Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity

This study was performed to determine whether the sisters of women with polycystic ovary syndrome (PCOS) have evidence for insulin resistance. Three hundred and thirty-six women with PCOS, 307 sisters of these probands, and 47 control women were studied. The sisters were grouped by phenotypes: PCOS [hyperandrogenemia (HA) with chronic oligo- or amenorrhea, n = 39], HA with regular menses (n = 36), unaffected (UA; n = 122), and unknown (n = 110). The analyses were adjusted for age and body mass index. PCOS and HA sisters of women with PCOS had similar and significantly elevated fasting insulin levels (P = 0.001) as well as similar and significantly decreased fasting glucose/insulin ratios (P < 0.001) suggestive of insulin resistance compared with UA sisters and control women. Markers of insulin resistance were associated with hyperandrogenemia and not with menstrual irregularity. PCOS sisters also had decreased levels of SHBG (P = 0.02) suggestive of higher ambient insulin levels. PCOS sisters had increased levels of proinsulin (P = 0.04) compared with control women, which suggested pancreatic beta-cell dysfunction in this group of sisters. The magnitude of obesity also differed significantly among the groups of sisters. The PCOS sisters were significantly more obese than all the other groups, and the HA sisters were more obese than the UA sisters. We conclude that markers of insulin resistance are associated with hyperandrogenemia rather than menstrual irregularity in the sisters of women with PCOS. Menstrual irregularity may be related to the magnitude of insulin sensitivity or insulin secretion or to other factors associated with obesity.     

Evidence for metabolic and reproductive phenotypes in mothers of women with polycystic ovary syndrome

Dyslipidemia is a feature of polycystic ovary syndrome (PCOS), but its pathogenesis remains controversial. We performed this study of mothers of women with PCOS to test the hypothesis that dyslipidemia is a heritable trait in families of women with PCOS and to investigate the impact of age on reproductive and metabolic phenotypes. Fasting blood was obtained in 215 non-Hispanic white mothers of women with PCOS and 62 control women. The prevalence of metabolic syndrome was compared with that in non-Hispanic white women of comparable age from the National Health and Nutrition Examination Survey III. Mothers had higher total (P < 0.001) and low-density lipoprotein (LDL) cholesterol levels (P = 0.007), whereas high-density lipoprotein and triglyceride levels did not differ compared with control women. The only predictors of LDL levels in mothers were their daughters' LDL levels (r2 = 0.11, P < 0.001) and their own unbound testosterone levels (r2 = 0.04, P = 0.03). The prevalence of metabolic syndrome was increased in obese (body mass index > or = 30 kg/m2) mothers compared with obese non-Hispanic white women from the National Health and Nutrition Examination Survey III (P = 0.04). Thirty-one percent of mothers reported a history of menstrual irregularity. These mothers had higher androgen levels, markers of insulin resistance, and LDL levels than mothers with regular menses. LDL levels are increased in mothers of women with PCOS, suggestive of a heritable trait. A history of menstrual irregularity identifies mothers with features of PCOS. Obese mothers have a very high prevalence of metabolic syndrome. These findings suggest that both the reproductive and metabolic abnormalities persist with age in PCOS.     

Characterizing discrete subsets of polycystic ovary syndrome as defined by the Rotterdam criteria: the impact of weight on phenotype and metabolic features

CONTEXT: The Rotterdam criteria for polycystic ovary syndrome (PCOS) defines discrete subgroups whose phenotypes are not yet clear. OBJECTIVE: The phenotypic characteristics of women in the PCOS subgroups defined by the Rotterdam criteria were compared. DESIGN: The study was observational. SETTING: Subjects were studied in an outpatient setting in Boston and Reykjavik. PATIENTS: Four subgroups of subjects with PCOS defined by 1) irregular menses (IM), hyperandrogenism (HA), and polycystic ovary morphology (PCOM, n = 298); 2) IM/HA (n = 7); 3) HA/PCOM (n = 77); and 4) IM/PCOM (n = 36) and a group of controls (n = 64), aged 18-45 yr, were examined. INTERVENTION: Subjects underwent a physical exam; fasting blood samples for androgens, gonadotropins, and metabolic parameters; and a transvaginal ultrasound. MAIN OUTCOME MEASURES: The phenotype was compared between groups. RESULTS: Ninety-seven percent of women with IM/HA had PCOM. Therefore, the groups with and without PCOM were combined. The Ferriman-Gallwey score and androgen levels were highest in the hyperandrogenic groups (IM/HA and HA/PCOM), whereas ovarian volume was higher in all PCOS subgroups compared with controls, as expected based on the definitions of the PCOS subgroups. Body mass index and insulin levels were highest in the IM/HA subgroup. CONCLUSIONS: Subjects with PCOS defined by IM/HA are the most severely affected women on the basis of androgen levels, ovarian volumes, and insulin levels. Their higher body mass index partially accounts for the increased insulin levels, suggesting that weight gain exacerbates the symptoms of PCOS.     

