Dissociation of endothelial function and arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS)

Objective Polycystic ovary syndrome (PCOS) is associated with cardiovascular risk but it is not clear if this is independent of obesity and insulin resistance. This study therefore investigates endothelial function and arterial stiffness in nonobese, noninsulin resistant women with PCOS. Design This is cross‐sectional case–control study. Patients A total of 19 young women with PCOS, with body mass index (BMI) <30 kg/m², and 19 healthy controls matched for age and BMI were included in the study. Measurements Endothelial function was assessed with flow mediated dilatation (FMD) of the brachial artery, while arterial stiffness was assessed with pulse wave velocity (PWV) and augmentation index (AI). Results There were no significant differences between PCOS and control subjects when assessing the following clinical and biochemical variables: blood pressure, homeostasis model assessment insulin‐resistance index, lipids and oestradiol. Women with PCOS had higher free androgen index scores (5·14 ± 3·47 vs. 3·25 ± 1·42, P = 0·036). The PCOS subjects had significantly lower FMD of the brachial artery compared with the controls (6·5 ± 2·9%vs. 10·5 ± 4·0%, P < 0·01). There were no significant differences in markers of arterial stiffness (PWV 5·8 ± 1·1 vs. 6·0 ± 1·0, P = 0·58, AI 16·5 ± 10·2 vs. 20·3 ± 10·2, P = 0·25). Conclusions Women with polycystic ovary syndrome who are young, nonobese, and have no biochemical evidence of insulin resistance, have abnormal vascular function, but normal arterial stiffness, when compared with age and weight matched control subjects. Whether this leads to a greater risk of cardiovascular disease requires further investigation.     

The lack of association between polycystic ovary syndrome and metabolic syndrome: Iranian PCOS prevalence study

Objective This study was designed to evaluate the prevalence of the metabolic syndrome (MetS) and insulin resistance (IR) in a large population‐based study in Iran. Research design and methods Anthropometric measurements, biochemical parameters and IR were compared between 136 polycystic ovary syndrome (PCOS) subjects and 423 healthy controls recruited from among 1126 reproductive aged women (18–45 year). PCOS and MetS were diagnosed using the Rotterdam criteria and Joint Interim Statement, respectively. IR was defined using the homeostatic model assessment‐IR). Results Among the PCOS subjects, the mean ± SD age, body mass index (BMI) and waist circumference were 31 ± 7·7 years, 26·4 ± 5·8 kg/m² and 84 ± 13·3 cm, respectively; corresponding values among healthy controls were 36 ± 7·5 years, 26·4 ± 5·0 kg/m² and 85 ± 11·9 cm, respectively. Age and BMI adjusted prevalences of MetS in PCOS subjects and controls were 18·5% (CI 95%, 15·3–21·7%) and 18·3% (CI 95%, 15·1–21·5%), respectively [P = not significant (NS)]. Age and BMI adjusted prevalences of IR in PCOS and healthy controls were 27·2% (CI 95%, 23·5–30·9%) and 24·2% (CI 95%, 20·6–27·8%), respectively (P < 0·01). Conclusions Metabolic syndrome was no more frequent in a representative sample of PCOS Iranian population than in healthy controls. However, the prevalence of IR in PCOS appears to be higher than in controls. It seems that the association between PCOS and MetS needs more consideration.     

The molecular characteristics of polycystic ovary syndrome (PCOS) ovary defined by human ovary cDNA microarray

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders; it is characterized by polycystic ovaries, hyperandrogenism and chronic anovulation. To obtain a global view of those genes that might be involved in the development of this complex clinical disorder, we used recently developed cDNA microarray technology to compare differential gene expressions between normal human ovary and ovaries from PCOS patients. A total of 9216 clones randomly selected from a commercial human ovary cDNA library were screened. Among them, 290 clones showed differential expressions, including 119 known genes and 100 known or unknown expressed sequence tags (ESTs). Among 119 known genes, 88 were upregulated and 31 downregulated in the PCOS ovary, as compared with normal human ovary. These differentially expressed genes are involved in various biologic functions, such as cell division/apoptosis, regulation of gene expression and metabolism, reflecting the complexity of clinical manifestations of PCOS. The molecular characteristics established from our study will further our understanding of the pathogenesis of PCOS and help us to identify new targets for further studies and for the development of new therapeutic interventions.     

