Anne-Marie Coady

The Effect of Atorvastatin in Patients with Polycystic Ovary Syndrome: A Randomized Double-Blind Placebo-Controlled Study

CONTEXT Polycystic ovary syndrome (PCOS) is associated with increased risk of cardiovascular morbidity, whereas statins are proven to reduce cardiovascular mortality and morbidity through lipid-lowering and perhaps through their pleiotropic effects. Statins can also reduce testosterone in vitro by inhibiting ovarian theca-interstitial cell proliferation and steroidogenesis and reducing inflammation in vivo. OBJECTIVE Our objective was to assess the effect of atorvastatin on inflammatory markers, insulin resistance, and biochemical hyperandrogenemia in patients with PCOS. DESIGN AND SETTING We conducted a randomized, double-blind, placebo-controlled study at a tertiary care setting in United Kingdom. PATIENTS Patients included 40 medication-naive patients with PCOS and biochemical hyperandrogenemia. METHODS Patients were randomized to either atorvastatin 20 mg daily or placebo. MAIN OUTCOME MEASURES The primary endpoint of the study was a change in the inflammatory marker high-sensitivity C-reactive protein. The secondary endpoints were a change in insulin resistance and total testosterone. RESULTS After 12 wk atorvastatin, there was a significant reduction (mean +/- sem) in total cholesterol (4.6 +/- 0.2 vs. 3.4 +/- 0.2 mmol/liter, P < 0.01), low-density lipoprotein cholesterol (2.9 +/- 0.2 vs. 1.8 +/- 0.2 mmol/liter, P < 0.01), triglycerides (1.34 +/- 0.08 vs. 1.08 +/- 0.13 mmol/liter, P <0.01), high-sensitivity C-reactive protein (4.9 +/- 1.4 vs. 3.4 +/- 1.1 mg/liter, P = 0.04), free androgen index (13.4 +/- 0.6 vs. 8.7 +/- 0.4, P < 0.01), testosterone (4.1 +/- 0.2 vs. 2.9 +/- 0.1 nmol/liter, P < 0.01) and insulin resistance as measured by homeostasis model assessment for insulin resistance (HOMA-IR) (3.3 +/- 0.4 vs. 2.7 +/- 0.4). There was a significant increase in SHBG (31.1 +/- 1.0 vs. 35.3 +/- 1.2 nmol/liter, P < 0.01). There was a positive correlation between the reduction in HOMA-IR in the atorvastatin group with the reduction in triglycerides and the reduction of free androgen index. There was a significant deterioration of HOMA-IR in the placebo group (3.0 +/- 0.4 vs. 3.8 +/- 0.5). CONCLUSIONS This study suggests that atorvastatin is effective in reducing inflammation, biochemical hyperandrogenemia, and metabolic parameters in patients with PCOS after a 12-wk period.

Effect of metformin, orlistat and pioglitazone treatment on mean insulin resistance and its biological variability in polycystic ovary syndrome

Context  Mean insulin resistance (IR) is greater and it is also more variable in overweight women with polycystic ovarian syndrome (PCOS) compared to weight matched controls. Whilst treatment will reduce the mean IR, it is not known if the IR variability is also reduced.

Atorvastatin Increases 25-Hydroxy Vitamin D Concentrations in Patients with Polycystic Ovary Syndrome

BACKGROUND It has been shown that many women with polycystic ovary syndrome (PCOS) are 25-hydroxyvitamin D (25OHD) insufficient. Both statin treatment and vitamin D supplementation have been shown to improve biochemical hyperandrogenemia, insulin resistance, and markers of inflammation in patients with PCOS, raising the possibility that some of the statin effects are mediated through vitamin D. METHODS We conducted this randomized, double-blind placebo controlled study to assess the effect of atorvastatin on serum 25OHD concentrations in patients with PCOS. Forty medication-naive patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. After completing the initial 3 months of atorvastatin or placebo, both groups of patients participated in a 3-month extension study with metformin 1500 mg daily. We measured changes in 25OHD concentrations by use of tandem mass spectrometry. RESULTS Mean (SD) baseline 25OHD concentrations were comparable between the 2 groups [45.9 (2.4) vs 44.8 (1.8) nmol/L; P = 0.7]. There was a significant increase in 25OHD concentrations with atorvastatin [45.9 (2.4) vs 60.8 (3.5) nmol/L] compared with placebo [44.8 (1.8) vs 41.8 (3.2) nmol/L; P = 0.02]. Three-month treatment with metformin maintained the improvement of 25OHD with atorvastatin compared to baseline [45.9 (2.4) vs 61.8 (3.5), P ≤ 0.01). There were no significant changes in 25OHD concentrations in the placebo group after 12 weeks of metformin. CONCLUSIONS Among patients with polycystic ovary syndrome, 12 weeks of atorvastatin led to a clinically significant rise in 25OHD concentrations. This may represent a beneficial pleiotropic effect of statins on 25OHD concentrations.