Cardiovascular disease risk characteristics of the main polycystic ovary syndrome phenotypes

The aim of this article was to evaluate the clinical, endocrine, and cardiovascular disease risk profile differences among main polycystic ovary syndrome (PCOS) phenotypes. One hundred and thirty-nine consecutive women were included in the study. Body mass index (BMI), serum follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, estradiol, testosterone, dehydroepiandrosterone sulfate, fasting glucose, low density lipoprotein (LDL-C), total cholesterol, high density lipoprotein (HDL-C) high sensitive CRP, c-peptide, insulin, insulin sensitivity and carotid intima thickness were compared among different phenotype groups of PCOS: Group 1-PCO (polycystic ovaries)-anovulation (n = 34), Group 2-Hyperandrogenemia (HA)-anovulation (n = 30), Group 3-HA-PCO (n = 32), and Group 4-HA-PCO-anovulation (n = 43). Statistically significant differences among the different phenotype groups in terms of waist hip ratio, total cholesterol, LH, estradiol, fasting glucose, progesterone, free testosterone, and carotid intima media thickness were observed. The lowest mean CIMT was observed in Group 3, and the highest fasting glucose levels were in Group 4, while the lowest mean free testesterone was measured in Group 1. BMI, LDL-C, and total cholesterol showed significant positive correlations with CIMT (r = 0.411, P = 0.001; r = 0.258, P = 0.006; r = 0.199, P = 0.033). The lowest LDL-C, total cholesterol, and BMI were found in Group 3, but differences were not statistically significant. High-sensitive CRP levels were similar among the groups (P = 0.103). Group 3 PCOS with PCO and hyperandrogenemia phenotype has lower cardiovascular disease risk compared to other phenotypes.     

Oligoanovulation with polycystic ovaries but not overt hyperandrogenism

OBJECTIVES: By requiring a minimum of two of three items [hyperandrogenism (HA), oligoanovulation (OA), and polycystic ovaries (PCO) at ultrasound], the Rotterdam definition recognizes four PCO syndrome (PCOS) phenotypes: HA+OA+PCO (full-blown syndrome), HA+OA (former National Institutes of Health definition), HA+PCO (ovulatory PCOS), and OA+PCO. However, the latter phenotype is controversial, and it is not known to what extent it shares similarities with the others. DESIGN: The study was a comparative analysis of hormonal, metabolic, and ultrasound parameters obtained from patients and controls that were consecutively included in a database. PATIENTS AND METHODS: Sixty-six patients having OA+PCO without hirsutism or elevated serum androstenedione and testosterone levels were compared with 118 normally cycling nonhyperandrogenic age-matched women without PCO (controls). These patients (phenotype D) were also compared with patients with HA+OA+PCO (phenotype A, n = 246), HA+OA (phenotype B, n = 27), and HA+PCO (phenotype C, n = 67). RESULTS: Patients with phenotype D had higher mean values of waist circumference and higher mean levels of serum testosterone, androstenedione, and LH than controls. Conversely, they had lower mean serum levels of FSH and SHBG (P < 0.05 for each parameter). Variance analysis disclosed significant group effects between the different patients' phenotypes for all parameters, except age, BMI, and FSH. After multiple comparisons with post hoc analysis, phenotype D had milder endocrine and metabolic abnormalities than phenotype A, although it did not differ from phenotype C, except for androgen data, by definition. Phenotypes A and B were statistically similar, except for the ultrasound data, by definition. CONCLUSION: Oligoanovulatory patients with PCO but without HA have mild endocrine and metabolic features of PCOS.     

