The Effect of Exenatide on Cardiovascular Risk Markers in Women With Polycystic Ovary Syndrome.

Background: Polycystic ovary syndrome (PCOS) is associated with an adverse cardiovascular risk profile including a prothrombotic state. Exenatide has been shown to be effective at improving insulin sensitivity and weight loss in PCOS; therefore this study was undertaken to assess its effects on weight, endothelial function, inflammatory markers, and fibrin structure/function in overweight/obese women with PCOS. Methods: Thirty overweight/obese anovulatory women with all 3 Rotterdam criteria received exenatide 5 mcg bd for 4 weeks then 10 mcg bd for 12 weeks. The primary outcome was change in weight; secondary outcomes were changes in endothelial function [Reactive Hyperemia-Peripheral Arterial Tonometry (RH-PAT)], serum endothelial markers (ICAM-1, VCAM-1, E-selectin, and P-selectin), change in inflammation (hsCRP), and alteration in clot structure and function [maximum absorbance (MA), and time from full clot formation to 50% lysis (LT)]. Results: Twenty patients completed the study. Exenatide reduced weight 111.8 ± 4.8 to 108.6 ± 4.6 kg p = 0.003. Serum endothelial markers changed with a reduction in ICAM-1 (247.2 ± 12.9 to 231.3 ± 11.5 ng/ml p = 0.02), p-selectin (101.1 ± 8.2 to 87.4 ± 6.6 ng/ml p = 0.01), and e-selectin (38.5 ± 3.3 to 33.6 ± 2.6 ng/ml p = 0.03), without an overt change in endothelial function. Inflammation improved (CRP; 8.5 ± 1.4 to 5.6 ± 0.8 mmol/L p = 0.001), there was a reduction in clot function (LT; 2,987 ± 494 to 1,926 ± 321 s p = 0.02) but not clot structure. Conclusion: Exenatide caused a 3% reduction in weight, improved serum markers of endothelial function, inflammation, and clot function reflecting an improvement in cardiovascular risk indices in these women with PCOS. This suggests exenatide could be an effective treatment for obese women with PCOS. Clinical Trial Registration: ISRCTN81902209.

The Effect of Phytoestrogen on Thyroid in Subclinical Hypothyroidism: Randomized, Double Blind, Crossover Study.

Objective: Soy phytoestrogens are suggested to impair thyroid function but the effects of pharmacological doses of soy phytoestrogens are unknown; therefore, this study was performed to determine the effect of high dose soy phytoestrogens (66 mg) on thyroid function in subclinical hypothyroidism. Design and setting: Randomized, double-blind, crossover study. Participants: Forty four patients with subclinical hypothyroidism. Intervention: Participants were randomly allocated to either 66 mg phytoestrogen with 30 g soy protein (active) or 0 mg phytoestrogen with 30 g soy protein (placebo) supplementation for 8 weeks, washed out for 8 weeks and then crossed over for another 8 week period. Main outcome measures: The primary outcome was progression to overt hypothyroidism with the secondary outcome measures were changes in thyroid function tests. Results: Two patients in this trial progressed into overt hypothyroidism after high dose phytoestrogen supplementation. TSH, free thyroxine and triiodothyronine did not differ between groups. Conclusion: A pharmacological dose of 66 mg of soy phytoestrogens did not increase the overt thyroid failure rate or alter thyroid function tests in patients with subclinical hypothyroidism.

Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss.

BACKGROUND: Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. METHODS: Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). RESULTS: Treatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1ß, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT. CONCLUSION: Rimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD. TRIAL REGISTRATION: ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

Insulin resistance and cardiovascular risk marker evaluation in morbid obesity 12 months after bariatric surgery compared to weight-matched controls.