Metformin maintains the weight loss and metabolic benefits following rimonabant treatment in obese women with polycystic ovary syndrome (PCOS)

Objective Rimonabant has been shown to reduce weight, free androgen index (FAI) and insulin resistance in obese patients with polycystic ovary syndrome (PCOS) compared to metformin. Studies have shown that significant weight regain occurs following the cessation of rimonabant therapy. This study was undertaken to determine if subsequent metformin treatment after rimonabant would maintain the improvement in weight, insulin resistance and hyperandrogenaemia in PCOS. Design An extension study for 3 months with the addition of metformin to the randomised open labelled parallel study of metformin and rimonabant in 20 patients with PCOS with a body mass index ≥ 30 kg/m². Patients who were on 3 months of rimonabant were changed over to metformin for 3 months, whereas those on 3 months of metformin were continued on metformin for another 3 months. Measurements The primary end‐point was a change in weight; secondary end‐points were a change in FAI and insulin resistance. Results The mean weight loss of 6·2 kg associated with 3 months of rimonabant treatment was maintained by 3 months of metformin treatment (mean change +0·2 kg, P = 0·96). Therefore, the percentage reduction in weight remained significantly higher in the rimonabant/metformin group compared to metformin only subjects at 6 months compared to baseline (–6·0 ± 0·1%vs. –2·8 ± 0·1%, P = 0·04). The percentage change in testosterone and FAI from baseline to 6 months was also greater in the rimonabant/metformin group. [Testosterone (–45·0 ± 5·0%vs. –16 ± 2·0%, P = 0·02); FAI (–53·0 ± 5·0%vs. –17·0 ± 12·2%, P = 0·02)]. HOMA‐IR continued to fall significantly in the rimonabant/metformin group between 0, 3 and 6 months (4·4 ± 0·5 vs. 3·4 ± 0·4 vs. 2·7 ± 0·3, respectively, P < 0·01) but not at all in the metformin only group (3·4 ± 0·7 vs. 3·4 ± 0·8 vs. 3·7 ± 0·8, respectively, P = 0·80). Total cholesterol and LDL reduced significantly in both groups, but improvements in triglycerides and HDL were limited to the rimonabant/metformin group. Conclusions In these obese patients with PCOS, metformin maintained the weight loss and enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone.     

Long term complications of polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is a frequent endocrine disease affecting 10 to 15% of women. Menstrual disorders, hyperandrogenism and ultrasonographic aspect of ovaries are typical of the disease and are established diagnostic criteria. But PCOS has also long term complications frequently forgotten and underestimated. During pregnancy, gestational diabetes and gestational hypertensive disorders can occur. At an older age, metabolic disease such as glucose intolerance, type 2 diabetes or dyslipidaemia are frequently described. Women with PCOS have increased classical cardiovascular risks and increased subclinical cardio-vascular disease without proven increase of cardiovascular morbidity and mortality. Finally, endometrial cancer seems to be more frequent in women with PCOS. Therefore, PCOS have numerous long-term health risks and a life-long follow-up is necessary for these women “at-risk” to detect and prevent complications as soon as possible.     

A comparison of polysomnographic variables between obese adolescents with polycystic ovarian syndrome and healthy,normal-weight and obese adolescents

Purpose  

The purpose of this study was to determine the differences in polysomnographic variables between obese adolescents with polycystic ovarian syndrome (PCOS) and healthy, normal-weight and obese controls, as the prevalence of obstructive sleep apnea syndrome (OSAS) is increased in adults with PCOS.     

Body composition, fat distribution and metabolic characteristics in lean and obese women with polycystic ovary syndrome

The polycystic ovary syndrome (PCOS), characterized by chronic anovulation and hyperandrogenism, has many features of metabolic syndrome and can be considered a metabolic disease. Approximately 50% of patients with PCOS are overweight or obese with abdominal fat accumulation. Some metabolic alterations and abdominal fat distribution have also been reported in lean women with PCOS. The aim of this study was to evaluate the effect, if any, of obesity on metabolic features, body composition and fat distribution in patients with PCOS. Body composition and abdominal fat distribution (evaluated by DEXA), waist circumference, blood pressure, lipid profile, glucose tolerance and homeostasis model assessment index were determined in 23 lean [mean age 23 +/- 5 yr, mean body mass index (BMI) 22 +/- 2 kg/m2] and 27 overweight-obese (mean age 21 +/- 5 yr, mean BMI 32 +/- 5 kg/m2) patients with PCOS and in 20 age- and weight-matched eumenorrhoic women. Patients exhibited slight but non-significant differences in metabolic parameters, waist circumference, blood pressure and total and abdominal fat content compared with weight-matched controls. None of the lean subjects suffered from metabolic syndrome according to the National Cholesterol Education Program--Adult Treatment Panel III (NCEP-ATPIII) criteria as opposed to 10 overweight-obese patients and three overweight-obese control subjects (37% and 33.3% of each subgroup, respectively). Our data do not show significant metabolic alterations in lean PCOS women. Results indicate that obesity seems to underpin the metabolic alterations exhibited by the overweight-obese patients. However, since women with PCOS are at increased cardiovascular risk, further studies are needed to evaluate metabolic alterations and body composition in these patients.     

