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PubMed2004

Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is characterized by insulin resistance with compensatory hyperinsulinemia. Insulin resistance also plays a role in the metabolic syndrome (MBS). We hypothesized that the MBS is prevalent in PCOS and that women with both conditions would present with more hyperandrogenism and menstrual cycle irregularity than women with PCOS only. We conducted a retrospective chart review of all women with PCOS seen over a 3-yr period at an endocrinology clinic. Of the 161 PCOS cases reviewed, 106 met the inclusion criteria. The women were divided into two groups: 1) women with PCOS and the MBS (n = 46); and 2) women with PCOS lacking the MBS (n = 60). Prevalence of the MBS was 43%, nearly 2-fold higher than that reported for age-matched women in the general population. Women with PCOS had persistently higher prevalence rates of the MBS than women in the general population, regardless of matched age and body mass index ranges. Acanthosis nigricans was more frequent in women with PCOS and the MBS. Women with PCOS and the MBS had significantly higher levels of serum free testosterone (P = 0.002) and lower levels of serum SHBG (P = 0.001) than women with PCOS without the MBS. No differences in total testosterone were observed between the groups. We conclude that the MBS and its components are common in women with PCOS, placing them at increased risk for cardiovascular disease. Women with PCOS and the MBS differ from their counterparts lacking the MBS in terms of increased hyperandrogenemia, lower serum SHBG, and higher prevalence of acanthosis nigricans, all features that may reflect more severe insulin resistance.

Adult↗

PubMed2005

Increased transcription and increased messenger ribonucleic acid (mRNA) stability contribute to increased GATA6 mRNA abundance in polycystic ovary syndrome theca cells.

CONTEXT: Polycystic ovary syndrome (PCOS) theca cells secrete increased levels of androgens. The mRNA and protein levels of the transcription factor GATA6, which regulates expression of several steroidogenic enzymes, are increased in PCOS theca cells. Thus, GATA6 is a PCOS candidate gene. OBJECTIVE: The objective of the study was to explore mechanisms by which GATA6 mRNA levels are increased in PCOS theca cells. DESIGN: Theca cell cDNA and genomic DNA from normal individuals and PCOS patients were subjected to quantitative RT-PCR and sequence analysis, respectively. SETTING: The experiments were performed in a university laboratory. PARTICIPANTS: Four hundred sixty-nine families that contain at least one PCOS patient were ascertained for genetic studies. Theca cells were obtained from four normal individuals and four PCOS patients. RESULTS: Nascent GATA6 transcript levels, which reflect GATA6 gene transcription, were significantly increased in PCOS theca cells. In normal theca cells, GATA6 mRNA has a short half-life, which was attributed to an AU-rich 3'-untranslated region sequence. The half-life of GATA6 transcripts was also significantly longer in the PCOS theca cells. However, no sequence variations in the GATA6 gene locus were associated with PCOS. CONCLUSIONS: In PCOS theca cells, GATA6 gene transcription and the stability of the GATA6 mRNA are increased. Because there is no sequence variation in the GATA6 gene locus, which is associated with PCOS, it is likely that the increased gene transcription and mRNA stability are due to intrinsic differences in PCOS theca cells.

Base Sequence↗

PubMed1999

A preponderance of basic luteinizing hormone (LH) isoforms accompanies inappropriate hypersecretion of both basal and pulsatile LH in adolescents with polycystic ovarian syndrome.

