Anuja Dokras

Assessment of Cardiovascular Risk and Prevention of Cardiovascular Disease in Women with the Polycystic Ovary Syndrome: A Consensus Statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society

OBJECTIVE Women with polycystic ovary syndrome (PCOS) often have cardiovascular disease (CVD) risk factors. The Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society created a panel to provide evidence-based reviews of studies assessing PCOS-CVD risk relationships and to develop guidelines for preventing CVD. PARTICIPANTS An expert panel in PCOS and CVD reviewed literature and presented recommendations. EVIDENCE Only studies comparing PCOS with control patients were included. All electronic databases were searched; reviews included individual studies/databases, systematic reviews, abstracts, and expert data. Articles were excluded if other hyperandrogenic disorders were not excluded, PCOS diagnosis was unclear, controls were not described, or methodology precluded evaluation. Inclusion/exclusion criteria were confirmed by at least two reviewers and arbitrated by a third. CONSENSUS PROCESS Systematic reviews of CVD risk factors were compiled and submitted for approval to the AE-PCOS Society Board. CONCLUSIONS Women with PCOS with obesity, cigarette smoking, dyslipidemia, hypertension, impaired glucose tolerance, and subclinical vascular disease are at risk, whereas those with metabolic syndrome and/or type 2 diabetes mellitus are at high risk for CVD. Body mass index, waist circumference, serum lipid/glucose, and blood pressure determinations are recommended for all women with PCOS, as is oral glucose tolerance testing in those with obesity, advanced age, personal history of gestational diabetes, or family history of type 2 diabetes mellitus. Mood disorder assessment is suggested in all PCOS patients. Lifestyle management is recommended for primary CVD prevention, targeting low-density and non-high-density lipoprotein cholesterol and adding insulin-sensitizing and other drugs if dyslipidemia or other risk factors persist.

Screening women with polycystic ovary syndrome for metabolic syndrome.

Objective: Women with polycystic ovary syndrome (PCOS) are at an increased risk for insulin resistance and hyperlipidemia. Metabolic syndrome is a cluster of risk factors that confers an increased risk for cardiovascular disease. The objectives of this study were to compare the prevalence of metabolic syndrome in women with PCOS and controls and to identify the role of androgens or insulin resistance in the development of metabolic syndrome. Methods: Women with PCOS (n = 129) and women with regular menses and no hirsutism seen for an annual examination (n = 177) were studied. Results: The age-adjusted prevalence of metabolic syndrome was higher in women with PCOS (47.3%, 95% confidence interval 35.3–56.9%) compared with controls (4.3%, 95% confidence interval 1.9–7.6%, P < .001). Compared by age group, the risk of metabolic syndrome in women with PCOS was higher for all groups (P < .001). There were no significant differences in serum androgen levels between women with PCOS with or without metabolic syndrome. In contrast, all markers of insulin resistance were abnormal in women with PCOS with metabolic syndrome compared with those without metabolic syndrome (P < .001). We found serum triglyceride/high density lipoprotein cholesterol (TG/HDL-C) ratio correlated with insulin resistance in this population (P < .001). Serum TG/HDL-C > 3.2 has a high sensitivity and specificity for the detection of metabolic syndrome in women with PCOS. Conclusion: Women with PCOS have a 11-fold increase in the prevalence of metabolic syndrome compared with age-matched controls. The risk of metabolic syndrome is high even at a young age, highlighting the importance of early and regular screening. The TG/HDL-C ratio may serve as a screening tool and needs to be prospectively validated in this group. Level of Evidence: II-2

Obstetric outcomes after in vitro fertilization in obese and morbidly obese women.

OBJECTIVE: In addition to numerous health detriments caused by obesity, fertility and pregnancy success may also be compromised. The aims of this study were to compare the effects of obesity and morbid obesity on in vitro fertilization (IVF) outcomes. We also investigated the effects of obesity on obstetric outcomes after IVF treatment. METHODS: Retrospective study of women less than 38 years of age during their first fresh IVF cycle (January 1995 to April 2005). RESULTS: A total of 1,293 women were included in the study, with 236 obese women (body mass index [BMI] = 30–39.9) and 79 morbidly obese women (BMI ≥ 40). The morbidly obese group had a 25.3% IVF cycle cancellation rate compared with 10.9% in normal-weight women (odds ratio 2.73, 95% confidence interval 1.49–5.0), P < .001). Morbidly obese women without polycystic ovarian syndrome had an even higher cancellation rate (33%). Women with higher BMI required significantly more days of gonadotropin stimulation but had lower peak estradiol levels (P < .001). There were no significant differences in clinical pregnancy or delivery rates between the four BMI groups. Of the women who delivered, there was a significant linear trend for risk of preeclampsia, gestational diabetes, and cesarean delivery with increasing BMI (P < .03). CONCLUSION: We report a significantly higher risk for IVF cycle cancellation in morbidly obese patients with no effect of BMI on clinical pregnancy or delivery rate. However, obese and morbidly obese subjects had a significantly higher risk for obstetric complications. This target population should be aggressively counseled regarding their increased obstetric risk and offered treatment options for weight reduction before the initiation of fertility therapy. LEVEL OF EVIDENCE: II-2

Risk of depression and other mental health disorders in women with polycystic ovary syndrome: a longitudinal study.