Increased arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS) without comorbidities: one more characteristic inherent to the syndrome?

Background Polycystic ovary syndrome (PCOS) is associated with adverse metabolic effects. Some cardiovascular disease (CVD) risk markers are increased in women with PCOS. However, early markers of atherosclerosis are also associated with obesity and insulin resistance, which are related to PCOS. These markers may result either directly from PCOS or indirectly as a consequence of the comorbidities associated with the syndrome. Context To assess the presence of early CVD markers in young, nonobese women with PCOS. Patients Forty women with PCOS and 50 healthy women with regular menstrual cycles, matched for age and body mass index (BMI). Measurements The following CVD markers were assessed by ultrasonography: common carotid artery (CCA) stiffness index (β), distensibility and intima–media thickness (IMT), and brachial artery flow‐mediated dilatation (FMD). Inflammatory markers, including interleukin (IL)‐6, tumour necrosis factor (TNF)‐α, homocysteine, C‐reactive protein (CRP), glycaemia, lipid profile and insulin, were also assessed. Results CCA β was higher in PCOS than in control women (3·72 ± 0·96 vs. 3·36 ± 0·96, P = 0·04) and CCA distensibility was lower (0·31 ± 0·08 vs. 0·35 ± 0·09 mmHg^?1, P = 0·02). Waist circumference, total testosterone and the Free Androgen Index (FAI) were higher in PCOS patients than in controls (78·2 ± 10·0 vs. 71·5 ± 7·2 cm, P = 0·001; 88·1 ± 32·4 vs. 57·1 ± 21·2 ng/dl, P < 0·01; 12·7 ± 15·7%vs. 4·7 ± 2·3%, P < 0·01, respectively), while SHBG was reduced (37·9 ± 19·1 vs. 47·8 ± 18·3 nmol/l, P = 0·01). The remaining variables did not differ between the groups. Conclusions Young women with PCOS exhibit changes in vascular elasticity even in the absence of classical risk factors for CVD, such as hypertension and obesity.     

Adiponectin levels in adolescent girls with polycystic ovary syndrome (PCOS)

Objective To determine serum adiponectin concentrations in adolescent girls with and without polycystic ovary syndrome (PCOS) and to assess possible correlations of adiponectin levels with insulin and androgen levels. Design Prospective case–control study. Setting Endocrine clinics in the community. Patients Forty‐four adolescent girls were grouped as follows: 14 were overweight [body mass index (BMI) standard deviation score >1·645] with PCOS; 16 were lean (BMI SDS <1·036) with PCOS; and 14 were lean (BMI SDS <1·036) without PCOS. Intervention Blood samples were collected from all girls between 8 and 11 am , after an overnight fast. Main outcome measures Serum levels of adiponectin, leptin, insulin, Müllerian‐inhibiting substance, luteinizing hormone, follicle‐stimulating hormone, testosterone, 17‐alpha‐hydroxyprogesterone, androstendione, dehydroepiandrosterone sulphate (DHEAS) and 17β‐oestradiol. Results Adiponectin concentrations were significantly decreased in obese adolescents with PCOS (10·5 ± 5·5 μg/ml) compared with that in lean girls with or without PCOS (16·9 ± 8·64 and 18·0 ± 7·4 μg/ml respectively). Leptin levels were significantly elevated in obese adolescents with PCOS compared with the levels in normal weight adolescents with PCOS, and compared with that in normal weight controls. Insulin levels were markedly higher in obese adolescents with PCOS compared with that in normal weight adolescents (12·3 ± 12·2 vs. 4·5 ± 2·9, P < 0·05), and compared with that in normal weight PCOS adolescents (7·4 ± 4·9); however, this difference was not statistically significant. Insulin levels did not differ between normal weight adolescents with PCOS and normal controls. Adiponectin concentrations correlated inversely with BMI, leptin and insulin. Conclusions Hypoadiponectinaemia is evident only in obese adolescents with PCOS and therefore does not seem to be involved in the pathogenesis of PCOS in this age group.     