Determinants of dyslipidaemia in probands with polycystic ovary syndrome and their sisters

Objective Polycystic ovary syndrome (PCOS) is associated with dyslipidaemia and obesity. It is not clear whether the dyslipidaemia of PCOS is attributable to PCOS itself, obesity, or a combination of both. Our objective was to assess the importance of familial dyslipidaemia in PCOS by comparing fasting lipids between probands and their (affected and nonaffected) sisters. Design Retrospective data set analyses. Patients Family study; 157 probands, 214 sisters and 76 control women (normal ovaries and regular cycles). All probands had PCOS, defined by symptoms of anovulation and/or hyperandrogenism with polycystic ovaries on ultrasound. Affected or unaffected status of sisters was defined by ovarian morphology. Measurements Serum concentrations of triglycerides, total cholesterol, high‐density lipoprotein (HDL)‐cholesterol and low‐density lipoprotein (LDL)‐cholesterol. Results Triglyceride levels and body mass index (BMI) were higher and HDL cholesterol levels were lower in the probands than affected sisters, unaffected sisters and controls. These differences in lipid profiles between the groups disappeared after adjustment for BMI. No differences in lipids were seen between affected and unaffected sisters. Conclusions These data are consistent with heritability of lipid levels in sisters but strongly suggest that the predominant influence on the manifestation of dyslipidaemia in PCOS is body weight.     

Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome

Our preliminary family studies have suggested that some female first-degree relatives of women with polycystic ovary syndrome (PCOS) have hyperandrogenemia per se. It was our hypothesis that this may be a genetic trait and thus could represent a phenotype suitable for linkage analysis. To investigate this hypothesis, we examined 115 sisters of 80 probands with PCOS from unrelated families. PCOS was diagnosed by the combination of elevated serum androgen levels and ≤6 menses per year with the exclusion of secondary causes. The sisters were compared with 70 healthy age- and weight-comparable control women with regular menses, no clinical evidence of hyperandrogenemia, and normal glucose tolerance. Twenty-two percent of the sisters fulfilled diagnostic criteria for PCOS. In addition, 24% of the sisters had hyperandrogenemia and regular menstrual cycles. Circulating testosterone (T) and nonsex hormone-binding globulin-bound testosterone (uT) levels in both of these groups of sisters were significantly increased compared with unaffected sisters and control women (P < 0.0001 for both T and uT). Probands, sisters with PCOS, and hyperandrogenemic sisters had elevated serum luteinizing hormone levels compared with control women. We conclude that there is familial aggregation of hyperandrogenemia (with or without oligomenorrhea) in PCOS kindreds. In affected sisters, only one-half have oligomenorrhea and hyperandrogenemia characteristic of PCOS, whereas the remaining one-half have hyperandrogenemia per se. This familial aggregation of hyperandrogenemia in PCOS kindreds suggests that it is a genetic trait. We propose that hyperandrogenemia be used to assign affected status in linkage studies designed to identify PCOS genes.     

Metabolic profile in sons of women with polycystic ovary syndrome

CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder with strong familial aggregation. It has been demonstrated that parents and brothers of PCOS women exhibit insulin resistance and related metabolic defects. However, metabolic phenotypes in sons of PCOS women have not been described. OBJECTIVE: Our objective was to assess the metabolic profiles in sons of women with PCOS during different stages of life: early infancy, childhood, and adulthood. DESIGN: Eighty sons of women with PCOS (PCOS(S)) and 56 sons of control women without hyperandrogenism (C(S)), matched for age, were studied. In early infancy, glucose and insulin were determined in the basal sample. In children and adults, a 2-h oral glucose tolerance test was performed with measurements of glucose and insulin. Adiponectin, leptin, C-reactive protein, SHBG, and serum lipids were determined in the basal sample during the three periods. RESULTS: During early infancy, PCOS(S) showed higher weight (P = 0.038) and weight sd score (P = 0.031) than C(S). During childhood, weight (P = 0.003), body mass index (BMI) (P < 0.001), BMI sd score (P < 0.001), waist circumference (P = 0.001), total cholesterol (P = 0.007), and low-density lipoprotein cholesterol (P = 0.022) were higher in PCOS(S) compared with C(S), but after adjusting for BMI, these differences were nonsignificant. During adulthood, PCOS(S) exhibited higher weight (P = 0.022), BMI (P = 0.046), and waist circumference (P = 0.028) than C(S). Fasting insulin (P = 0.030), homeostasis model assessment for insulin resistance (P = 0.034), total cholesterol (P = 0.043), low-density lipoprotein cholesterol (P = 0.034), and 2-h insulin (P = 0.006) were also significantly higher and insulin sensitivity index composite significantly lower in PCOS(S) than in C(S) (P = 0.003). After adjusting for BMI, only 2-h insulin and insulin sensitivity index composite remained significantly different. CONCLUSIONS: This study indicates that sons of PCOS women exhibit higher body weight from early infancy. In addition, insulin resistance became evident as the subjects got older, which may place them at risk for the development of type 2 diabetes and cardiovascular disease.     