OBJECTIVE To determine the conversion risk and predictors for depression in women with polycystic ovary syndrome. DESIGN Prospective longitudinal study. SETTING University practice. PATIENT(S) Subjects with polycystic ovary syndrome who had participated in a previous study. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The Primary Care Evaluation of Mental Disorders Patient Health Questionnaire was used to diagnose major depressive disorder and other depressive syndromes, anxiety syndromes, and binge eating disorder. Subjects completed a questionnaire on knowledge about polycystic ovary syndrome and treatment satisfaction. RESULT(S) A total of 60 of 103 subjects responded to the second survey. Mean time between the two surveys was 22 months (range 12-26 months). The overall prevalence of depression was 40% (24/60). Of these, 10 women screened positive for major depressive disorder or other depressive syndromes and 14 were receiving antidepressant medications. There were 11 new cases identified in the second survey (19% conversion). Total subjects with mood disorders in this study were 34/60 (56.6%), including 11.6% with anxiety syndromes and 23.3% with binge eating disorder. Difficulties with menstrual function, fertility, and body image (weight, hirsutism, acne) were not significantly different in women with and without depression. CONCLUSION(S) There is a significant risk for mood disorders (defined by the Diagnostic and Statistical Manual of Mental Disorders-IV) in women with polycystic ovary syndrome. This finding together with a high conversion risk for depression over a 1- to 2-year period underscores the importance of routine screening and aggressive treatment of mental health disorders in this population.

Increased risk for abnormal depression scores in women with polycystic ovary syndrome: a systematic review and meta-analysis.

OBJECTIVE: Polycystic ovary syndrome (PCOS) and depression both have a high prevalence in reproductive-aged women. This study aimed to determine the prevalence of abnormal depression scores in women who meet currently recognized definitions of PCOS compared with women in a well-defined control group. DATA SOURCES: The search was performed in MEDLINE, EMBASE Classic plus EMBASE, PsycINFO, Current Contents-Clinical Medicine and Current Contents-Life Sciences and Web of Science. Cochrane software Review Manager 5.0.24 was used to construct forest plots comparing risk of abnormal depression scores in those in the PCOS and control groups. METHODS OF STUDY SELECTION: Studies with well-defined criteria of women with PCOS and control groups of women without PCOS, with demographic information including age and body mass index (BMI), were included. Of 752 screened articles, 17 met the selection criteria for systematic review and 10 studies were included in the meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Data were abstracted independently by three reviewers. All studies were cross-sectional and most used the Rotterdam criteria for the diagnosis of PCOS (n=10). The odds ratio (OR) for abnormal depression scores was 4.03 (95% confidence interval [CI] 2.96–5.5, P<.01) in women with PCOS (n=522) compared with those in the control groups (n=475). A subanalysis showed that the odds for abnormal depression scores was independent of BMI (OR 4.09, 95% CI 2.62–6.41). Several validated tools were used to screen for depression; the common tool used was the Beck Depression Inventory. CONCLUSION: The results of our study suggest the need to screen all women with PCOS for depression using validated screening tools. Women with PCOS are at an increased risk for abnormal depression scores independent of BMI.

Cardiovascular disease risk factors in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy associated with an increasing number of cardiovascular comorbidities. The relationship between insulin resistance and PCOS was described more than 3 decades ago. Women with PCOS also have an increased prevalence of several established cardiovascular risk factors such as diabetes, hypertension, and dyslipidemia. These factors contribute to the increased risk of endothelial dysfunction, increased carotid artery intima media thickness, and coronary artery calcification noted in women with PCOS compared with controls. Although truncal obesity is very prevalent in PCOS, these surrogate markers of atherosclerosis have been shown to be independent of body weight in young, asymptomatic subjects. Metabolic syndrome is a cluster of risk factors that also confer an increased risk of cardiovascular disease. Women with PCOS have also been shown to have a significantly higher prevalence of metabolic syndrome compared with age-matched controls. Currently, there are no longitudinal studies confirming increased cardiovascular morbidity and/or mortality in women with PCOS. However, the early presence of traditional and other cardiovascular risk factors underscores the need to screen and aggressively counsel and treat these women to prevent future symptomatic cardiovascular disease.

