Glucagon-like peptide-1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has been linked to polycystic ovary syndrome (PCOS) and carries an increased risk of liver cirrhosis. Procollagen type 3 amino-terminal peptide (PIIINP) is an independent predictor of liver cirrhosis. OBJECTIVE: To assess whether 6-month treatment with GLP-1 analogue, liraglutide, improves markers of liver fibrosis. DESIGN: A case-control study comparing women with PCOS to age- and weight-matched controls. PCOS was diagnosed according to the Rotterdam criteria. All participants underwent liver function tests and liver ultrasound scan to assess for fatty infiltration. Serum marker for liver fibrosis, PIIINP, was measured at baseline and after 6-month treatment with liraglutide 1·8 mg od. RESULTS: Nineteen women with PCOS and 17 controls were recruited, age 32·8 ± 7·2 vs 33·5 ± 6·7 years and weight 100·9 ± 16·7 vs 99·3 ± 14·7 kg, respectively. At baseline, the PCOS group had higher testosterone 1·2 ± 0·3 vs 0·9 ± 0·3 nm (P = 0·01), HOMA-IR 5·1 ± 2·6 vs 3·5 ± 1·3 (P = 0·03), AST 22·4 ± 5·2 vs 18·8 ± 3·4 u/l (P = 0·04), PIIINP 4·4 ± 0·8 vs 3·5 ± 0·8 ug/ml (P = 0·01) and NAFLD seven (35%) vs none (P = 0·005), respectively. Twenty-five (69%) participants completed the study (13 PCOS, 12 controls). Following treatment, weight was reduced by 3·0 ± 4·2 kg (P = 0·01) and 3·8 ± 3·4 kg (P = 0·001), respectively. Similarly, HOMA-IR, hsCRP, triglycerides and urinary isoprostane significantly reduced in both groups. PIIINP significantly reduced the in PCOS group 4·4 ± 0·8 vs 3·7 ± 0·9 ug/ml (P < 0·01), but not in controls 3·5 ± 0·8 vs 3·2 ± 0·7 ug/ml (P = 0·08). CONCLUSIONS: Treatment with liraglutide, and/or associated weight loss, significantly reduced PIIINP levels in obese women with PCOS. This may be an additional beneficial factor when considering the use of liraglutide in women with PCOS, obesity and NAFLD.

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

AIM: This study investigated the effect of long-term niacin/laropiprant therapy on CV risk and IR in obese women with PCOS. METHODS: In this double-blind randomized placebo-controlled trial, 13 and 12 PCOS women completed a 12 week course of niacin/laropiprant or placebo, respectively. Fasted subjects had an endothelial function test (EndoPat2000) and then consumed a mixed meal with blood sampled postprandially for 6 h before and after intervention. RESULTS: By 12 weeks, niacin/laropiprant lowered low-density lipoprotein cholesterol (LDL-c) (13%) and increased HDL-c (17%). Despite a reduction in fasting triglycerides (21%), the drug had no effect on their postprandial rise (2.69 ± 1.44 vs. 2.49 ± 1.14 mmol/l, p = 0.72). However, following the mixed meal, plasma glucose area under the response curve increased from 13.1 ± 2.9 to 14.0 ± 2.8 mmol/l, p = 0.05, as a consequence of both increased insulin resistance [HOMA-IR: 2.2 (1.2, 4.2) vs. 3.8(1.3, 5.5), p = 0.02] and a reduced acute insulin response to glucose [424 (211, 975) vs. 257(122, 418) pmol/mmol, p = 0.04]. Niacin/laropiprant did not improve RHI (1.97 ± 0.40 vs. 2.05 ± 0.58, p = 0.33) or hsCRP. CONCLUSIONS: In PCOS, niacin/laropiprant had a significant negative impact on postprandial glucose and no improvement in postprandial hypertriglyceridaemia, with at least the former mediated through increased IR and reduced ß-cell function. This data may help explain why the improvement in fasting lipids has not translated into improved CV risk markers in PCOS.

Polycystic ovary syndrome has no independent effect on vascular, inflammatory or thrombotic markers when matched for obesity.

INTRODUCTION: Previous studies investigating cardiovascular (CV) risk in obese women with polycystic ovary syndrome (PCOS) have been potentially confounded by not adequately accounting for body weight. OBJECTIVE: To assess if PCOS increases CV risk independently in young obese women by examining carotid intima-media wall thickness (cIMT) and platelet function. DESIGN: A case-control study comparing women with PCOS (n = 21) to age (32·8 ± 7·2 vs 33·5 ± 6·7 years), and weight (100·9 ± 16·7 vs 99·3 ± 14·7 kg)-matched controls (n = 19). Platelet function was examined by flow cytometry, clot structure and fibrinolysis by turbidimetric assays and endothelial function by ELISA and post ischaemic reactive hyperaemia. RESULTS: The PCOS group had higher testosterone 1·2 ± 0·3 vs 0·9 ± 0·3 nmol/l (P = 0·01), HOMA-IR 2·5 ± 1·7 vs 1·7 ± 1·0 (P = 0·08), impaired glucose regulation 33·3% vs 5·3% (P = 0·02), and urinary isoprostane 16·0 ± 4·4 vs 11·8 ± 7·1 ng/ml (P = 0·04) compared to controls. Mean cIMT 0·5 ± 0·05 vs 0·48 ± 0·06 mm (P = 0·36), and basal platelet surface expression (percentage of positive cells) of P-selectin 0·52 ± 0·3 vs 0·43 ± 0·23 (P = 0·40) and fibrinogen binding 0·97 ± 0·4 vs 0·83 ± 0·3 (P = 0·48) did not significantly differ between the PCOS and control groups respectively. Furthermore, platelets sensitivity to stimulation with adenosine-5'-diphosphate or inhibition with prostacyclin, clot structure and fibrinolytic efficiency ex vivo, endothelial reactive hyperaemic index (RHI), inflammation (hsCRP) and adhesion markers (sE-selectin, sP-selectin, sVCAM-1 and sICAM-1) were not significantly different between the two groups. CONCLUSIONS: PCOS appeared not to independently increase atherothrombotic risk when matched for obesity. It is likely that any excess CV risk in young obese women with PCOS can either be attributed to obesity or is not yet apparent at this early stage of the condition.