Genetic variation in 11beta-hydroxysteroid dehydrogenase type 1 predicts adrenal hyperandrogenism among lean women with polycystic ovary syndrome

CONTEXT: Elevated adrenal androgen levels are common in polycystic ovary syndrome (PCOS), but the underlying pathogenetic mechanism is poorly understood. In the rare cortisone reductase deficiency, impaired regeneration of active cortisol from inert cortisone by 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) results in compensatory activation of ACTH secretion and adrenal hyperandrogenism. 11beta-HSD1 deficiency may protect against obesity and its metabolic consequences because of impaired regeneration of cortisol in adipose tissue. OBJECTIVE: Our objective was to investigate a functional polymorphism in HSD11B1 (T-->G in the third intron rs12086634, which associates with lower 11beta-HSD1 activity) in PCOS with and without obesity. Design and Setting: We conducted a case-control study in lean and obese PCOS patients and controls at an academic hospital. PARTICIPANTS: Participants included 102 Caucasian PCOS patients and 98 controls comparable for age, weight, and race. MAIN OUTCOME MEASURES: We assessed genotype distribution and influence of genotypes on clinical, hormonal, and metabolic parameters. RESULTS: The G allele was significantly related to PCOS status (P = 0.041), and this association was mainly attributable to lean (P = 0.025), rather than obese (P = 0.424), PCOS patients. The G allele was associated with lower 0800-0830 h plasma cortisol (P < 0.001) and higher cortisol response to ACTH(1-24) (P < 0.001) in all women with PCOS and with higher dehydroepiandrosterone sulfate levels (P < 0.001), greater suppression of dehydroepiandrosterone sulfate by dexamethasone (P < 0.001), and lower fasting plasma low-density lipoprotein cholesterol (P = 0.002) levels in lean PCOS women. CONCLUSIONS: Genetic variation in 11beta-HSD1 contributes to enhanced cortisol clearance and compensatory adrenal hyperandrogenism in lean patients with PCOS but may be protective against obesity and some features of the metabolic syndrome.     

Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome

CONTEXT: Polycystic ovary syndrome (PCOS) and the metabolic syndrome have many features in common and may share the same pathogenesis. OBJECTIVE: This study was performed to determine the prevalence and predictors of the metabolic syndrome in PCOS. DESIGN: The clinical, hormonal, and oral glucose tolerance test results were analyzed in 394 PCOS women who were screened for participation in a multicenter trial to evaluate the effects of troglitazone on ovulation and hirsutism. SETTING: A multicenter clinical trial is presented. PATIENTS OR OTHER PARTICIPANTS: The subjects were women with PCOS who had or lacked the metabolic syndrome. MAIN OUTCOME MEASURES: Waist circumference, fasting glucose, high-density lipoprotein cholesterol and triglyceride concentrations, and blood pressure were the main outcome measures. RESULTS: Twenty-six (6.6%) subjects had diabetes; among the 368 nondiabetics, the prevalence for individual components comprising the metabolic syndrome were: waist circumference greater than 88 cm in 80%, high-density lipoprotein cholesterol less than 50 mg/dl in 66%, triglycerides greater than or equal to 150 mg/dl in 32%, blood pressure greater than or equal to 130/85 mm Hg in 21%, and fasting glucose concentrations greater than or equal to 110 mg/dl in 5%. Three or more of these individual criteria were present in 123 (33.4%) subjects overall. The prevalence of the metabolic syndrome did not differ significantly between racial/ethnic groups. The prevalence of the metabolic syndrome from lowest to highest quartile of free testosterone concentration was 19.8, 31.3, 46.9, and 35.0%, respectively [P = 0.056 adjusted for body mass index (BMI)]. None of the 52 women with a BMI less than 27.0 kg/m2 had the metabolic syndrome; those in the top BMI quartile were 13.7 times more likely (95% confidence interval, 5.7-33.0) to have the metabolic syndrome compared with those in the lowest quartile. Thirty-eight percent of those with the metabolic syndrome had impaired glucose tolerance compared with 19% without the metabolic syndrome (P < 0.001). CONCLUSIONS: The metabolic syndrome and its individual components are common in PCOS, particularly among women with the highest insulin levels and BMI. Hyperinsulinemia is a likely common pathogenetic factor for both PCOS and the metabolic syndrome.     