We recently demonstrated that adolescent girls with polycystic ovarian syndrome (PCOS) exhibit augmented LH secretion due to an increase in immunofluorometric and deconvolution-estimated LH secretory burst mass and pulse frequency. Concurrently, we inferred either a prolongation of apparent (endogenous) LH half-life or elevated basal (nonpulsatile) LH release in PCOS. The in vivo half-life of LH molecules can be affected by the oligosaccharide side-chains, which also modify in vitro bioactivity and electrostatic change. Accordingly, as a surrogate estimator of altered endogenous LH half-life and/or biopotency in PCOS, we characterized the isoelectric properties of secreted LH isoforms and determined their in vitro biological activity in adolescent girls with PCOS compared with healthy age-matched eumenorrheic controls. To this end, 12-h (overnight) serum samples from PCOS patients (n = 12) and normal adolescents (n = 10) were pooled by subject. Bioactive LH concentrations were then quantitated in a rat Leydig cell in vitro bioassay, and immunological activity was determined by immunofluorometry. The distribution of LH isoforms was evaluated by preparative chromatofocusing (pH window, 10.5 to <4.0) of samples further combined to yield three independent serum pools for each of the patient and control groups. Fasting serum concentrations of 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone, estrone, estradiol, and sex hormone-binding globulin were determined as possible endocrine correlates of LH isotypes. Mean serum concentrations of immunoreactive and bioactive LH in adolescents with PCOS were 3 and 2 times higher than values in controls: immunoreactive: PCOS, 7.8+/-0.9; controls: 2.6+/-0.3 IU/L (P < 0.001); and bioactive: PCOS, 52+/-10; controls, 25+/-4.1 IU/L (P = 0.002), respectively. Bioactive LH concentrations correlated positively with 17-OHP (P = 0.022), androstenedione (P = 0.012), and testosterone (P = 0.046) concentrations in PCOS. Chromatofocusing of LH isoforms disclosed greater LH immunoreactivity at pI values greater than 8 and 7.99-7.0 in adolescents with PCOS compared with controls (P = 0.031). The percentage of basic LH isoforms was related positively to serum concentrations of 17-OHP (P = 0.032), androstenedione (P = 0.046), and testosterone (P = 0.040). In conclusion, the present isotype analysis demonstrates elevated in vitro LH bioactivity and a preponderance of basic LH isoforms in girls with PCOS. Since previously reported heterologous in vivo assays of LH kinetics point toward accelerated removal of such alkaline isotypes, our findings would favor the earlier alternative hypothesis of inappropriate hypersecretion of basal (interpulse) LH rather than prolongation of the LH half-life as the mechanism for elevated interpulse serum LH concentrations in adolescents with PCOS. In ensemble, the foregoing data thus suggest 3-fold amplification of basal LH secretion as well as both a heightened amplitude and frequency of the pulsatile mode of LH release in PCOS.

17-alpha-Hydroxyprogesterone↗

PubMed2002

Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome.

There is an inherited susceptibility to polycystic ovary syndrome (PCOS). Some investigators have suggested that premature male-pattern balding is a male phenotype in PCOS families, but this remains controversial. We recently reported evidence for an autosomal monogenic abnormality in ovarian and adrenal steroidogenesis in the sisters of women with PCOS. We performed this study to determine whether we could identify a clinical or biochemical phenotype in the brothers of women with PCOS. One hundred nineteen brothers of 87 unrelated women with PCOS and 68 weight- and ethnicity-comparable unrelated control men were examined and had fasting blood samples obtained. The odds of balding (Hamilton score > or = V) did not differ in the brothers of PCOS women compared with control men. Brothers of women with PCOS had significantly elevated dehydroepiandrosterone sulfate (DHEAS) levels [brothers 3035 +/- 1132 ng/ml (mean +/- SD) vs. control men 2494 +/- 1172 ng/ml; P < 0.05]. There was a significant positive linear relationship between DHEAS levels in PCOS probands and their brothers (r = 0.35; P = 0.001). There was no significant bimodal distribution in DHEAS levels, and there were no significant differences in other parameters in brothers of PCOS women with high DHEAS levels compared with those with low DHEAS levels. There is familial clustering of elevated DHEAS levels in the brothers of women with PCOS, suggesting that this is a genetic trait. This might reflect the same underlying defect in steroidogenesis that we found in the sisters of women with PCOS. Balding was not increased in the brothers of women with PCOS. We conclude that there is a biochemical reproductive endocrine phenotype in men in PCOS families.

Adult↗

PubMed2004

The polycystic ovary syndrome per se is not associated with increased chronic inflammation.

OBJECTIVE: The syndrome of polycystic ovaries (PCOS) is a known risk factor for type 2 diabetes. It is not known, however, whether the increase in diabetes risk is related to endocrine abnormalities associated with PCOS such as hyperandrogenemia, or whether it is a consequence of the anthropometric or metabolic alterations frequently observed in PCOS women. DESIGN: Since markers of inflammation are supposed to predict type 2 diabetes, interleukin-6 (IL-6) and C-reactive protein (CRP) in combination with parameters of obesity, insulin resistance and hyperandrogenism were determined in 57 PCOS women and in 20 age-matched healthy controls. In addition, the C-174G IL-6 promoter polymorphism was analyzed as a determinant in influencing IL-6, obesity, and androgen levels in women. RESULTS: Neither CRP nor IL-6 were significantly elevated in lean or obese PCOS women compared with age-matched lean or obese controls. In PCOS patients, variables of body composition (body mass index (BMI), waist to hip ratio, dual-energy X-ray-absorptiometry fat mass) and of insulin resistance were correlated with IL-6 or CRP, while parameters of hyperandogenism were not. Multivariate linear regression analysis revealed that obesity is the dominant force, thus explaining 18% and 24% of the IL-6 or CRP levels, respectively, in PCOS women. No association of IL-6 or BMI to a certain genotype at C-174G could be demonstrated in 50 PCOS patients. The heterozygous GC genotype, however, was associated with lower androstendione levels. Metformin treatment of 9 obese, insulin-resistant PCOS patients over a period of 6 months caused a significant decrease in body weight, body fat mass and total testosterone, but showed no significant decline in IL-6 or CRP concentrations. CONCLUSIONS: In PCOS women, plasma levels of IL-6 and CRP were not increased when compared with age- and BMI-matched controls. BMI was, however, the parameter most strongly related to IL-6 and CRP in PCOS; thus PCOS-related endocrine abnormalities do not appear to activate inflammatory parameters thereby enhancing the risk of diabetes. In PCOS, the type 2 diabetes risk may, therefore, be confined to those with obesity and/or metabolic alterations rather than affecting all women suffering from the syndrome.