Severe Feto-Placental Abnormalities Precede the Onset of Hypertension and Proteinuria in a Mouse Model of Preeclampsia

Abstract Preeclampsia is a prevalent and potentially devastating disorder of pregnancy. Characterized by a sudden spike in blood pressure and urinary protein levels, it is associated with significant obstetric complications. BPH/5 is an inbred mouse model of preeclampsia with borderline hypertension before pregnancy. BPH/5 mice develop hypertension, proteinuria, and endothelial dysfunction during late gestation (after E14.5). We hypothesized that BPH/5 mice might exhibit early feto-placental abnormalities before the onset of maternal disease. All placental cell lineages were present in BPH/5 mice. However, the fetal and placental weights were reduced, with abnormalities in all the placental zones observed starting early in gestation (E9.5-E12.5). The fractional area occupied by the junctional zone was significantly reduced at all gestational timepoints. Markedly fewer CDKN1C-stained trophoblasts were seen invading the proximal decidual zone, and this was accompanied by reductions in Cdkn1c gene expression. Trophoblast giant cell morphology and cytokeratin staining were not altered, although the mRNA levels of several giant cell-specific markers were significantly downregulated. The labyrinth layer displayed decreased branching morphogenesis of endothelial cells, with electron microscopy evidence of attenuated trophoblast layers. The maternal decidual arteries showed increased wall-to-lumen ratios with persistence of actin-positive smooth muscle cells. These changes translated into dramatically increased vascular resistance in the uterine arteries, as measured by pulse-wave Doppler. Collectively, these results support the hypothesis that defects at the maternal-fetal interface are primary causal events in preeclampsia, and further suggest the BPH/5 model is important for investigations of the underlying pathogenic mechanisms in preeclampsia.

Is PCOS an inflammatory process

PRO--PCOS is associated with low-grade systemic inflammation as evidenced by elevation of multiple markers of inflammation such as C-reactive protein, interleukin-18, monocyte chemoattractant protein-1 and white blood cell count as well as endothelial dysfunction and increased oxidative stress. CON--Current studies examining the evidence for low grade inflammation in PCOS are small, heterogeneous for the diagnosis, confounded by degree of adiposity and do not consistently demonstrate a clinically relevant increase in the above mentioned biomarkers.

Increased prevalence of anxiety symptoms in women with polycystic ovary syndrome: systematic review and meta-analysis.

OBJECTIVE To perform a systematic review and meta-analysis of studies that compared the prevalence of anxiety symptoms in women with polycystic ovary syndrome (PCOS) and control women. DESIGN Meta-analysis and systematic review. SETTING University practice. PATIENT(S) Cross-sectional studies comparing PCOS subjects and geographically matched clearly defined non-PCOS control subjects with data on age and body mass index (BMI). INTERVENTION(S) Anxiety screening tool. MAIN OUTCOME MEASURE(S) The primary analysis contrasted prevalence of anxiety. Cochrane Review Manager 5.0.24 software was used to construct forest plots comparing frequency of anxiety symptoms in case and control subjects. RESULT(S) Of 613 screened articles, nine met our selection criteria for a systematic review and four were included in the meta-analysis. The prevalence of generalized anxiety symptoms was available in four studies and was significantly greater in PCOS subjects (42/206, 20.4%) compared to controls (8/204, 3.9%). The odds for anxiety symptoms were significantly greater in women with PCOS compared with control subjects (odds ratio 6.88, 95% confidence interval 2.5-18.9). The mean anxiety score was significantly increased in three of the remaining five studies. Other anxiety disorders, such as social phobia, panic attacks, and obsessive compulsive disorders, were assessed infrequently. CONCLUSION(S) Our systematic review suggests an increased odds of anxiety symptoms in women with PCOS, underscoring the importance of screening all women with PCOS for anxiety symptoms. Follow-up evaluation and treatment are essential, because generalized anxiety disorder is a chronic condition. Potential contributors for anxiety symptoms, such as hirsutism, obesity, and/or infertility may be specific to women with PCOS but need further investigation.

Cardiovascular disease risk in women with PCOS

Cardiac disease is the number one killer in women. Adolescents and reproductive age women with PCOS have an increased prevalence of cardiovascular risk factors. These include obesity, impaired glucose tolerance, diabetes, hypertension, mood disorders and metabolic syndrome. There is sufficient evidence to confirm the presence of subclinical atherosclerosis in women with PCOS compared to age matched controls. There are, however, few prospective studies examining non-fatal and fatal cardiac events in women with well-defined PCOS. Future directions of research should include longitudinal studies in peri- and post-menopausal women with prospectively defined PCOS to better estimate the risk of cardiac morbidity and mortality in this high-risk population. In the meantime, regular screening for risk factors and timely early interventions are critical to reduce the overall risk burden.