Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome.

Hum Reprod Update. 2011 May 30. [Epub ahead of print]

Toulis KA, Goulis DG, Mintziori G, Kintiraki E, Eukarpidis E, Mouratoglou SA, Pavlaki A, Stergianos S, Poulasouchidou M, Tzellos TG, Makedos A, Chourdakis M, Tarlatzis BC.

BACKGROUND The relation between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD) remains unclear. In an attempt to provide high-quality evidence on the relation between PCOS and CVD, relevant literature for CVD risk markers [C-reactive protein (CRP), homocysteine (Hcy), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) [Lp(a)], advanced glycation end-products (AGEs), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and fibrinogen] in women with PCOS was reviewed and analyzed. METHODS A systematic search was conducted electronically using specific eligibility criteria. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. RESULTS A total of 130 data sets were included in 11 different outcomes, involving 7174 and 5076 CVD markers in women with PCOS and controls, respectively. Women with PCOS demonstrated significantly elevated CRP [WMD (95% CI) 0.99 (0.77-1.21)], Hcy [2.25 (1.46-3.03)], PAI-1 antigen [16.96 (7.25-26.28)], PAI-1 activity [0.71 (0.18-1.23)], VEGF [1.72 (0.96-2.48)], ADMA [0.19 (0.08-0.3)], AGEs [3.91 (2.36-5.45)] and Lp(a) [0.81 (0.58-1.04)] concentrations compared with controls, yet with significant between-study heterogeneity. Borderline significance (not robust in the sensitivity analyses) was detected for TNF-α [0.75 (0.07-1.44)], ET-1 [1.06 (0.52-1.59)] and fibrinogen [0.20 (0.01-0.39)], whereas no difference was detected for IL-6 [0.71 (-0.16 to 1.59)]. CONCLUSIONS Women with PCOS have increased serum concentrations of CVD risk markers compared with controls. Whether this apparent risk is translated into increased incidence of CVD in later life remains to be elucidated.

Early Metformin Therapy (Age 8-12 Years) in Girls with Precocious Pubarche to Reduce Hirsutism, Androgen Excess, and Oligomenorrhea in Adolescence.

J Clin Endocrinol Metab. 2011 Jun 1. [Epub ahead of print]

Ibáñez L, López-Bermejo A, Díaz M, Marcos MV, de Zegher F.

Context: Girls with a combined history of low(-normal) birth weight (LBW) and precocious pubarche (PP) are at high risk to develop polycystic ovary syndrome (PCOS). Objective: The objective of the study was to compare the capacity of early vs. late metformin treatment to prevent adolescent PCOS. Design: This was a randomized, open-label study over 7 yr. Setting: The study was conducted at a university hospital. Patients: Thirty-eight LBW-PP girls were followed up from the mean age 8 until age 15 yr. Intervention: Early metformin (study yr 1-4; age 8-12 yr) vs. late metformin (yr 6; age 13-14 yr). Main Outcome Measures: Measures included height; weight; hirsutism score; menstrual cycle; endocrine-metabolic screening (fasting; follicular phase); C-reactive protein; body composition (absorptiometry); abdominal fat partitioning (magnetic resonance imaging); ovarian morphology (ultrasound); PCOS (National Institutes of Health and Androgen Excess Society definitions) after yr 7 (all girls thus untreated for at least 1 yr). Results: None of the girls dropped out of the study. At age 15 yr, early-metformin girls were taller (4 cm), were in a less proinflammatory state, and had less central fat due to reductions in visceral and hepatic fat. Hirsutism, androgen excess, oligomenorrhea, and PCOS were between 2- and 8-fold more prevalent in late- than early-treated girls. Abdominal adiposity was the first variable to diverge (at age 8-10 yr) between girls without vs. with PCOS at age 15 yr. Conclusions: In LBW-PP girls, early metformin therapy was found to prevent or delay the development of hirsutism, androgen excess, oligomenorrhea, and PCOS more effectively than late metformin. The time window of late childhood and early puberty may be more critical for the development, and thus for the prevention, of adolescent PCOS than the first years beyond menarche.

Effect of high-protein or normal-protein diet on weight loss, body composition, hormone, and metabolic profile in southern Brazilian women with polycystic ovary syndrome: a randomized study.

Gynecol Endocrinol. 2011 May 31. [Epub ahead of print]

Toscani MK, Mario FM, Radavelli-Bagatini S, Wiltgen D, Cristina Matos M, Spritzer PM.