BACKGROUND: Insulin resistance (IR) after bariatric surgery is significantly lower than controls matched for body mass index (BMI) and is indistinguishable from lean subjects however it is not known if this is the same for associated cardiovascular risk (CVR) markers (endothelial function (EF) and clot structure and function (maximum absorbance (MA) lysis potential (LT) and clot formation time (FT). OBJECTIVE: We sought to determine if IR and associated CVR markers one year after bariatric surgery were comparable to post surgery age and BMI matched controls. METHODS: Ten patients had before and 12 months after Roux-en-Y surgery CVR measurements compared to controls. RESULTS: BMI reduced after surgery to 33.3±1.7 kg/m(2) p<0.001 comparable to controls 32.6±1.6 kg/m(2) p=0.87. Fasting glucose reduced after surgery to 4.6±0.1 mmol/L, lower than controls 5.0±0.1 mmol/L p=0.03. IR (calculated using HOMA-IR) reduced 0.77±0.14 p=0.03 and was lower than controls 2.35±0.32 p= 0.02. Systolic blood pressure (BP) reduced to 114.2±3.6 mmHg which was lower than controls 127.7±4.1 mmHg p=0.04, but diastolic BP was unaffected by surgery and no different to controls. EF, hsCRP and HDL-cholesterol improved after surgery and did not differ to controls. Markers of blood clotting: MA and FT were unaffected by surgery and no different to controls, LT improved after surgery 3078±580 to 1665±330s p= 0.04) and was no different to controls (2088±556s p=0.12) CONCLUSIONS: Bariatric surgery improved cardiovascular risk parameters to that of the equivalent controls post surgery for weight including EF, hsCRP and LT supporting bariatric surgery as an effective management of obesity.

A comparison of cardiovascular risk indices in patients with polycystic ovary syndrome with and without coexisting nonalcoholic fatty liver disease.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have an adverse cardiovascular risk profile and an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which is also associated with an adverse cardiovascular risk profile. OBJECTIVE: To compare the cardiovascular risk profile of women with PCOS alone and women with PCOS and NAFLD. DESIGN, SETTING AND PARTICIPANTS: Twenty-five oligoanovulatory women with PCOS were screened for NAFLD (including liver biopsy if appropriate) and had their cardiovascular risk factors measured which included the inflammatory marker C-reactive protein (CRP), endothelial function {measured using endoPAT 2000 and serum markers [intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin]}, clot structure and function [maximum absorbance (MA) and lysis potential (LT)]. RESULTS: Twelve patients had confirmed PCOS without evidence of NAFLD, and 13 patients had confirmed PCOS with evidence of NAFLD. The PCOS and NAFLD group were heavier (BMI 43·9 ± 2·2 kg/m(2) ) compared with the PCOS alone group (BMI 37·6 ± 1·4 kg/m(2) P = 0·03). There was no difference in CRP (7·57 ± 0·95 vs 6·59 ± 1·87 mm P = 0·62) or endothelial function (RH-PAT 1·96 ± 0·1 vs 1·74 ± 0·16 P = 0·25), ICAM-1 (221 ± 48 vs 250 ± 60 ng/ml P = 0·19), VCAM-1 (2124 ± 78 vs 2314 ± 91 ng/ml P = 0·13), E-selectin (33·9 ± 3·3 vs 39·5 ± 15·5 ng/ml P = 0·31) and P-selectin (101·0 ± 6·6 vs 95·9 ± 10·2 ng/ml P = 0·69). There was no difference in clot formation or lysis. CONCLUSION: The patients with PCOS and NAFLD were heavier compared with patients with PCOS alone. Despite this, we were unable to demonstrate differences in inflammatory markers, endothelial function or clot structure and function, suggesting that severity of steatosis is not the most important determinant of cardiovascular risk in PCOS.

Elemental mercury toxicity due to aspiration following intentional massive ingestion.

Deliberate poisoning with intentional ingestion of elemental mercury is reported not to result in systemic toxicity due to minimal absorption from the gastrointestinal tract. We report a case of a 43 year old male who intentionally ingested 200 ml elemental mercury which resulted in abdominal pain and vomiting. The patient subsequently aspirated globules of mercury which was confirmed on chest x-ray and his blood mercury levels were markedly raised. He was treated with chelating agents and managed in a negative pressure room to reduce the risk of staff being exposed to exhaled mercury vapour from the patient.