Adult↗

PubMed2004

Genetic basis of metabolic abnormalities in polycystic ovary syndrome: implications for therapy.

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. The syndrome is frequently associated with an increased risk for insulin resistance and type 2 diabetes mellitus; obesity exacerbates insulin resistance and favors the progression from impaired glucose tolerance to diabetes in these patients. In young women, precocious pubarche and hyperinsulinemia are early manifestations of PCOS. The familial clustering of women with PCOS suggests that heredity is implicated in the origin of the syndrome. However, genetic approaches to its pathogenesis have been hampered by the heterogeneity of phenotypic features within families, and the lack of uniform criteria for diagnosis. Currently, PCOS is considered a polygenic trait that might result from the interaction of susceptibility and protective genomic variants under the influence of environmental factors. Both linkage analysis and association studies are valid tools for the study of the genetics of PCOS. Candidate genes for PCOS include those related to androgenic pathways and metabolic associations of the syndrome. More recently, genes encoding inflammatory cytokines have been identified as target genes for PCOS, as proinflammatory genotypes and phenotypes are also associated with obesity, insulin resistance, type 2 diabetes, PCOS, and increased cardiovascular risk. This paper reviews the candidate genes involved in the metabolic pathways that are altered in patients with PCOS. Despite a significant amount of research in this area, none of the genes studied so far has been identified as the PCOS susceptibility gene for the majority of cases. PCOS is the first component of the metabolic syndrome to be detected in many women, so the identification and correct diagnosis of PCOS has important preventive and therapeutic implications for the affected women and their families. In the future, new therapeutic approaches to PCOS will rely on knowing the genes, environmental influences, and etiologic mechanisms associated with the disorder.

Animals↗

PubMed2006

[Epidemiological study of clinical characteristics of Chinese Han ethnic women with polycystic ovary syndrome].

OBJECTIVE: To carry out an epidemiological study of clinical characteristics of Chinese Han ethnic women with polycystic ovary syndrome (PCOS). METHODS: According to Revised 2003 European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine criteria, PCOS can be diagnosed with 2 manifestations out of oligo-or anovulation, clinical and/or biochemical signs of hyperandrogenism exclusion of other etiologies and polycystic ovaries. One thousand and twenty-seven women in reproductive age from one area in Jinan city were investigated and the clinical, metabolic characteristics of the PCOS patients were analyzed. RESULTS: (1) A total of 828 questionnaires were collected from 1027 women; the response rate was 80.62%. Eighty-five PCOS patients were diagnosed; PCOS accounted for 97.65% (83/85) in <or= 35 years old population groups; (2) Clinical manifestations were different between PCOS groups and controls in each age stage (P < 0.05); Menstruation, body hair Ferriman-Gallny (F-G) score, acne, ovarian follicle numbers decreased with aging among PCOS groups, and menstruation cycle was longer, testosterone (T), free androgen index (FAI) and ovarian follicle numbers were higher, sex hormone-binding globulin (SHBG) was lower than control groups of the same age respectively (P < 0.01); (3) Homeostasis model assessment-insulin resistance (Homa-IR) index in infertility PCOS group was higher than in fertility group (1.49 +/- 0.73 vs 1.31 +/- 0.66; t = 2.058; P < 0.05); fasting insulin, fasting blood glucose in obesity PCOS group was higher than in non-obesity group (8.50 +/- 3.46 vs 5.7 +/- 2.3, t = 2.984; P < 0.01, 5.45 +/- 0.54 vs 4.88 +/- 0.45, t = 2.891; P < 0.01), in contrast, insulin sensitivity index was lower in obesity PCOS group than in non-obesity group (0.025 +/- 0.015 vs 0.044 +/- 0.026; t = 2.292, P < 0.05). CONCLUSIONS: (1) PCOS mainly distributes in <or= 35 years old population; (2) clinical manifestations of oligo-ovulation, clinical and/or biochemical signs of hyperandrogenism, polycystic ovaries of PCOS change with age increase. (3) PCOS with infertility and obesity is usually associated with glucose metabolic changes, especially insulin resistance.

