Susanne Tan

Prevalence and implications of anxiety in polycystic ovary syndrome: results of an internet-based survey in Germany

BACKGROUND Comparatively little attention has been paid to the symptoms of anxiety in polycystic ovary syndrome (PCOS), although anxiety disorders constitute the most common psychiatric diagnoses among endocrine patients and in the general population. Therefore, our goal was to address the prevalence, determinants and implications of anxiety alone or anxiety in combination with depression in German women with PCOS. METHODS In this nation-wide, internet-based survey, anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (SF-12) were assessed together with sociodemographic information and clinical PCOS symptoms in 448 PCOS women. RESULTS Of the patients, 34% showed clinically relevant HADS anxiety scores and 21% had clinically relevant HADS depression scores. Quality of life was significantly impaired in PCOS women with anxiety (P < 0.001), in particular, in women with comorbid anxiety and depression (P < 0.001). The risk for clinically relevant HADS anxiety scores was significantly enhanced in PCOS women with acne (odds ratio (OR) = 1.52; 95% confidence interval (CI) = 1.03-2.52) and an unfulfilled wish to conceive (OR = 1.50; 95% CI = 1.01-2.23). CONCLUSIONS PCOS women may be at an increased risk for clinically relevant anxiety, and comorbid anxiety and depression is also very common. Anxiety contributes to impaired quality of life in PCOS. Given the high prevalence and the serious implications, and the availability of effective treatment options given proper diagnosis, clinicians should be more aware of anxiety disorders in women with PCOS.

Disturbed stress responses in women with polycystic ovary syndrome

BACKGROUND We analyzed the neuroendocrine and immune cell responses to psychosocial stress in PCOS patients compared to BMI-matched healthy controls. METHODS Responses to public speaking stress were analyzed in 32 PCOS patients and 32 BMI-matched healthy controls. At baseline, during, and 10- and 45-min after stress, state anxiety, cardiovascular responses, cortisol, ACTH, as well as circulating leukocyte subpopulations were analyzed, together with hsCRP and serum IL-6 concentrations. RESULTS In response to public speaking stress, both groups showed significant but comparable increases in state anxiety, and blood pressure (all p<0.001; time effects). The ACTH and cortisol stress responses were significantly enhanced in PCOS (both p<0.05; interaction effect). In addition, heart rate was significantly higher in PCOS (p<0.05; group effect). PCOS patients displayed a reduced upregulation of IL-6 levels in response to stress (p<0.05; interaction effect). Baseline levels of circulating leukocyte subpopulations, IL-6 and hsCRP concentrations did not differ between BMI-matched controls and PCOS patients. PCOS patients were characterized by markedly increased psychological distress. CONCLUSIONS PCOS patients showed enhanced HPA-axis and heart rate reactivity as well as a reduced upregulation of IL-6 in response to stress. The altered stress reactivity in PCOS patients may constitute a link between depression, overweight, and the cardiovascular and diabetes risks associated with the diagnosis.

Psychological implications of infertility in women with polycystic ovary syndrome

BACKGROUND In polycystic ovary syndrome (PCOS), one of the main features is chronic anovulation associated with lower pregnancy rates. Little is known regarding the psychological aspects associated with infertility in these patients. Therefore, we examined the influence of an unfulfilled wish to conceive on various aspects of psychological functioning in PCOS women. METHODS Standardized questionnaires assessing quality-of-life (36-item short-form health survey, SF-36), depressiveness (Beck Depression Inventory), emotional distress (Symptom Check List 90, SCL-90-R), sexual satisfaction and self-worth (visual analogue scales), and a questionnaire on the desire for a child (FKW) were administered at the outpatient endocrine clinic to consecutive PCOS patients. RESULTS Questionnaires from 115 PCOS patients were analysed. The majority (76.1%) worried about remaining childless in the future, and 51.3% reported a current wish to conceive. 23.9% of patients had scores indicating mild to moderate depression, and 25.2% had scores indicating clinically relevant depression. Furthermore, all quality-of-life scores were significantly lower compared with normative data (P < 0.001). Unexpectedly, comparisons of patients with a current unfulfilled desire to conceive to those with no present wish for a child revealed no discernable impact on depressive symptoms, quality-of-life or emotional distress. Reduced sexual satisfaction and self-worth were largely determined by partnership status and not infertility. However for PCOS patients who wished to conceive, the wish for a child was a significantly greater priority when compared with normative data from infertile patients. CONCLUSIONS PCOS represents a major risk factor for psychosocial and emotional problems, but at least in this sample of PCOS patients, infertility does not appear to constitute a primary determinant of psychological problems.

Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance

OBJECTIVE Insulin resistance (IR) and obesity are common features of the polycystic ovary syndrome (PCOS). Insulin-sensitizing agents have been shown to improve both reproductive and metabolic aspects of PCOS, but it remains unclear whether it is also beneficial in lean patients without pre-treatment IR. The aim of this study was to determine the influence of metformin on the clinical and biochemical parameters of PCOS irrespective of the presence of basal obesity and IR. DESIGN The effect of 6 months of metformin treatment was prospectively assessed in 188 PCOS patients, divided into three groups according to body mass index (BMI; lean: BMI<25 kg/m2, overweight: BMI 25-29 kg/m2, and obese: BMI30 kg/m2). Outcome parameters, which were also assessed in 102 healthy controls, included body weight, homeostasis model assessment for IR (HOMA-IR), fasting glucose and insulin levels, area under the curve of insulin response (AUCI), hyperandrogenism, and menstrual irregularities. RESULTS In comparison with the respective BMI-appropriate control groups, only obese but not lean and overweight PCOS patients showed differences in fasting insulin and HOMA-IR. Metformin therapy significantly improved all outcome parameters except fasting glucose levels. Subgroup analyses revealed that in the group of lean PCOS patients without pre-treatment IR, metformin significantly improved HOMA-IR (1.7+/-1.0 vs 1.1+/-0.7 micromol/lxmmol/l2) and fasting insulin levels (7.7+/-4.2 vs 5.4+/-3.9 mU/l), in addition to testosterone levels (2.6+/-0.9 vs 1.8+/-0.7 nmol/l), anovulation rate (2.3 vs 59.5%), and acne (31.8 vs 11.6%; all P<0.017). In the overweight and obese PCOS groups, metformin also showed the expected beneficial effects. CONCLUSION Metformin improves parameters of IR, hyperandrogenemia, anovulation, and acne in PCOS irrespective of pre-treatment IR or obesity.

The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome.

Background  Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation. The genetic background of the insulin resistance frequently associated with PCOS is unclear.

Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS).

BackgroundThe polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS.MethodsWe conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4).ResultsThe FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously.ConclusionThe stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease.

Effects of obesity on neuroendocrine, cardiovascular, and immune cell responses to acute psychosocial stress in premenopausal women

OBJECTIVE To analyze the neuroendocrine and immune cell responses to acute psychosocial stress in obese compared to non-obese premenopausal women. METHODS N=15 obese (BMI> or =30) and N=24 (BMI<30) non-obese premenopausal women underwent public speaking stress. State anxiety, ACTH, cortisol, and the redistribution of immune cells were measured before, during, and 10 and 45min after public speaking. Serum hsCRP and serum IL-6 levels were analyzed before, and IL-6 additionally 45min after stress. RESULTS In response to public speaking stress, both groups showed significant but comparable increases in state anxiety, plasma ACTH, and blood pressure (all p<0.01; time effects). The cortisol stress response was significantly enhanced in obese women (p<0.05; interaction effect). In addition, heart rate and diastolic blood pressure were significantly higher in obese women 10min following stress (p<0.05, t-tests). Public speaking stress led to a significant increase in IL-6 concentrations (p<0.001; time effect), and obese women displayed higher IL-6 levels both pre- and post-stress (p<0.05; group effect; between-group t-tests: pre-stress p<0.05; post-stress p<0.01). Baseline numbers of circulating leukocytes, granulocytes, CD3+ cells and hsCRP concentration were significantly higher in obese women (between-group t-tests: all p<0.05, but the groups did not differ in the stress-induced redistribution of circulating leukocyte subpopulations. CONCLUSIONS Our data reveal a strong association of obesity with chronic low-grade inflammation in premenopausal women. This pro-inflammatory state, together with altered neuroendocrine and cardiovascular stress responsiveness, may conceivably constitute one of the mechanisms linking psychological stress and the long-term health risks associated with obesity.

Diagnostic value of calculated testosterone indices in the assessment of polycystic ovary syndrome.