Evaluation of metabolic risk markers in polycystic ovary syndrome (PCOS). Adiponectin, ghrelin, leptin and body composition in hirsute PCOS patients and controls

OBJECTIVE: Polycystic ovary syndrome (PCOS) patients are abdominally obese and are at increased risk of developing the metabolic syndrome. Low adiponectin and ghrelin levels in PCOS patients could be caused by insulin resistance as well as high testosterone levels. DESIGN: Adiponectin and ghrelin levels were evaluated in 51 hirsute PCOS patients referred to the outpatient clinic of an academic, tertiary care medical centre and in 63 weight-matched female controls. Relationships between adiponectin, ghrelin, leptin, body composition, testosterone and insulin were examined. METHODS: Measurements of body composition including waist-hip-ratio (WHR), body mass index (BMI) and whole body dual-energy X-ray absorptiometry scan measures of body fat mass. Measurements of fasting levels of adiponectin, ghrelin, leptin, androgen status, oestradiol, lipid variables and insulin during follicular phase. RESULTS: Adiponectin levels were significantly decreased in obese PCOS patients compared with weight-matched controls (geometric mean (-2 to 2 s.d.) 5.3 (2.5-11.1) vs 7.3 (3.0-17.4) mg/l, P<0.05). Mean ghrelin was significantly lower in hirsute PCOS patients than in controls (0.6 (0.3 to 1.4) vs 0.8 (0.4 to 1.7) microg/l, P<0.001) and this remained significant after subdividing subjects according to waist circumference and BMI. During multiple regression analysis, testosterone correlated positively with adiponectin and negatively with ghrelin independent of BMI, WHR and total fat mass. CONCLUSION: Obese hirsute PCOS patients demonstrated significantly lower adiponectin levels than weight-matched controls suggesting a very high risk for the metabolic syndrome. Furthermore, ghrelin levels were decreased in hirsute PCOS patients and showed a significant, negative correlation with testosterone independent of body composition.     

PCOS Forum: research in polycystic ovary syndrome today and tomorrow

Objective To summarize promising areas of investigation into polycystic ovary syndrome (PCOS) and to stimulate further research in this area. Design Summary of a conference held by international researchers in the field of polycystic ovary syndrome. Results Potential areas of further research activity include the analysis of predisposing conditions that increase the risk of PCOS, particularly genetic background and environmental factors, such as endocrine disruptors and lifestyle. The concept that androgen excess may contribute to insulin resistance needs to be re‐examined from a developmental perspective, since animal studies have supported the hypothesis that early exposure to modest androgen excess is associated with insulin resistance. Defining alterations of steroidogenesis in PCOS should quantify ovarian, adrenal and extraglandular contribution, as well as clearly define blood reference levels by some universal standard. Intraovarian regulation of follicle development and mechanisms of follicle arrest should be further elucidated. Finally, PCOS status is expected to have long‐term consequences in women, specifically the development of type 2 diabetes, cardiovascular diseases and hormone dependent cancers. Identifying susceptible individuals through genomic and proteomic approaches would help to individualize therapy and prevention. Conclusions There are several intriguing areas for future research in PCOS. A potential limitation of our review is that we focused selectively on areas we viewed as the most controversial.     

Unravelling the phenotypic map of polycystic ovary syndrome (PCOS): a prospective study of 634 women with PCOS