A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, chronic anovulation, and oligomenorrhea (O/M). PCOS has variable clinical phenotypes, biochemical features, and metabolic abnormalities. To determine the prevalence of PCOS in the Greek population as well as the metabolic parameters, we performed a cross-sectional study of 192 women of reproductive age (17-45 yr), living on the Greek island of Lesbos. They were divided into 4 groups according to the presence of hirsutism (defined as a Ferriman-Gallwey score > or = 6) and O/M: group N (n = 108), regular menses and absence of hirsutism; group 1 (n = 56), regular menses and hirsutism; group 2 (n = 10), O/M and absence of hirsutism; and group 3 (n = 18), O/M and hirsutism. Body mass index, waist to hip ratio, and mean blood pressure did not differ among the studied groups. Hormonal profile was assessed by measuring free testosterone (FT). The prevalence of PCOS, defined by the presence of O/M and biochemical hyperandrogenism (FT > or = 95th percentile of the normal women), was estimated to be 6.77% (13 women of 192). Higher FT levels were observed in group 3 (O/M and hirsutism) compared with groups N (P < 0.00001) and 1 (P < 0.0001) and in groups 1 (hirsutism) and 2 (O/M) compared with group N (P < 0.0001 and P < 0.005, respectively). Sex hormone-binding globulin levels were lower in women with PCOS and in groups 1 and 3 than those in group N (P < 0.002, P < 0.02, and P < 0.002, respectively) independently of the body mass index. The metabolic profile was investigated by measurements of fasting glucose (FG), fasting insulin (FI), and estimation of the fasting glucose to insulin ratio (FG:I ratio). After covariance adjusted for the BMI, FI levels were higher in group 3 and in women with PCOS than in the normal (P < 0.005 and P < 0.002, respectively) and the hirsute (P < 0.05 and P < 0.02, respectively) women, whereas FG levels did not differ among the studied groups. The FG:I ratio was lower in group 3, group 1, and in women with PCOS than in normal women (P < 0.05). Finally, a high incidence of family history of diabetes mellitus (P = 0.001) and menstrual disorders (P = 0.01) was observed in women with PCOS, in contrast to the normal and hirsute women. In conclusion, PCOS appears to be a particularly common endocrine disorder in the Greek population under study (prevalence, 6.77%); furthermore, it is associated with certain metabolic abnormalities. These data also suggest that the severity of the fasting hyperinsulinemia is associated with the severity of the clinical phenotype of hyperandrogenism independently of obesity.     

Identification of a polycystic ovary syndrome susceptibility variant in fibrillin-3 and association with a metabolic phenotype

