalence of subclinical thyroid dysfunction compared to infertile controls. While no significant association was detected between TSH value and the presence of hyperandrogenism, overweight and obese PCOS patients, as well as IR PCOS patients showed significantly higher prevalence of subclinical thyroid dysfunction. Moreover, among IR PCOS patients, 6 months treatment with insulin sensitizers significantly reduces TSH levels. Infertile PCOS patients have a high prevalence of subclinical thyroid dysfunction, which may be successfully treated in IR PCOS patients by insulin sensitizers.

The Relationship Between Insulin Resistance and CpG Island Methylation of LMNA Gene in Polycystic Ovary Syndrome

We sought to investigate the relationship between the changes of CpG island methylation status of LMNA gene and insulin resistance in polycystic ovary syndrome (PCOS) patients. The genome-wide methylation microarray screening was done in three PCOS cases of insulin resistance and one case of a normal woman. The PCOS insulin resistance-related genes were identified as indicated by the results of gene chip screening. Then, 24 cases of insulin-resistant PCOS patients and 24 cases of normal individuals were studied to identify the effects of the candidate genes using genome-wide study of DNA from the peripheral blood analyzed by MassARRAY(®)EpiTYPER™ DNA methylation analysis technique. We found that the methylation status of CpG island in the promoter area of LMNA gene was changed. The 20 CG sites in CpG island of LMNA gene were examined using case control experiment among which 12 CpG sites differed significantly (P < 0.05) between two groups while the remaining eight CpG sites differed non-significantly. We, therefore, concluded that the changes in the hypermethylation status of CpG island of LMNA gene were related to the insulin resistance in PCOS patients, indicating that this gene may be involved in the regulation of PCOS-associated insulin resistance.

Functional neuroimaging of emotional processing in women with polycystic ovary syndrome: a case-control pilot study

To evaluate emotional processing in women with insulin-resistant polycystic ovary syndrome (IR-PCOS) and its relationship to glucose regulation and the mu-opioid system. Case-control pilot. Tertiary referring medical center. Seven women with IR-PCOS and five non-insulin-resistant controls, aged 21-40 years, recruited from the general population. Sixteen weeks of metformin (1,500 mg/day) in women with IR-PCOS. Assessment of mood, metabolic function, and neuronal activation during an emotional task using functional magnetic resonance imaging (fMRI), and mu-opioid receptor availability using positive emission tomography (PET). We found that insulin-resistant PCOS patients [1] had greater limbic activation during an emotion task than controls (n = 5); [2] trended toward decreased positive affect and increased trait anxiety; [3] after metformin treatment, had limbic activation that no longer differed from controls; and [4] had positive correlations between fMRI limbic activation during emotional processing and mu-opioid binding potential. Patients with IR-PCOS had greater regional activation during an emotion task than the controls, although this resolved with metformin therapy. Alterations in mu-opioid neurotransmission may underlie limbic system activity and mood disorders in IR-PCOS.

A Combined Treatment with Myo-Inositol and Monacolin K Improve the Androgen and Lipid Profiles of Insulin-Resistant PCOS Patients

Objective: We sought to assess and compare the effects of myo-inositol combined with monacolin k (Group A) versus inositol only (Group B) and metformin (Group C), on the clinical, hormonal, metabolic and lipid profiles of insulin-resistant PCOS patients. Study design: 60 insulin resistant PCOS patients were randomly assigned into three groups. All groups were treated for 6 months with either myo-inositol and monacolin k, inositol only or metformin. Patients clinical, hormonal and metabolic profiles were compared between all groups, and within each group, prior and following the aforementioned treatment. Results: All treatment arms improved patients’ clinical, hormonal and metabolic profiles, with a tendency toward better results in patients using the combination of myo-inositol and monacolin k. Conclusion: The combined treatment with the natural products: monacolin K and myo-inositol represents a valid and well tolerated alternative to the common medical therapy, improving the PCOS related symptoms, with minimal side effects.