The aim of the present study was to assess the effects of a high protein (HP) and a normal protein (NP) diet on patients with polycystic ovary syndrome (PCOS) and body mass index-matched controls in a sample of southern Brazilian women. This 8-week randomized trial was carried out at a university gynecological endocrinology clinic and included 18 patients with PCOS and 22 controls. Changes in weight, body composition, hormone, and metabolic profile were analyzed in women randomized to receive HP (30% protein, 40% carbohydrate, and 30% lipid) or NP (15% protein, 55% carbohydrate, and 30% lipid). The energy content was estimated for each participant at 20-25 kcal/kg current weight/day. Physical activity, blood pressure, homeostasis model assessment (HOMA) index, and fasting and 2-h glucose and insulin remained stable during the intervention in PCOS and controls, even in the presence of weight loss. There were no changes in lipid profile in either group. In contrast, body weight, body mass index (BMI), waist circumference, percent of body fat, and sum of trunk skinfolds decreased significantly after both diets in both groups. Total testosterone also decreased in PCOS and controls regardless of diet. In conclusion, calorie reduction, rather than protein content, seemed to affect body composition and hormonal profile in this short-term study. These findings emphasize the role of non-pharmacological interventions to reduce weight and ameliorate the anthropometric and clinical phenotype in PCOS.

Analysis of factors predicting success of metformin and clomiphene treatment for women with infertility owing to PCOS-related ovulation dysfunction in a randomised controlled trial.

Aust N Z J Obstet Gynaecol. 2011 Jun;51(3):252-6. doi: 10.1111/j.1479-828X.2011.01295.x. Epub 2011 Mar 16.

Johnson NP, Bontekoe S, Stewart AW.

Background: Metformin has failed to gain wide acceptance as a first-line treatment option for women with anovulatory infertility related to polycystic ovary syndrome. This study aimed to ascertain factors that predict fertility success with treatment that included metformin compared to standard (nonmetformin) treatment. Methods: Randomised trial data analysis by logistic regression of factors likely to have a differential influence on the likelihood of success of metformin versus nonmetformin treatment amongst women with ovulation dysfunction related to polycystic ovary syndrome. Results: For women within a BMI > 32 kg/m(2) subpopulation, BMI had a significantly greater impact on the chance of pregnancy amongst women receiving metformin versus those receiving placebo and those with lower BMI who received metformin were more likely to become pregnant than their lower BMI counterparts who received placebo (P = 0.039). The subpopulation of women with BMI ≤ 32 kg/m(2) had no factors showing a significantly different impact on the chance of pregnancy for women treated with metformin versus those receiving clomiphene treatment or combination metformin/clomiphene treatment versus clomiphene treatment. There were no significantly different effects of free testosterone, fasting insulin, duration of infertility or ultrasound appearance of polycystic ovaries in any treatment groups. Conclusion: This study provides preliminary evidence that BMI may be an important prognostic factor in response to metformin for women with ovulation dysfunction related to polycystic ovary syndrome, suggesting that women with a lower BMI may respond better to metformin treatment versus placebo amongst women with BMI > 32 kg/m(2) . Individual patient data meta-analysis of existing randomised trials would clarify this further and would assess whether other factors might predict better response to metformin versus standard treatments.

Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in PCOS women-a pilot study.

J Endocrinol Invest. 2011 May 24. [Epub ahead of print]

Wehr E, Pieber TR, Obermayer-Pietsch B.

Background: Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances, in particular from insulin resistance. Accumulating evidence suggests that vitamin D deficiency may contribute to the development of insulin resistance. Hence, we aimed to examine the effect of vitamin D supplementation on metabolic and endocrine parameters in PCOS women. Methods: 57 PCOS women were included in the study. PCOS women received 20.000 IU cholecalciferol weekly for 24 weeks. Anthropometric measures, oral glucose tolerance test, and blood analyses of endocrine parameters were performed at baseline and after 12 weeks (V2) and 24 weeks (V3). Results: 46 PCOS women finished the study. 25-hydroxyvitamin D (25[OH)]D) levels significantly increased from 28.0±11.0 ng/ml at baseline to 51.3±17.3 and 52.4±21.5 at V2 and V3, respectively (p<0.001). We observed a significant decrease of fasting and stimulated glucose (V3, p<0.05) and C-peptide levels (V2 and 3, p<0.001) after vitamin D treatment. Moreover, triglyceride and estradiol levels significantly decreased at V3 (p=0.001) and V2 (p=0.022), respectively, whereas total cholesterol (V2, p=0.008) and LDL cholesterol levels (V2, p=0.005; V3, p=0.026) significantly increased after vitamin D treatment. There were no changes in androgens. At V2, 14 out of 46 PCOS women previously affected by menstrual disturbances (30.4%) reported improvement of menstrual frequency; at V3, 23 out of 46 women (50.0%), who were oligo- or amenorrhoeic at baseline reported improvement. Discussion: Our results suggest that vitamin D treatment might improve glucose metabolism and menstrual frequency in PCOS women. Further randomized controlled trails are warranted to confirm our findings.