CONTEXT: Polycystic ovary syndrome (PCOS), the most common reproductive endocrine disorder of premenopausal women, is also associated with metabolic abnormalities including insulin resistance and an increased risk for diabetes mellitus. We previously mapped a PCOS susceptibility locus to chromosome 19p13.2 near the dinucleotide repeat marker D19S884. OBJECTIVE: Our objective is to localize the chromosome 19p13.2 PCOS susceptibility locus and determine its impact on metabolic features of PCOS. DESIGN: Resequencing and family-based association testing were used to examine the effect of sequence variation within 100 kb of D19S884 on the reproductive and metabolic phenotypes of PCOS. SETTING: The study was conducted in an academic medical center. SUBJECTS: Genetic analyses were performed on DNA obtained from1723 individuals in 412 families with 412 index cases and 43 affected sisters of predominantly European origin (>94%). Genotype-phenotype associations were assessed in 601 women with PCOS and 168 brothers of affected women. RESULTS: D19S884 allele 8 (A8) within intron 55 of the fibrillin-3 (FBN3) gene showed the strongest evidence for association with PCOS of 53 variants tested (P(corrected) = 0.0037). A8 was also associated with higher levels of fasting insulin and homeostasis model assessment for insulin resistance in women with PCOS and higher fasting levels of proinsulin and proinsulin/insulin ratio in brothers. CONCLUSIONS: These findings strongly suggest that A8 of D19S884 is the chromosome 19p13.2 PCOS susceptibility locus. The association of D19S884 with markers of insulin resistance and pancreatic beta-cell dysfunction suggests that the same variant contributes to the reproductive and metabolic abnormalities of PCOS in affected women and their brothers.     

Hyperandrogenism and hyperinsulinism in children of women with polycystic ovary syndrome: a controlled study

OBJECTIVE: Hyperandrogenia and insulin resistance are heritable family traits, likely to cluster in children of polycystic ovary syndrome (PCOS) mothers. DESIGN: We performed a case control study of PCOS children (n = 32) compared with children from control women (n = 38) for reproductive and metabolic abnormalities, stratifying results by three Tanner stage groupings. The children underwent history and physical examinations, a 3-h timed urine collection, a 2-h oral glucose tolerance test, and abdominal ultrasound examination (females only). Serum was obtained in older children (age > 8 yr) who consented. RESULTS: Urine LH levels were significantly lower in the Tanner IV-V PCOS girls compared with controls (P = 0.04). Urine testosterone levels were significantly elevated in Tanner II-III PCOS boys compared with controls (P = 0.007). There were no significant differences in dehydroepiandrosterone levels. We validated the correlation between salivary and serum levels of insulin (insulin areas under the curve) in an adult population [n =30, Pearson correlation coefficient (r) = 0.67; P < 0.0001], which also replicated in the children (2-h insulin r = 0.57; P = 0.0004). Mean area under the curve salivary insulin levels were significantly higher in the Tanner IV-V PCOS girls in the later stages of puberty when compared with controls (3625 +/- 1372 vs. 1766 +/- 621 min x muU/ml, 95% confidence interval 475-3242; P < 0.02). CONCLUSIONS: Hyperinsulinism may be a familial characteristic of PCOS children (or at least girls) but does not appear until the later stages of puberty. Other reproductive abnormalities that characterize PCOS may develop later.     

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.     

Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment

CONTEXT: Insulin resistance plays a significant role in the pathogenesis of the polycystic ovary syndrome (PCOS) and represents a link to the unfavorable cardiovascular risk profile frequently found in affected patients. The endogenous nitric oxide synthase inhibitor asymmetrical dimethyl-L-arginine (ADMA) is associated with atherosclerosis and represents an independent marker for cardiovascular morbidity and mortality. OBJECTIVE: We investigated ADMA levels among other cardiovascular, metabolic, and hormonal parameters in women with PCOS and the effects of metformin treatment on these parameters. DESIGN: A cross-sectional study and clinical trial were performed. PATIENTS AND PARTICIPANTS: Women with PCOS (n = 83) compared with a control group of healthy women (n = 39) were studied. INTERVENTIONS: In a subgroup of patients with PCOS (n = 21), the effect of metformin was assessed after 6 months of treatment. MAIN OUTCOME MEASURES: ADMA, intima media thickness (IMT), metabolic and hormonal parameters, and markers of inflammation were investigated. RESULTS: ADMA levels were significantly higher in the PCOS group compared with controls (0.57 +/- 0.15 vs. 0.50 +/- 0.11; P = 0.024). Androgens, C-reactive protein, fasting C-peptide, area under the curve (AUC) insulin, AUC glucose, homeostatic assessment of insulin resistance, fasting insulin, glycosylated hemoglobin, cholesterol, low-density lipoprotein cholesterol, triglycerides, and IMT were significantly higher in women with PCOS compared with controls. In PCOS patients ADMA was found to be positively correlated with body mass index (BMI), waist to hip ratio, parameters of insulin sensitivity, hyperandrogenemia (free testosterone, free androgen index), and IMT. Treatment with metformin ameliorated hyperandrogenemia and decreased ADMA levels (0.53 +/- 0.06 vs. 0.46 +/- 0.09, P = 0.013). Decrease in ADMA levels subsequent to metformin treatment did not correlate with change in BMI or metabolic parameters. CONCLUSIONS: ADMA amd parameters of insulin sensitivity are elevated in women with PCOS and the degree of insulin resistance confers the greatest influence on ADMA level. Metformin treatment led to improvement of hormonal and metabolic parameters and decreased ADMA levels possibly independent of BMI and metabolic changes.     