Efficacy predictors for metformin and clomiphene citrate treatment in anovulatory infertile patients with polycystic ovary syndrome

To evaluate ovulation and pregnancy predictors in infertile polycystic ovary syndrome (PCOS) patients who received clomiphene citrate (CC) and metformin as first-line ovulation inductors. Prospective controlled study. Departments of Obstetrics and Gynecology, Universities Magna Graecia of Catanzaro and Federico II of Naples, Italy. Eighty infertile anovulatory PCOS patients allocated in two groups matched for body mass index (BMI) and age. Metformin (1700 mg/day for 6 months) or CC (50 mg/day, increasing doses up to 250 mg/day). Baseline clinical and biochemical parameters categorized according to interventions response. The BMI was statistically significantly lower in patients who ovulated under both treatments. Insulin sensitivity indexes were statistically significantly worse in patients who ovulated under metformin and statistically significantly better in patients who ovulated under CC. Androgen levels and free androgen index (FAI) were statistically significantly lower in ovulatory patients than in anovulatory ones who received CC. Age, BMI, infertility duration, and insulin sensitivity indexes were statistically significantly different between patients who achieved and those who did not achieve a pregnancy under both treatments. Androgens levels and FAI were statistically significantly lower in patients who achieved a pregnancy under CC. Insulin-resistant PCOS patients with low BMI are more likely to respond to metformin whereas CC treatment is more effective in less hyperandrogenic and insulin-resistant PCOS patients with low BMI.

Pioglitazone Treatment Increases Spontaneous Growth Hormone (GH) Secretion and Stimulated GH Levels in Polycystic Ovary Syndrome

Low GH levels, probably due to insulin resistance and increased abdominal fat mass, are well described in polycystic ovary syndrome (PCOS). GH acts as an important ovarian cogonadotropin, and GH disturbances may be an additional pathogenic factor in PCOS. Decreased abdominal fat mass and improved insulin sensitivity during pioglitazone treatment may affect GH secretion. The objective of the study was to investigate the effect of pioglitazone on GH levels in PCOS. Thirty insulin-resistant PCOS patients were randomized to either 16 wk pioglitazone (30 mg/d) or placebo treatment. Before and after intervention, levels of fasting insulin, GH, total IGF-I, free IGF-I, IGF binding protein-1, IGF-II, free fatty acids, testosterone, and SHBG were measured. Patients underwent whole-body dual x-ray absorptiometry scans, pyridostigmine-GHRH tests, and 24-h 20-min integrated blood sampling for measurement of GH. Peak GH and area under the curve for GH in pyridostigmine-GHRH tests and 24-h mean GH concentrations and pulsatile GH secretion significantly increased after pioglitazone treatment. No significant changes were observed in GH pulse frequency, pulse duration, approximate entropy levels, or basal GH release. Levels of IGF binding protein-1 significantly increased, whereas no significant differences were measured in total IGF-I and free IGF-I. Pioglitazone treatment significantly decreased fasting insulin and homeostasis model assessment levels. No significant changes were observed in Ferriman Gallwey score or androgen levels. Pioglitazone treatment significantly increased GHRH-stimulated GH levels and 24-h pulsatile GH secretion, probably directly or indirectly due to improved insulin sensitivity.

Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine.

Elevated levels of plasma homocysteine have recently been implicated as a significant risk factor for cardiovascular disease, pre-eclampsia, and recurrent pregnancy loss, and have been found to be associated with insulin resistance in a number of clinical situations. We examined the relationship between plasma homocysteine and insulin resistance in patients with polycystic ovary syndrome (PCOS). A total of 155 infertile patients with PCOS as defined by clinical, biochemical and ultrasound criteria were screened for insulin resistance utilizing single-sample fasting insulin and glucose measurement, calculated by glucose:insulin ratio or homeostasis model assessment (HOMA) index. Total plasma homocysteine was measured by fluorescence polarization immunoassay. One hundred normo-ovulatory women with normal ovaries being treated for other infertility diagnoses served as a control group. Insulin resistance was found in the majority of PCOS patients: -53.5% (83/155), 60.6% (94/155) and 65.8% (102/155), when defined by fasting insulin, glucose:insulin ratio, or logHOMA respectively. Mean plasma homocysteine in the PCOS group was significantly higher than in the normal ovary group (11.5 +/- 7.4 versus 7.4 +/- 2.1 micromol/l, P < 0.001). Insulin-resistant PCOS patients had significantly higher plasma homocysteine (12.4 +/- 8.4 micromol/l) than non-insulin-resistant PCOS patients (9.6 +/- 4.4 micromol/l) regardless of body mass index (P = 0.003 by groups, P = 0.005 by correlation of single samples). Thirty-four per cent (53/155) of the PCO patients had homocysteine values >95th percentile of the controls (11.0 micromol/l, P < 0.0001). Statistically significant correlations were found between all insulin resistance indices and homocysteine levels. Multiple logistic regression defined insulin resistance as the major factor examined that influenced homocysteine levels. Insulin resistance and hyperinsulinaemia in patients with PCOS is associated with elevated plasma homocysteine, regardless of body weight. This finding may have important implications in the short term regarding reproductive performance, and in the long term regarding cardiovascular complications associated with insulin-resistant PCOS.