Adult↗

PubMed2005

Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome.

OBJECTIVE: To determine plasma adiponectin concentration in women with and without polycystic ovary syndrome (PCOS) and to assess possible correlations of adiponectin to the hormonal and metabolic parameters, including measures of insulin resistance (IR). DESIGN: Case-control study. SETTING: Tertiary-referral university hospital. PATIENT(S): One hundred eighty selected women were classified as follows: 45 obese (body mass index [BMI] >30 kg/m2) with PCOS; 45 lean (BMI <25 kg/m2) with PCOS; 45 obese (BMI >30 kg/m2) without PCOS, and 45 lean (BMI <25 kg/m2) without PCOS. INTERVENTION(S): Blood samples were collected from all women with or without PCOS between 8 and 11 am, after an overnight fast. MAIN OUTCOME MEASURE(S): Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), free T4, testosterone (T), 17-alpha-hydroxyprogesterone, Delta4-androstenedione (Delta4-A), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), insulin, and plasma levels of adiponectin and glucose. Measures of IR included fasting serum insulin, glucose-to-insulin ratio, and homeostasis model assessment (HOMA). RESULT(S): Adiponectin concentrations were found to be significantly decreased in women with PCOS and in obese women without PCOS as compared with lean women without PCOS. Adiponectin concentrations correlated inversely with body weight, BMI, fasting plasma glucose, serum insulin, Delta4-A, DHEA, DHEAS, and HOMA but correlated positively with serum T, SHBG, FAI, and glucose-to-insulin ratio. Multiple regression analysis showed that BMI, HOMA, Delta4-A, and insulin were independent determinants of adiponectin concentrations. CONCLUSION(S): Hypoadiponectinemia is evident in obese and lean women with PCOS with variable degree of IR; and it is suggested that IR per se or other metabolic abnormalities of PCOS are involved in the regulation of adiponectin concentration in women with PCOS.

Adiponectin↗

PubMed2003

Polycystic ovary syndrome, the G1691A factor V Leiden mutation, and plasminogen activator inhibitor activity: associations with recurrent pregnancy loss.

Our specific aim was to assess associations of thrombophilia, hypofibrinolysis, and polycystic ovary syndrome (PCOS) with recurrent pregnancy loss (RPL) (>/=3 consecutive pregnancy losses < 20 weeks gestation). Prospective studies were performed in 33 Caucasian women referred for diagnosis and treatment of PCOS who were subsequently found to have RPL and in 16 Caucasian women referred for diagnosis and treatment of RPL, who did not have PCOS. Cases (PCOS-RPL, RPL without PCOS) were compared with controls (116 healthy Caucasian females) for the G1691A Factor V Leiden, G20210A prothrombin, C677T methylenetetrahydrofolate reductase (MTHFR), plasminogen activator inhibitor 4G/5G, and platelet glycoprotein PL A1A2 gene mutations. Cases were compared with controls (44 healthy adult Caucasian females) for serologic coagulation tests including homocysteine, proteins C, S, free S, antithrombin III, anticardiolipin antibodies IgG and IgM, dilute Russel's viper venom time, activated partial thromboplastin time, Factor VIII, Factor XI, lipoprotein (Lp)(a), and plasminogen activator inhibitor activity (PAI-Fx). The 33 Caucasian women with PCOS subsequently found to have RPL were 10% of a cohort of 322 Caucasian women who had >/= 1 previous pregnancy and had been referred for diagnosis and therapy of PCOS over a 4.3-year period. The Factor V Leiden G1691 mutation was present in 6 of 33 women (18%) with PCOS-RPL and in 3 of 16 women with RPL without PCOS (19%) versus 2 of 116 (1.7%) female controls, Fisher's P (p(f)) =.0016, p(f) =.013. The 33 PCOS-RPL cases also differed from the 44 female controls for high PAI-Fx (>21.1 U/mL), 38% versus 8%, p(f) =. 004. The thrombophilic G1691A Factor V Leiden mutation is associated with RPL in women with and without PCOS; hypofibrinolysis (high PAI-Fx) is also associated with RPL in women with PCOS.

Abortion, Spontaneous↗

PubMed2006

Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia.