Effect of long-term orlistat treatment on serum levels of advanced glycation end-products in women with polycystic ovary syndrome

BACKGROUND Women with polycystic ovary syndrome (PCOS) exhibit elevated serum advanced glycation end-products (AGE) compared with healthy subjects. Short-term administration of orlistat has been shown to reduce the postmeal increase in serum AGE levels in women with PCOS and in controls. OBJECTIVE: To evaluate the long-term effect of orlistat and a low-calorie diet on serum AGE levels, and on the hormonal and metabolic profile of obese PCOS and normal women. DESIGN: A clinical trial of 6 months of orlistat administration with an energy-restricted diet [basic metabolic rate (BMR) 600 kcal/day] in all subjects. SUBJECTS: Twenty-nine women with PCOS [aged 27.52 +/- 5.77 years; body mass index (BMI) 35.43 +/- 5.31 kg/m(2)] and 18 controls (aged 32.06 +/- 5.64 years; BMI 36.39 +/- 6.47 kg/m(2)). MEASUREMENTS: Serum AGE levels (U/ml), hormonal and metabolic profile. RESULTS: PCOS and controls did not differ in BMI (P = 0.58), waist-to-hip ratio (WHR) (P = 0.44), fasting insulin concentration (P = 0.45) and glucose-to-insulin ratio (GIR) (P = 0.34). PCOS women exhibited statistically higher AGE (P < 0.001) and testosterone levels (P < 0.001) compared with controls. After 6 months of orlistat treatment, AGE levels showed a statistically significant decrease in both groups (PCOS: baseline 9.08 +/- 1.84, post-orlistat 8.56 +/- 1.95, P = 0.001; controls: baseline 5.02 +/- 0.62, post-orlistat 4.91 +/- 0.69, P = 0.03), independently of the BMI reduction in the PCOS group. A significant reduction was observed in BMI (PCOS: P < 0.001; controls: P < 0.001), WHR (PCOS: P = 0.002; controls: P = 0.04), fasting insulin (PCOS: P < 0.001; controls: P = 0.008), and testosterone concentrations in PCOS (P < 0.001). SHBG concentration (PCOS: P = 0.004; controls: P = 0.008) and GIR (PCOS: P < 0.001; controls: P = 0.03) were significantly increased. A significant improvement was also observed in insulin resistance indices post-treatment in both groups. CONCLUSIONS: Our data suggest that orlistat has a beneficial effect in reducing elevated AGE levels and improving the hormonal and metabolic profile in women with PCOS after 6 months of treatment, independently of BMI changes.     

Effects of metformin and ethinyl estradiol-cyproterone acetate on lipid levels in obese and non-obese women with polycystic ovary syndrome