Long term metformin treatment is able to reduce the prevalence of metabolic syndrome and its hepatic involvement in young hyperinsulinaemic overweight patients with polycystic ovarian syndrome.

Clin Endocrinol (Oxf). 2011 May 13. doi: 10.1111/j.1365-2265.2011.04093.x. [Epub ahead of print]

Gangale MF, Miele L, Lanzone A, Sagnella F, Martinez D, Tropea A, Moro F, Morciano A, Ciardulli A, Palla C, Pompili M, Cefalo C, Grieco A, Apa R.

Ability of metformin treatment in reducing the prevalence of metabolic syndrome and its hepatic involvement in young hyperinsulinaemic overweight PCOS patients. Design: Clinical Trial.

We recruited 140 hyperinsulinaemic overweight PCOS women in their reproductive age. Metformin treatment (500 mg x 3/die) was prescribed to each patient for twelve months.

The primary outcome was to evaluate the prevalence of NAFLD and MS in hyperinsulinaemic overweight PCOS. The secondary outcome was to evaluate, in the same patients, the effects of metformin therapy on endocrine, metabolic and hepatic parameters.

At basal evaluation NAFLD was diagnosed in 81 out of 140 PCOS patients (57,85%); MS was present only in the NAFLD group (32,09% vs 0%; p<0.001). After twelve months, metformin is able to significantly reduce, in the same group, the prevalence of MS (28.9% vs 13,5%; p<0,01). Was also observed also an improvement of hepatic parameters and a significant decrease in oligomenorrhea (85.7% vs 19%, p<0.001).

Treatment with metformin is indicated in all hyperinsulinaemic overweight PCOS especially in those with NAFLD. These data appear even more interesting considering their increased risk to develop metabolic and hepatic complications.

Simvastatin Effects on Androgens, Inflammatory Mediators, and Endogenous Pituitary Gonadotropins Among Patients With PCOS Undergoing IVF: Results From a Prospective, Randomized, Placebo-Controlled Clinical Trial.

J Investig Med. 2011 Apr 27. [Epub ahead of print]

Rashidi B, Abediasl J, Tehraninejad E, Rahmanpour H, Sills ES.

To evaluate effects of simvastatin on selected biochemical parameters and reproductive outcome among patients with polycystic ovary syndrome (PCOS) who undergo in vitro fertilization (IVF).

Patients with PCOS were randomized to receive either oral simvastatin, 20 mg/d (n = 32), or placebo (n = 32) in a prospective, double-blind, randomized clinical trial (NCT 005-75601) in parallel with controlled ovarian hyperstimulation for IVF. All patients were determined to be at average risk for cardiovascular disease, based on high-sensitivity C-reactive protein (hsCRP) measurement at entry. After an 8-week treatment interval concluding at periovulatory human chorionic gonadotropin administration, selected clinical and laboratory parameters were measured.

Mean serum total testosterone level decreased by 25% in the simvastatin group, compared to a 10% reduction in the placebo group (P < 0.001). A trend of lower serum luteinizing hormone levels was noted in experimental and control groups (29% vs 22%, respectively), although this difference was not significant (P > 0.05). Neither fasting insulin nor quantitative insulin sensitivity check index were significantly impacted by simvastatin (P > 0.05). As expected, total cholesterol was not modified among placebo patients but was significantly reduced after simvastatin (P = 0.001). In addition, hsCRP and vascular cell adhesion protein-1 were both significantly lower after simvastatin therapy compared to controls (P ≤ 0.005 for both). At study completion, no important change in body mass index was observed in either group (P ≥ 0.60). Although oocyte maturation, fertilization, and clinical pregnancy rates were all higher after simvastatin, none of these improvements were statistically significant.