The authors hypothesized that a metformin (MET)-diet would improve symptoms of idiopathic intracranial hypertension (IIH) in women who also had polycystic ovary syndrome (PCOS) or hyperinsulinemia without PCOS. Changes in weight, papilledema, headache, visual fields, and overall life status were prospectively assessed in response to 6 to 14 months on 2.25 g/day MET-diet or diet alone in 36 women with IIH, 23 with PCOS, selected by baseline body mass index (BMI) > or = 25, and no previous surgery for IIH. Overall life status was graded using a self-reported 1-5 scale (1 = well, normal activities; 2 = unwell, usual activities; 3 = poor, usual activities; 4 = poor, no usual activities; 5 = totally disabled). Conventional treatment for IIH was maintained unchanged during MET-diet intervention. The diet was hypocaloric (1500 calories/day), high protein (26% of calories), and low carbohydrate (44%). Of the 23 women with PCOS, 20 received MET-diet and 3 diet only (could not tolerate MET). Of the 13 women without PCOS, 7 were hyperinsulinemic and received MET-diet and 6 received diet alone. The 3 treatment groups (diet only [n = 9], PCOS-MET-diet [n = 20], and hyperinsulinemia-MET-diet [n = 7]) did not differ by median entry BMI (33.3, 37.6, and 35.7 kg/m(2)) or by duration of treatment (10.2, 11.4, and 10.9 months). Median percent weight loss was greatest in the PCOS-MET group (7.7%, P = 0.0015), was 3.3% in the diet only group, and 2.4% (P = 0.04) in the hyperinsulinemia-MET group. Papilledema significantly improved in the diet-alone group from 100% at baseline to 13% (P = 0.03), and in the PCOS-MET group from 95% to 30% (P = 0.002). If headache persisted on therapy, it was less intense-less frequent (P = 0.03) in the diet-only group and in the PCOS-MET group (P = 0.04). As many women with IIH have PCOS, and because weight loss is central to IIH treatment, diet-MET is a novel approach to treat IIH in women with concurrent PCOS or hyperinsulinemia without PCOS.

Adolescent↗

PubMed2002

Obesity and serum luteinizing hormone level have an independent and opposite effect on the serum inhibin B level in patients with polycystic ovary syndrome.

OBJECTIVE: To elucidate whether the negative effect of obesity on the serum inhibin B level that we previously reported is specific or not to polycystic ovary syndrome (PCOS) and whether it may explain the wide interindividual variability in serum inhibin B levels found in patients with PCOS. DESIGN: Prospective study. SETTING: Reproductive endocrinology unit of an academic medical center. PATIENT(S): One hundred thirty-four consecutive patients with PCOS (mean age, 27.4 +/- 4.7 years; mean body mass index [BMI], 28.3 +/- 7.6 kg/m(2); BMI > 25, 53%) and in 78 control women (mean age, 30.1 +/- 4.1 years; mean BMI, 24.3 +/- 4.9; BMI > 25, 34%). INTERVENTION: Blood sampling was performed in the early follicular phase in patients and in control women. MAIN OUTCOME MEASURE(S): BMI and waist circumference (WC), serum levels of inhibin B, LH, FSH, E(2), androstenedione, T, fasting insulin, and leptin were assessed in all subjects. RESULT(S): No difference was observed in the mean inhibin B level between patients and controls. The BMI and WC correlated negatively with inhibin B in patients with PCOS and in controls, with similar regression slopes, thus indicating that the influence of obesity on inhibin B is not specific to PCOS. In addition, we found a positive relationship between serum LH and inhibin B levels in PCOS. There was no significant interaction between the effects of BMI and LH on the serum inhibin B levels by analysis of variance (ANOVA). The mean serum inhibin B level in patients with PCOS with high serum LH (i.e., >the 90th percentile of LH in controls) was significantly higher than in those patients with normal LH or in controls. The highest mean inhibin B level was noted in nonobese patients with PCOS with high LH levels (121.0 +/- 51.2 pg/mL), while nonobese patients with PCOS with normal LH levels and obese patients with normal LH or high LH levels had similar mean levels (94.5 +/- 40.0, 84.9 +/- 34 and 91.6 +/- 51.7 pg/mL, respectively). CONCLUSION(S): We confirm that obesity has a negative effect on inhibin B serum level, which is not specific to PCOS. Obesity and excess LH, acting oppositely and independently on inhibin B production, may explain the discrepancies between the previous reports studying serum inhibin B level in patients with PCOS. Further work is required to elucidate the mechanisms underlying the antagonistic effects of LH and obesity on inhibin B production in patients with PCOS.

Adolescent↗

PubMed1998

Altered morning and nighttime pulsatile corticotropin and cortisol release in polycystic ovary syndrome.