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit risk factors for cardiovascular diseases such as abdominal obesity, insulin resistance and dyslipidemia. Insulin sensitizers, especially metformin, have been shown to improve these metabolic disturbances, but there are only a few studies on their effects on serum lipids in polycystic ovary syndrome. METHODS: Thirty-five women with PCOS (18 obese and 17 non-obese) were randomized to 6-month treatments with metformin or ethinyl estradiol-cyproterone acetate oral contraceptive pills. RESULTS: In the whole-study population (non-obese and obese women) serum levels of high-density lipoprotein cholesterol increased from 1.4+/-0.2 to 1.6+/-0.1 mmol/l (means +/-S.E. throughout) at 3 and 6 months (P < 0.001), the total cholesterol:high-density lipoprotein cholesterol ratio decreased significantly from 3.8+/-0.3 to 3.3+/-0.2 at 6 months (P < 0.001) and a similar trend was observed in serum triglyceride levels during metformin treatment. In the oral contraceptive group, serum levels of total cholesterol increased from 4.9+/-0.3 to 5.4+/-0.3 mmol/l (P < 0.05), high-density lipoprotein cholesterol increased from 1.2+/-0.1 to 1.5+/-0.1 mmol/l (P < 0.001), the total cholesterol:high-density lipoprotein cholesterol ratio decreased from 4.6+/-0.4 to 3.7+/-0.2 (P < 0.001) and triglycerides increased from 1.3+/-0.1 to 1.9+/-0.2 mmol/l at 6 months of treatment (P < 0.001). Serum low-density lipoprotein cholesterol levels remained unchanged during both treatments. Milder but similar changes in the subgroups of obese and non-obese women were observed during both treatments. Moreover, in the whole-study population both systolic (P = 0.02) and diastolic (P = 0.05) blood pressures decreased over the 6 months of metformin treatment. CONCLUSION: In women with PCOS, metformin treatment had beneficial effects on lipid profile and blood pressure, and therefore it could be useful in the prevention of cardiovascular complications in these women.     

Plasma plasminogen activator inhibitor-1 levels in the different phenotypes of the polycystic ovary syndrome

We aimed to evaluate plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels in women with polycystic ovary syndrome (PCOS) and different levels of adiposity and PCOS phenotypes. We studied 199 women with PCOS and 50 age-matched healthy women divided in normal weight (n=100 and n=25, respectively) and overweight/obese (n=99 and n=25, respectively). Normal weight and overweight/obese patients with PCOS were further divided in patients diagnosed according to the 1990 criteria (i.e. with anovulation and hyperandrogenemia; 1990 criteria group) and in patients with the additional phenotypes introduced in 2003 (i.e. with polycystic ovaries and either anovulation or hyperandrogenemia; additional 2003 criteria group). In normal weight subjects, plasma PAI-1 levels did not differ between women with PCOS (regardless of group) and controls, or between the 1990 criteria and the additional 2003 criteria groups of PCOS. In overweight/obese subjects, plasma PAI-1 levels were higher in both the 1990 criteria and the additional 2003 criteria groups of PCOS compared with controls (p<0.001 and p=0.004, respectively), but did not differ between the 1990 criteria and the additional 2003 criteria groups of PCOS. In conclusion, plasma PAI-1 levels are elevated in overweight/obese women with PCOS but not in normal weight women with this syndrome. Plasma PAI-1 levels do not differ between the phenotypes of PCOS.     

Vascular dysfunction and metabolic parameters in polycystic ovary syndrome

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and the metabolic syndrome; however, the cardiovascular (CV) manifestations of PCOS remain unclear. OBJECTIVE: The objective of this study was to examine the relationships between IR, metabolic parameters, androgens, and markers of early CV disease in PCOS. DESIGN: We conducted an observational study examining noninvasive markers of early CV disease in women with PCOS including structural [carotid intimal media thickness (IMT)] and functional measures (arterial function with pulse wave velocity and endothelial function with brachial arterial flow-mediated vasodilation). Metabolic parameters included insulin and glucose during an oral glucose tolerance test and lipid and androgen levels. SETTING: Participants were recruited from the general community. PATIENTS: Eighty overweight women with PCOS who were nonsmokers and not on oral contraceptives or other medications known to affect IR participated in the study. RESULTS: Stepwise regression analysis showed that after adjustment for age and body mass index, IMT was significantly correlated with blood pressure (BP) load (P = 0.03) and inversely with dehydroepiandrosterone sulfate (DHEAS) (P = 0.01). After correction for androgen status, IMT was correlated with fasting glucose and area under curve (AUC) insulin. Flow-mediated vasodilation was inversely related to lipids (P = 0.02), whereas pulse wave velocity was related to BP (P < 0.001), AUC insulin (P = 0.04), and AUC glucose (P = 0.035). CONCLUSION: In overweight women with PCOS, insulin resistance and BP interacted negatively with arterial structural and functional measures. DHEAS correlated inversely with arterial structure, suggesting possible cardioprotective effects of endogenous DHEAS in women with PCOS. Additional research is needed to clarify these findings.     

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.