This report presents data from the first prospective, randomized, placebo-controlled clinical investigation of simvastatin in the setting of PCOS and IVF. Simvastatin seems to be compatible with gonadotropin therapy for IVF and can offer beneficial endocrine and cardiovascular effects for patients with PCOS who undergo embryo transfer. Although the observed improvements in reproductive function were mild, the reductions in hsCRP and vascular cell adhesion protein-1 after simvastatin treatment were significant, suggesting the need for further clinical trials to clarify simvastatin's impact on reproductive physiology.

Reproductive Hormone Levels and Anthropometry in Postmenopausal Women with Polycystic Ovary Syndrome (PCOS): A 21-Year Follow-Up Study of Women Diagnosed with PCOS around 50 Years Ago and Their Age-Matched Controls.

J Clin Endocrinol Metab. 2011 Apr 20. [Epub ahead of print]

Schmidt J, Brännström M, Landin-Wilhelmsen K, Dahlgren E.

Context: The hormonal and anthropometric profile of premenopausal women with polycystic ovary syndrome (PCOS) is well described, but there is a lack of data concerning changes in these variables into the postmenopausal period. Objective: Our objective was to examine whether PCOS women differ from normal women regarding levels of reproductive hormones, anthropometry, and presence of hirsutism/climacteric symptoms also after menopause. Design and Setting: In this prospective study, women with PCOS (61-79 yr) and age-matched controls, examined in 1987, were reinvestigated at a university hospital. Participants: Twenty-five PCOS patients (Rotterdam criteria) and 68 controls (randomly allocated from the Gothenburg WHO MONICA study) participated. Interventions: Reexamination and hormonal measurements were done 21 yr after previous visit. Main Outcome Measures: FSH, LH, TSH, thyroid peroxidase antibodies, prolactin, estrone, estradiol, SHBG, androstenedione, total testosterone, dehydroepiandrosterone sulfate, free androgen index, and anthropometry were determined. Presence of climacteric symptoms, hirsutism, and menopausal age were recorded. Results: PCOS women had higher free androgen index (P = 0.001) but lower FSH (P < 0.001) and SHBG (P < 0.01) than controls. Menopausal age, body weight, body mass index, waist to hip ratio, LH, prolactin, androstenedione, dehydroepiandrosterone sulfate, total testosterone, estradiol, and estrone were similar in PCOS and controls. Women with PCOS reported hirsutism more frequently (P < 0.001) but had fewer climacteric symptoms (P < 0.05) and hypothyroidism than controls (P < 0.05). Conclusions: PCOS women differ from controls with regard to levels of certain reproductive hormones also after menopause, but the established premenopausal increase in waist to hip ratio in PCOS patients disappeared after menopause, mainly due to weight gain among controls. A novel finding was the lower prevalence of hypothyroidism in PCOS women.

Metformin is a reasonable first-line treatment option for non-obese women with infertility related to anovulatory polycystic ovary syndrome - A meta-analysis of randomised trials.

Aust N Z J Obstet Gynaecol. 2011 Apr;51(2):125-9. doi: 10.1111/j.1479-828X.2010.01274.x. Epub 2011 Jan 28.

Johnson N.

Background: There are differences in opinion as to whether metformin should play a role in the primary treatment of anovulatory infertility for women with polycystic ovary syndrome (PCOS). Aim: The aim of this study was to ascertain the best available evidence comparing metformin versus clomiphene treatment for non-obese women with anovulatory infertility related to PCOS. Methods: Meta-analysis of available data from randomised controlled trials that examined metformin versus clomiphene for the subgroup of women in the lower body mass index (BMI) range (primarily non-obese). Primary outcomes were clinical pregnancy and live birth. Results: For women with BMI ≤ 30-32 kg/m(2) , clinical pregnancy rates were 36.7% (52/142) for metformin and 35.7% (51/143) for clomiphene; live birth rates were 30.3% (43/142) for metformin and 30.8% (44/143) for clomiphene. Conclusion: The available randomised trial data show no significant difference in effectiveness of metformin versus clomiphene as ovulation induction agents for non-obese women with anovulatory PCOS. Metformin and clomiphene are both suitable options for first-line treatment.

PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis.

Hum Reprod Update. 2011 Feb 18. [Epub ahead of print]

de Groot PC, Dekkers OM, Romijn JA, Dieben SW, Helmerhorst FM.