Impaired insulin action on granulosa-lutein cells in women with polycystic ovary syndrome and insulin resistance

We studied the in vitro response to insulin of granulosalutein cells derived from patients with polycystic ovary syndrome (PCOS) and clinically defined insulin resistance. Insulin sensitivity was assessed by continuous infusion of glucose with model assessment test (CIGMA). Insulin resistant (PCOS-IR; n = 8), non-insulin resistant (PCOS-NIR; n = 9) patients with PCOS, and women with tubal factor infertility (TF; n = 8) underwent controlled ovarian stimulation with long-term gonadotropin-releasing hormone (GnRH) agonist, recombinant follicle stimulating hormone (FSH), and in vitro fertilization. Primary cultures of granulosa-lutein cells were incubated with insulin (10, 100, 500 ng/ml) and/or luteinzing hormone (LH) (10, 100 ng/ml) in the presence of low density lipoprotein (100 μg/ml). The progesterone and lactate accumulation were measured in the culture medium. LH potently stimulated the progesterone secretion in all groups. Insulin alone had no effect on progesterone release in any of the groups, but stimulated lactate formation in the PCOS-NIR and TF groups. Insulin augmented the effect of LH on progesterone secretion selectively in the PCOS-NIR group. The expression of the insulin receptor was determined by Western blotting in separate cultures of granulosa-lutein cells, and showed receptor down-regulation in the PCOS-IR patients. We infer that the in vitro effect of insulin on progesterone and lactate release by granulosa-lutein cells is impaired in insulin resistant PCOS patients.

Octreotide effect on ovarian morphology in insulin-resistant PCOS patients following six-month decapeptyl treatment.

Regulation of ovarian folliculogenesis involves bidirectional communication between the immune and endocrine systems. Somatostatin analogues have been reported to acutely suppress elevated androgens in polycystic ovary syndrome (PCOS). The aim of our study was to analyze the morphologic and hormonal-metabolic response to octreotide therapy for one month in insulin-resistant PCOS patients in whom luteinizing hormone (LH) effect had formerly been separated by a six-month GnRH-agonist (GnRH-a) course. Fifteen PCOS patients were studied two months after completing a six-month GnRH-a (decapeptyl 3.75 mg monthly injection) course. Seven of the patients (group A), who were insulin-resistant and gave hyperinsulinemic response to a glucose challenge, received a 50-micrograms subcutaneous injection of octreotide twice a day for one month. The nonhyperinsulinemic patients (group B) received placebo injections. Hormonal measurements, oral glucose tolerance test (OGTT), and transvaginal ovarian ultrasound were performed before and toward the end of the treatment period. After octreotide ovarian volume dropped significantly in group A (x +/- SD) (19.2 +/- 5.1 versus 14.7 +/- 5.5 cc, P = .02). LH levels increased (3.25 +/- 1.22 versus 5.95 +/- 4.34 mu/ml, P = .05) as did E2 levels (38.0 +/- 11.4 versus 55.1 +/- 12.7 pg/ml, P = .005). There was no change in follicle-stimulating hormone, 17-hydroxy-progesterone, free testosterone, or androstenedione levels. Insulin secretion during OGTT dropped significantly (555 +/- 294 versus 68 +/- 29 mu u/ml/hr, P = .002). Glucose tolerance was not affected. In contrast, the placebo-treated group B patients showed an increase in ovarian volume (10.9 +/- 3.5 versus 14.8 +/- 3.3 cc, P = .001) while their gonadotropin and steroid profile relapsed, similarly to our patients receiving octreotide. Octreotide has an adjunctive beneficial effect to GnRH-a on ovarian morphology although, at the dose used, there was no suppression of gonadotropin or ovarian steroid levels. The changes in ovarian morphology are probably mediated through suppression of insulin levels and/or other ovarian growth factors.