An overdrive of the hypothalamic-pituitary-adrenal (HPA) axis has been postulated in patients with polycystic ovary syndrome (PCOS). However, little is known concerning the pulsatile modes of corticotropin (ACTH) and cortisol secretion in these patients. To further investigate this issue, spontaneous ACTH and cortisol release were evaluated in 16 normal-weight patients with PCOS and 16 control women. Nine PCOS patients and eight controls were studied between 8 AM and 12 AM (noon), and seven PCOS patients and eight controls between 11 PM and 3 AM. Venous blood samples were taken at 10-minute intervals. Cluster analysis was used to assess ACTH and cortisol pulse frequency and amplitude, deconvolution to calculate mean hormone secretion rates, and approximative entropy (ApEn) to measure the orderliness of ACTH and cortisol time-series data. PCOS patients compared with controls displayed increased ACTH and cortisol release (area under the curve [AUC] and mean plasma concentration) both in the morning and at night. This was not due to increased hormonal secretory burst frequency, but to higher hormonal interpeak valley concentrations and, in the case of ACTH, nighttime pulse amplitudes. Mean ACTH and cortisol secretion rates also were increased in PCOS patients. Further, both controls and PCOS patients exhibited significant (0 to 20 minutes lagged) concordance between individual daytime pulsatile ACTH and cortisol release episodes. As shown by increased ApEn values, PCOS patients had more disorderly daytime cortisol release. In addition, the normal daytime correlation between the amount of pulsatile ACTH and cortisol release as observed in the controls was lost in PCOS patients. Finally, cross-correlation analysis showed a more prominent negative correlation in PCOS patients versus controls between plasma cortisol and 40- to 120-minute delayed ACTH concentrations in the morning, indicating a more sustained negative feedback of cortisol on ACTH release in PCOS at this time. Taken together, these findings demonstrate the existence of multifaceted dysregulation of the HPA axis in PCOS.

Adolescent↗

PubMed1998

Lack of insulin resistance in fibroblasts from subjects with polycystic ovary syndrome.

Insulin resistance in polycystic ovary syndrome (PCOS) is characterized by a novel defect in insulin signal transduction expressed in isolated human adipocytes as impaired insulin sensitivity for glucose transport and antilipolysis. To determine whether this is a generalized defect of a potentially genetic basis, or possibly a tissue-specific one, fibroblast cultures were established from age- and weight-matched obese normal cycling (NC; n = 5) and PCOS (n = 6) subjects. Adipocytes from the current PCOS subjects displayed impaired sensitivity for glucose transport stimulation (half-maximal effective concentration [EC50], 317 +/- 58 pmol/L in PCOS v 130 +/- 40 in NC; P < .025). Specific insulin binding was similar in fibroblasts from NC (0.57% +/- 0.10%/10(6) cells) and PCOS (0.45% +/- 0.10%) subjects. Fibroblasts from NC (4.9- +/- 0.5-fold stimulation) and PCOS (4.6- +/- 0.3-fold) subjects were equally responsive to insulin for stimulation of glucose incorporation into glycogen. Insulin sensitivity for glycogen synthesis in fibroblasts did not differ between NC (EC50, 9.6 +/- 0.9 nmol/L) and PCOS (9.1 +/- 0.9) cells. For thymidine incorporation into DNA, relative insulin responsiveness was similar in NC (2.3- +/- 0.3-fold stimulation) and PCOS (2.1- +/- 0.1-fold) fibroblasts. Insulin sensitivity for DNA synthesis was similar in NC (EC50, 12.9 +/- 2.4 nmol/L) and PCOS (7.6 +/- 1.3) cells. In summary, (1) insulin receptor binding is normal in PCOS fibroblasts; and (2) PCOS fibroblasts have normal insulin sensitivity and responsiveness for metabolic and mitogenic responses. Impaired insulin signal transduction, while present in adipocytes from a group of PCOS subjects, is not found in fibroblasts from the same subjects. This defect is not generalized to all cell types, but may be limited to specific tissues and responses.

Adipose Tissue↗

PubMed1997

The counterregulatory response to hypoglycaemia in women with the polycystic ovary syndrome.