A comparison between rimonabant and metformin in reducing biochemical hyperandrogenaemia and insulin resistance in patients with polycystic ovary syndrome (PCOS) : a randomized open-label parallel study

Context  Weight loss and metformin therapy are reported to be beneficial in improving the biochemical hyperandrogenaemia and insulin resistance of polycystic ovary syndrome (PCOS). Rimonabant has been found to reduce weight and improve the metabolic profile in patients with obesity, type 2 diabetes and metabolic syndrome.

Multiple cerebral haematomata and peripheral nerve palsies associated with a case of juvenile diabetic ketoacidosis.

A 15‐year‐old girl presented de novo in diabetic ketoacidosis having been comatose for 24 h (day 1). A CT scan and lumbar puncture performed on admission were normal and her conscious level slowly improved over several days. On day 7 she had central neurological signs of bilateral knee clonus and an extensor plantar response. In addition, she had developed lower motor neurological signs of an ulnar nerve palsy of the left forearm, and ulnar, median, and radial nerve palsies of the right forearm. Magnetic resonance imaging (MRI), performed on day 12, showed multiple small cerebral haematomata with appearances at least several days of age. The scattered lesions were localized particularly to the parieto‐occipital region, with sparing of the basal ganglia and without cerebral oedema, a novel feature not previously described in juvenile ketoacidosis. Four months later there was minimal residual disability of her right arm. The clinical findings together with the MRI images suggested that the peripheral nerve and central lesions were temporally related, suggesting a common aetiology. However, it is likely that MRI showed cerebral lesions which may have been missed by the conventional CT scanning performed initially.

Atorvastatin Reduces Malondialdehyde Concentrations in Patients with Polycystic Ovary Syndrome

BACKGROUND It has been shown that there is an increase in oxidative stress in polycystic ovary syndrome (PCOS). Statins are considered to have a pleiotropic effect other than their lipid-lowering effect. These effects may be mediated in part by reducing oxidative stress. METHODS This randomized, double-blind, placebo-controlled study was conducted to assess the effect of atorvastatin on serum malondialdehyde (MDA) concentrations as a marker of oxidative stress in patients with PCOS. Forty medication-naïve patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. RESULTS There was a significant decrease of MDA concentrations with atorvastatin [mean (sem)] [0.29 (0.04) vs. 0.25 (0.02) μmol/liter; P < 0.01] compared with placebo [0.28 (0.02) vs. 0.29 (0.12) μmol/liter; P = 0.52]. Three months treatment with metformin resulted in further reduction of MDA levels with atorvastatin compared with baseline [0.25 (0.02) baseline vs. 0.23 (0.03) μmol/liter for atorvastatin treated; P = 0.02]. There was also a significant correlation between the reduction in MDA with a reduction in high-sensitivity C-reactive protein (r = 0.71, P < 0.01), an increase in 25-hydroxyvitamin D (25OHD; r = -0.68, P = 0.02), and a reduction in testosterone levels (r = 0.63, P = 0.01). Multiple linear regression analysis revealed Δ25OHD, ΔC-reactive protein, and Δtestosterone were independent predictors of changes in MDA after atorvastatin treatment. No correlation was observed between the reductions in serum MDA concentrations with changes in the lipid parameters. CONCLUSIONS Twelve weeks of atorvastatin led to a significant reduction in oxidative stress as determined by MDA concentrations among patients with polycystic ovary syndrome that was independently predicted by changes in testosterone, 25OHD, and high-sensitivity C-reactive protein.

Atorvastatin pretreatment augments the effect of metformin in patients with polycystic ovary syndrome (PCOS).

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Postprandial effects of long-term niacin/laropiprant use on glucose and lipid metabolism and on cardiovascular risk in patients with polycystic ovary syndrome

This study investigated the effect of long‐term niacin/laropiprant therapy on CV risk and IR in obese women with PCOS.

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.

Insulin Resistance Variability in Women with Anovulatory and Ovulatory Polycystic Ovary Syndrome, and Normal Controls

Women with polycystic ovary syndrome (PCOS) were found to have a higher biological variability in insulin resistance (IR) compared to controls, but it is unknown whether this variability in IR differs between PCOS who are anovulatory compared to those who have an ovulatory cycle. The primary aim of this study was to compare and contrast the variability of IR in women with ovulatory and anovulatory PCOS, in comparison to normal subjects. 53 Caucasian women with PCOS and 22 normal ovulating women were recruited. Fasting blood was collected each day on 10 consecutive occasions at 3-4 day intervals for analysis of insulin, glucose, progesterone, and testosterone. Analysis of progesterone levels showed 22 of 53 women with PCOS to have had an ovulatory cycle. Insulin resistance was calculated by HOMA method. Women with anovulatory PCOS had higher mean and variability of IR compared to those having an ovulatory cycle, and both were significantly higher than controls (mean ± SEM; HOMA-IR 4.14 ± 0.14 vs. 3.65 ± 0.15 vs. 2.21 ± 0.16, respectively) after adjustment or BMI. The mean BMI for individual PCOS patients correlated with mean HOMA-IR (p=0.009). Insulin resistance in women with anovulatory PCOS is both higher and more variable than in ovulatory PCOS. Since anovulatory PCOS therefore mimics the IR features of type 2 diabetes more closely, anovulation may be particularly associated with a higher cardiovascular risk compared to PCOS patients who ovulate.