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.

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. OBJECTIVE: To compare the change in IR and its variability before and after treatment with insulin sensitization through metformin and pioglitazone, compared to that induced by weight loss with orlistat. DESIGN: Randomized, open labelled parallel study. SETTING: Endocrinology outpatient clinic at a referral centre. PATIENTS: Thirty obese PCOS patients [BMI 36.0 +/- 1.2 kg/m(2) (mean +/- SEM)] participated in the study. INTERVENTION: The change in biological variability (BV) was assessed by measuring IR (homeostasis model assessment method) at 4-day intervals on 10 consecutive occasions before and 12 weeks after randomization to metformin, pioglitazone or orlistat. OUTCOME MEASURED: The primary end point of the study was a change in BV of IR. RESULTS: Treatment with pioglitazone, orlistat and metformin reduced the overall IR by 41.0 +/- 4.1%, 19.7 +/- 6.4% and 16.1 +/- 6.8% (P = 0.005, P = 0.013, P = 0.17, respectively) and IR variability by 28.5 +/- 18.0%, 41.8 +/- 11.6% and 23.7 +/- 17.0 (P = 0.20, P = 0.015 and P = 0.28, respectively). Free androgen index reduced significantly with all treatments. CONCLUSION: Only orlistat reduced both IR and its variability significantly, though all three drugs were effective in reducing hyperandrogenism within the 12-week period of the study.

Hyponatraemia secondary to cerebral salt wasting syndrome following routine pituitary surgery.

A female aged 53 years was found to have a suprasellar lesion, which was shown to be a Rathke's cyst after removal by transsphenoidal surgery. She presented 16 days postoperatively, and following two grand mal seizures was found to be profoundly hyponatraemic (sodium 101 nmol/l). She was initially thought to have the syndrome of inappropriate antidiuretic hormone and was treated accordingly, but central venous pressure measurement revealed the hypovolaemia of cerebral salt wasting syndrome. The patient subsequently developed severe neurological sequelae after the correction of her hyponatraemia, following the development of extrapontine myelinolysis. Cerebral salt wasting syndrome is a rare cause of hyponatraemia following pituitary transsphenoidal surgery, which may mimic the syndrome of inappropriate antidiuretic hormone secretion. This case emphasizes the poor prognosis that may result from the rapid correction of profound hyponatraemia.

Observer variability in the interpretation of contrast enhanced MRI of the breast.

The purpose of this study was to determine observer variability in the interpretation of contrast enhanced breast MRI and to evaluate its effect on the detection and differentiation of breast cancer. 57 women underwent breast MRI using spin echo and dynamic spoiled gradient-recalled sequences. Images were independently reviewed by three radiologists, two experienced and one newly trained in breast MRI interpretation. One of the experienced readers reviewed all examinations twice. Interpretation was based on lesion conspicuity, signal intensity, contour and enhancement pattern. Contrast uptake was assessed using region of interest (ROI) analysis of the dynamic images and calculation of a maximum enhancement index. Sensitivity and specificity in the diagnosis of malignancy irrespective of disease extent, and in the diagnosis of multifocal malignancy were estimated. 113 lesions were reported. Kappa coefficient estimations showed only a moderate agreement between the two experienced readers in rating morphological characteristics; the agreement between the newly trained reader and the experienced readers was even worse. Moreover, there was significant interobserver and intraobserver variation in the enhancement index measurements. Weighted kappa values indicated good agreement between the experienced readers in lesion and overall interpretation, excellent intraobserver agreement, but substantial disagreement between the newly trained reader and both experienced readers. All readers showed good sensitivity in cancer detection, but specificity was substantially lower. There is significant observer variability and a substantial learning curve in the interpretation of breast MRI, and variability in the ROI analysis of dynamic data. Further efforts to improve the reliability of ROI analysis and image interpretation are needed to help MRI realise its full potential in the clinical management of breast cancer.

A newly recognized, likely autosomal recessive syndrome comprising agammaglobulinemia, microcephaly, craniosynostosis, severe dermatitis, and other features.

We present a novel, likely autosomal recessive, multi-system disorder seen in three siblings, two males and one female, born to nonconsanguineous parents. The disease manifests as agammaglobulinemia with marked microcephaly, significant developmental delay, craniosynostosis, a severe dermatitis, cleft palate, narrowing of the choanae, and blepharophimosis. The constellation of clinical signs seen in this family likely represents a new and recognizable form of agammaglobulinemia due to a defect in early B-cell maturation.

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.