BACKGROUND Patients with polycystic ovary syndrome (PCOS) are at risk of arterial disease. We examined the risk of (non)fatal coronary heart disease (CHD) or stroke in patients with PCOS and ovulatory women without PCOS, and assessed whether obesity might explain a higher risk of CHD or stroke. METHODS We performed a systematic review and meta-analysis of controlled observational studies. Four definitions of PCOS were considered: World Health Organization type II anovulation, National Institutes of Health criteria, Rotterdam consensus and Androgen-excess criteria. Obesity was defined as BMI > 30 kg/m(2) and/or waist circumference >88 cm. Study quality was assessed using the Newcastle-Ottawa Scale. Primary outcome was fatal/non-fatal CHD or stroke. Definitions of CHD and stroke were based on criteria used by the various authors. The effect measure was the pooled relative risk in a random effects model. Risk ratios and rate ratios were combined here. RESULTS After identifying 1340 articles, 5 follow-up studies published between 2000 and 2008 were included. The studies showed heterogeneity in design, definitions and quality. In a random effects model the relative risk for CHD or stroke were 2.02 comparing women with PCOS to women without PCOS (95% confidence interval 1.47, 2.76). Pooling the two studies with risk estimates adjusted for BMI showed a relative risk of 1.55 (1.27, 1.89). CONCLUSIONS This meta-analysis showed a 2-fold risk of arterial disease for patients with PCOS relative to women without PCOS. BMI adjustment did not affect this finding, suggesting the increased risk for cardiovascular events in PCOS is not completely related to a higher BMI in patients with PCOS.

Lifestyle changes in women with polycystic ovary syndrome.

Cochrane Database Syst Rev. 2011 Feb 16;2:CD007506.

Moran LJ, Hutchison SK, Norman RJ, Teede HJ.

BACKGROUND: Polycystic ovary syndrome (PCOS) affects 4% to 18% of reproductive-aged women and is associated with reproductive, metabolic and psychological dysfunction. Obesity worsens the presentation of PCOS and weight management (weight loss, maintenance or prevention of excess weight gain) is proposed as an initial treatment strategy, best achieved through lifestyle changes incorporating diet, exercise and behavioural interventions.

OBJECTIVES: To assess the effectiveness of lifestyle treatment in improving reproductive, anthropometric (weight and body composition), metabolic and quality of life factors in PCOS.

SEARCH STRATEGY: Electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, PsycINFO, CINAHL, AMED), controlled trials register, conference abstracts, relevant journals, reference lists of relevant papers and reviews and grey literature databases, with no language restrictions applied.

SELECTION CRITERIA: Randomised controlled trials comparing lifestyle treatment (diet, exercise, behavioural or combined treatments) to minimal or no treatment in women with PCOS.

DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed methodological quality and risk of bias and extracted data.

MAIN RESULTS: Six studies were included. Three studies compared physical activity to minimal dietary and behavioural advice or no advice. Three studies compared combined dietary, exercise and behavioural interventions to minimal intervention. There were no studies assessing fertility primary outcomes and no data for meta-analysis on ovulation or menstrual regularity. For secondary outcomes, lifestyle intervention provided benefits when compared to minimal treatment for endpoint values for total testosterone (mean difference (MD) -0.27 nmol/L, 95% confidence interval (CI) -0.46 to -0.09, P = 0.004), hirsutism by the Ferriman-Gallwey score (MD -1.19, 95% CI -2.35 to -0.03, P = 0.04), weight (MD -3.47 kg, 95% CI -4.94 to -2.00, P < 0.00001), waist circumference (MD -1.95 cm, 95% CI -3.34 to -0.57, P = 0.006), waist to hip ratio (MD -0.04, 95% CI -0.07 to -0.00, P = 0.02), fasting insulin (MD -2.02 µU/mL, 95% CI -3.28 to -0.77, P = 0.002) and oral glucose tolerance test insulin (standardised mean difference -1.32, 95% CI -1.73 to -0.92, P < 0.00001) and per cent weight change (MD -7.00%, 95% CI -10.1 to -3.90, P < 0.00001). There was no evidence of effect of lifestyle for body mass index, free androgen index, sex hormone binding globulin, glucose or lipids; and no data for quality of life, patient satisfaction or acne.

AUTHORS' CONCLUSIONS: Lifestyle intervention improves body composition, hyperandrogenism (high male hormones and clinical effects) and insulin resistance in women with PCOS. There was no evidence of effect for lifestyle intervention on improving glucose tolerance or lipid profiles and no literature assessing clinical reproductive outcomes, quality of life and treatment satisfaction.