BACKGROUND: The phenotypic spectrum of PCOS has been broadened but the prevalence and clinical significance of PCOS phenotypes continue to challenge the scientific community. OBJECTIVE: Analysis of the phenotypic spectrum of PCOS and determination of the association between metabolic, hormonal and new ultrasonographic criteria. DESIGN: Clinical prospective study. PATIENTS: Six hundred and thirty-four women with PCOS (18-35 years) and comparable body mass index (BMI), diagnosed by ESHRE/ASRM criteria, were categorized into two major groups of phenotypes: classic (NIH) and nonclassic (ESHRE/ASRM), and then subdivided into phenotypes with all possible combinations of diagnostic characteristics. One hundred and eight healthy women of reproductive age, matched for BMI, were recruited as the control group. MEASUREMENTS: Ultrasonographic (ovarian follicle number and volume), hormonal and metabolic parameters. RESULTS: Classic PCOS phenotype was more frequent (85.96%) than the nonclassic phenotype (14.04%). The patients were also classified according to the presence of biochemical (80.60%) or clinical hyperandrogenaemia (12.62%), and, in the newly introduced group, to absence of evidence of hyperandrogenaemia (6.78%). Subjects with classic PCOS with biochemical hyperandrogenaemia (74.76%) were more insulin resistant than controls. In women with PCOS, follicle number was positively related to both insulin resistance and biochemical hyperandrogenaemia. Additionally, women with PCOS had a 6.58-fold increased relative risk (RR) of > 12 follicles on intravaginal ultrasound and a 2.94-fold increased RR of ovarian volume > 10 cm(3) compared to controls. CONCLUSION: The most frequent PCOS phenotype is the subgroup with biochemical hyperandrogenaemia only within the classic phenotype, which is more insulin resistant than the control group. The follicle number, a newly introduced ultrasonographic marker, is related to both metabolic and hormonal features of PCOS.     

Early metabolic derangements in daughters of women with polycystic ovary syndrome

CONTEXT: Polycystic ovary syndrome (PCOS) is a familial endocrine-metabolic dysfunction, increasingly recognized in adolescent girls with hyperandrogenism. However, it is difficult to establish whether the metabolic abnormalities described in PCOS are present before the onset of hyperandrogenism. In children, a strong association of adiponectin levels with metabolic parameters of insulin resistance has been described. OBJECTIVE: The objective of the study was to evaluate adiponectin serum concentrations and metabolic parameters in prepubertal and pubertal daughters of women with PCOS to identify girls with increased metabolic risk. DESIGN: Fifty-three prepubertal and 22 pubertal (Tanner stages II-V) daughters of PCOS women (PCOSd) and 32 prepubertal and 17 pubertal daughters of control women (Cd) were studied. In both groups, an oral glucose tolerance test was performed with measurement of glucose and insulin. Adiponectin, leptin, C-reactive protein, SHBG, sex steroids, and lipids were determined in the fasting sample. RESULTS: Both groups had similar chronological ages, body mass index sd score, and Tanner stage distribution. In the prepubertal girls, 2-h insulin was higher (P = 0.023) and adiponectin levels were lower (P = 0.004) in the PCOSd group, compared with the Cd group. In the pubertal girls, triglycerides (P = 0.03), 2-h insulin (P = 0.01), and serum testosterone concentrations were higher (P = 0.012) and SHBG lower (P = 0.009) in PCOSd, compared with Cd, but adiponectin levels were similar in both groups. CONCLUSIONS: Some of the metabolic features of PCOS are present in daughters of PCOS women before the onset of hyperandrogenism. Adiponectin appears to be one of the early markers of metabolic derangement in these girls.     

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.     

Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses

CONTEXT: Metformin treatment of women with polycystic ovary syndrome (PCOS) is widespread, as determined by studies with diverse patient populations. No comparative examination of weight changes or metabolite responses to different doses has been reported. OBJECTIVE: The aim of this study was to determine whether different doses of metformin (1500 or 2550 mg/d) would have different effects on body weight, circulating hormones, markers of inflammation, and lipid profiles. DESIGN: The study included prospective cohorts randomized to two doses of metformin. SETTING: The study was performed at a university teaching hospital with patients from gynecology/endocrinology clinics. PATIENTS: The patients studied were obese (body mass index, 30 to <37 kg/m2; n = 42) and morbidly obese (body mass index, > or =37 kg/m2; n = 41) women with PCOS. INTERVENTION: Patients were randomized to two doses of metformin, and parameters were assessed after 4 and 8 months. MAIN OUTCOME MEASURES: The main outcome measures were changes in body mass, circulating hormones, markers of inflammation, and lipid profiles. Results: Intention to treat analyses showed significant weight loss in both dose groups. Only the obese subgroup showed a dose relationship (1.5 and 3.6 kg in 1500- and 2550-mg groups, respectively; P = 0.04). The morbidly obese group showed similar reductions (3.9 and 3.8 kg) in both groups. Suppression of androstenedione was significant with both metformin doses, but there was no clear dose relationship. Generally, beneficial changes in lipid profiles were not related to dose. CONCLUSION: Weight loss is a feature of protracted metformin therapy in obese women with PCOS, with greater weight reduction potentially achievable with higher doses. Additional studies are required to determine whether other aspects of the disorder may benefit from the higher dose of metformin.