OBJECTIVE: The pathogenetic mechanisms behind insulin resistance in polycystic ovary syndrome (PCOS) are far from fully elucidated. Aberrant counterregulatory responses to hypoglycaemia have been reported in patients with insulin resistance, and recent reports suggest that plasma glucose may be regulated at lower levels in women with PCOS. In this study we investigated the complete hormonal counterregulatory response to hypoglycaemia in women with PCOS. DESIGN: Prospective cross-sectional study. PATIENTS: Eight obese (BMI > or = 25) and 10 non-obese (BMI < 25) women with PCOS, diagnosed by means of ultrasonography and clinical signs of chronic anovulation. Eight obese and 9 non-obese controls. MEASUREMENTS: Hypoglycaemia was induced by an intravenous bolus of soluble insulin (0.15 IU/kg body weight). The counterregulatory responses of cortisol, GH, catecholamines, glucagon, chromogranin A (CGA), and neuropeptide Y (NPY) were studied together with symptoms of hypoglycaemia. RESULTS: The obese women with PCOS had a more pronounced truncal-abdominal body fat distribution (waist hip ratio, WHR) and were hyperinsulinaemic, compared with the obese controls. All the women exhibited blood glucose levels (< 2 mmol/l) well below the threshold for the hormonal counterregulatory response and for the appearance of clinical symptoms. The non-obese women with PCOS showed a greater increase in serum concentrations of GH than the lean controls. The obese women with PCOS exhibited blunted responses of noradrenaline and NPY, but similar increases of adrenaline and CGA, compared with the obese controls. They also showed a lower symptom score during hypoglycaemia. The response of noradrenaline to hypoglycaemia correlated inversely with fasting insulin levels in the women with PCOS. Among all the obese women (PCOS and controls pooled) basal levels of noradrenaline correlated inversely with the WHR. CONCLUSIONS: All the women with PCOS, independent of BMI, body fat distribution and insulin levels, showed preserved counterregulatory responses to hypoglycaemia. The reduced plasma levels of noradrenaline and the lower perception of hypoglycaemic symptoms in the obese women with PCOS could both reflect a lower activation of the sympathetic nervous system. This aberration seems related to truncal-abdominal obesity and hyperinsulinaemia. The finding of an increased response of GH in the lean women with PCOS could support previous suggestions of an altered activity of the GH/IGF-I system in these women.

Adult↗

PubMed2002

Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: a comparison of two distinct populations.

OBJECTIVES: We sought to determine what differences, if any, existed between white and Mexican American women with polycystic ovary syndrome (PCOS) and whether the same values for fasting insulin, fasting glucose/insulin ratio, and homeostasis model assessment (HOMA) might be applied when screening both ethnic groups for insulin resistance. STUDY DESIGN: Eighty-three consecutive women suspected to have PCOS but who demonstrated absence of other endocrine disorders comprised the study population. Nineteen healthy ovulatory women volunteered as controls. Fasting serum samples were obtained for determination of thyroid-stimulating hormone (TSH), prolactin, glucose, insulin, free and total testosterone, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate in the early proliferative phase. An oral glucose load was administered, and blood samples for glucose and insulin were drawn at 1, 2, and 3 hours. Those with impaired glucose tolerance or diabetes mellitus were excluded from our final study population. Four different groups were defined: (1) women with PCOS and insulin resistance, (2) women with PCOS without insulin resistance, (3) women with irregular cycles but without PCOS or another identifiable endocrinopathy, and (4) regular, cycling control subjects. Each group was subdivided by ethnicity (white or Mexican American). A total of 65 white and 37 Mexican American women were studied, including control subjects. RESULTS: Among all study participants, Mexican American women with PCOS had significantly higher mean values for body mass index, fasting insulin, and HOMA but lower mean fasting glucose/insulin levels than white women. When group 1 patients (PCOS with insulin resistance) were compared between ethnic groups, mean fasting insulin and HOMA levels were significantly lower and glucose/insulin ratios higher in white than in Mexican American women. A single cutoff value for insulin resistance in PCOS was insensitive when applied to both ethnic groups. A fasting insulin value >20 microU/mL, HOMA value > 3.8, and glucose/insulin value <7.2 were reasonable screening values in our population of white women, whereas a fasting insulin value >23 microU/mL, HOMA value >4.5, and glucose/insulin ratio <4.0 were feasible screening values in Mexican American women. CONCLUSIONS: We conclude that (1) Mexican American women with PCOS are more insulin resistant than white women, (2) the incidence of insulin resistance is higher in Mexican American women with PCOS than in white women, (3) a single "screening" value for PCOS-related insulin resistance screening cannot be applied to both white and Mexican American women, and (4) normative values for insulin resistance screening in the PCOS population should be individualized for different racial or ethnic populations.

Adult↗

PubMed2005

Levels of lipoprotein and homocysteine in non-obese and obese patients with polycystic ovary syndrome.