Abstract Background: One of the main criteria to establish a diagnosis of polycystic ovary syndrome (PCOS) is hyperandrogenemia. Recent observations suggest that total testosterone may not be a sensitive marker for the detection of androgen excess. The aim of the present study was to compare the value of different androgen determinations for diagnosis of PCOS. Methods: Untreated PCOS patients (n=133; mean age 28 years) and healthy control women (n=54; mean age 28 years) were included in the study. Measurements of total testosterone and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstendione, dehydroepiandrosterone sulfate (DHEAS) and albumin were performed. In addition, the free androgen index (FAI), free and bioavailable testosterone were calculated. Clinical signs of hyperandrogenism were evaluated by physical examination. The area under the receiver operating characteristic curve (AUC-ROC) was used to compare the sensitivity and specificity of different androgen determinations to detect PCOS, defined as clinical hyperandrogenism and irregular cycles compatible with the National Institutes of Health criteria of chronic anovulation and clinical or biochemical hyperandrogenism. Results: All biochemical parameters of hyperandrogenism were significantly higher in PCOS patients than in controls (all p<0.0001). The highest AUC-ROC was found for bioavailable testosterone (0.852) followed by FAI (0.847) and free testosterone (0.837). Lower AUC-ROC was found for SHBG, total testosterone and androstendione (0.765, 0.799 and 0.706, respectively). When FAI=4.97 was taken as a cutoff value, sensitivity was 71.4% and specificity was 85.2%. A cutoff of 0.78 nmol/L for bioavailable testosterone had even higher sensitivity of 75.9%, but slightly lower specificity of 83.3%. FAI and bioavailable testosterone correlated significantly (all p<0.05) with total testosterone, androstendione, LH/FSH ratio and DHEAS. In addition, free testosterone, bioavailable testosterone and FAI correlated significantly with hirsutism scores, and ovarian volume and follicle count. Conclusions: ROC analysis provided evidence that calculated testosterone indices (bioavailable testosterone, FAI, free testosterone) are useful parameters for the discrimination of PCOS patients and healthy controls. Clin Chem Lab Med 2007;45:202–7.

Retinol-binding protein 4 levels are elevated in polycystic ovary syndrome women with obesity and impaired glucose metabolism

OBJECTIVE Insulin resistance and obesity are common features of the polycystic ovary syndrome (PCOS). Retinol-binding protein 4 (RBP4), a new fat-derived adipokine, has been described to be elevated in obesity and type 2 diabetes. The aim of the present study was to investigate whether serum RBP4 levels are correlated with metabolic parameters, indices of insulin resistance, and endocrine variables in German PCOS women. DESIGN We assessed the correlation between metabolic and endocrine parameters with RBP4 levels in 200 PCOS patients and 64 healthy controls. METHODS Serum RBP4 was measured by enzyme-linked immunosorbent assay (Immundiagnostik AG, Bensheim, Germany). In addition, anthropometric variables, clinical signs of hyperandrogenism, and body fat were evaluated, and a glucose tolerance test was performed to assess parameters of insulin resistance and glucose metabolism. RESULTS Taking the entire PCOS cohort, RBP4 levels were positively correlated with body mass index (BMI), body fat, waist circumference, fasting glucose, and area under the curve for glucose (all P<0.05), but not with indices of insulin resistance. On the other hand, PCOS women with impaired glucose metabolism had higher RBP4 levels than PCOS women with normal glucose metabolism (median 30.6, range 23.3-73.9 versus median 26.3, range 6.4-61.4, P<0.05). Furthermore, no differences were found in RBP4 levels between lean PCOS women and BMI-matched healthy controls. CONCLUSION In German PCOS women, serum RBP4 levels are associated with obesity and parameters of glucose metabolism but not with PCOS per se.

Apoptotic Markers Indicate Nonalcoholic Steatohepatitis in Polycystic Ovary Syndrome

BACKGROUND Polycystic ovary syndrome (PCOS) characterized by chronic anovulation and hyperandrogenism is highly associated with obesity and insulin resistance (IR), two key features of nonalcoholic steatohepatitis (NASH). NASH often leads to cirrhosis, including portal hypertension, liver failure, and hepatocellular carcinoma as long-term complications. The caspase 3-cleaved fragment of cytokeratin 18 (CK18) emerging from ongoing cell death during apoptosis process has been established as a serum marker for NASH. This study was conducted to evaluate the prevalence of NASH in PCOS patients by caspase-cleaved CK18 measurement. METHODS In 192 PCOS patients [age, 29.0 +/- 6.7 yr; body mass index (BMI), 31.5 +/- 8.2 kg/m(2)] and 73 age-matched controls (age, 28.6 +/- 8.0 yr; BMI, 24.1 +/- 4.6 kg/m(2)), obesity and IR were determined by BMI and area under the curve of insulin response (AUCI), respectively. Apoptotic cell death was measured by M30 ELISA detecting caspase-cleaved CK18 only. RESULTS M30 levels were significantly elevated in PCOS patients after correction for BMI (304.7 +/- 223.1 vs. 86.3 +/- 165.6 U/liter; P < 0.001). M30 correlated significantly with BMI, AUCI, glucose secretion, low-density lipoprotein, low high-density lipoprotein, and free androgen index. AUCI turned out to be the only independent M30-determining factor in the multiple regression analysis with an effect size of 7.9%. Fifty-one of 186 (27.4%) PCOS patients showed M30 levels of at least 395 U/liter, indicating NASH. CONCLUSION These data demonstrate elevation of apoptotic cell death, its correlation with IR, and a high prevalence of NASH in PCOS patients. Given this high prevalence, PCOS may be a risk factor for progressive hepatic sequelae. Incidence data are of strong interest.