AIM: This study was designed to examine the relationship between homocysteine (Hcy), lipoprotein levels and insulin resistance in obese and non-obese patients with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Eighty-five patients (38 obese, 47 non-obese) with PCOS and 50 healthy subjects (25 obese, 25 non-obese) were included in the study. PCOS was defined according to the Homburg criterion. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEA-S), insulin, 17-hydroxyprogesterone, free testosterone, androstenedione, vitamin B12 and folate were measured. Also, serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), lipoprotein (a) (Lp(a)), apoprotein B (Apo B) and apoprotein A (Apo A) were determined. Plasma Hcy levels were measured. Insulin resistance was evaluated by homeostasis model assessment (HOMA). RESULTS: Plasma Hcy levels were significantly higher in women with PCOS than in healthy women. HOMA-R (insulin resistance) was significantly higher in women with PCOS compared with healthy women. Serum fasting TC, LDL-C, TG, Apo B, vitamin B12 and folate levels were similar between PCOS and control groups. Lp(a) levels were higher in PCOS patients than in control subjects, whereas HDL-C and Apo A levels were lower. Compared with obese PCOS subjects, non-obese PCOS subjects had low HOMA-R, TC, LDL-C, TG, Apo B, Lp(a) and androgen levels. Plasma Hcy levels, serum HDL-C and Apo A levels were similar between obese and non-obese women with PCOS. Levels of HDL-C and Apo A were lower in both obese and non-obese PCOS patients than in obese and non-obese control subjects, whereas Lp(a) levels were higher. No correlation was observed between plasma Hcy, body mass index, HOMA-R, serum androgen levels, TC, LDL-C, HDL-C, Apo A, Apo B and Lp(a) levels. CONCLUSION: These results showed that elevated insulin resistance and plasma Hcy levels, and changes in serum lipid profile, which are possible risk factors for cardiovascular disorders, play important roles in the development of cardiovascular disease in both obese and non-obese patients with PCOS.

17-alpha-Hydroxyprogesterone↗

PubMed1998

Endocrino-metabolic features in women with polycystic ovary syndrome during pregnancy.

To elucidate the mechanism of metabolic adaptation of women with polycystic ovary syndrome (PCOS) during pregnancy, the endocrino-metabolic features of a group of PCOS patients with or without gestational diabetes were studied longitudinally during the three trimesters of gestation. Oral glucose tolerance test (OGTT, 100 g) and hyperinsulinaemic-euglycaemic clamp were performed throughout the study. Plasma concentrations of insulin and glucose were determined by radioimmunoassay and glucose oxidase technique, respectively. Five of 13 PCOS patients developed gestational diabetes (GD) at the third trimester (PCOS-GD), while the other eight patients did not develop any alteration of glucose metabolism (PCOS-nGD). Both fasting glucose and insulin plasma concentrations did not change significantly during pregnancy and no difference was seen between the two groups. On the contrary PCOS-GD group early exhibited higher values of area under the curve (AUC) for glucose and insulin response to OGTT with respect to those found in PCOS-nGD group. This difference was already significant in the first gestational trimester. Moreover insulin sensitivity value (M) was significantly lower in the first trimester of gestation in PCOS-GD as compared with that found in PCOS-nGD group. However, as gestation proceeded, M value decreased in PCOS-nDG group and the difference from PCOS patients developing gestational diabetes was not sustained into the second and third trimesters. Both groups had similar body mass index values and AUC insulin increase from first to third trimester of gestation. It is concluded that early alteration of insulin sensitivity and secretion constitute specific risk factors in PCOS patients for the development of abnormalities of glucose tolerance.

Adult↗

PubMed2001

Obstetric outcome in women with polycystic ovarian syndrome.

Women with polycystic ovarian syndrome (PCOS) often have insulin resistance and hyperinsulinaemia and may therefore be at an increased risk for gestational diabetes mellitus (GDM). Hyperinsulinaemia may also be associated with pre-eclampsia. Information concerning outcome of pregnancies in PCOS women is scanty and somewhat controversial. Therefore, 99 pregnancies were retrospectively evaluated in women with PCOS and the findings were compared with an unselected control population. The average body mass index (BMI) in PCOS patients was greater than that in controls (25.6 versus 23.0) (P < 0.0001), and PCOS patients were more often nulliparous than controls (76 versus 42%) (P < 0.001). The multiple pregnancy rate was 9.1% in PCOS patients and 1.1% in controls [odds ratio (OR) 9.0; 95% confidence interval (CI) 3.5-23.3]. GDM developed in 20% of the PCOS patients and in 8.9% of the controls (P < 0.001). After logistic regression analysis, BMI >25 seemed to be the greatest predictor for GDM (adjusted OR 5.1; CI 3.2-8.3), while PCOS remained as another independent predictor (adjusted OR 1.9; CI 1.0-3.5). In contrast, PCOS was not a significant predictor for pre-eclampsia, which was merely associated with nulliparity. Premature delivery (16.1% in PCOS and 6.5% in controls) was explained to a large extent by multiple pregnancies and marginally by nulliparity and PCOS. In singleton pregnancies, there was no difference in birth weights, Apgar scores or perinatal morbidity of infants. In conclusion, PCOS slightly increases the risk for GDM, but does not have an important effect on the rate of premature delivery and pre-eclampsia.

Adult↗