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

Abstract

BackgroundEvidence 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.MethodsPost 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).ResultsTreatment 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-1β, 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.ConclusionRimonabant 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 registrationISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

The Role of Antiobesity Agents in the Management of Polycystic Ovary Syndrome

“…20 The 3 agents induced comparable reductions in the free androgen index but none affected the lipid profi le. 20 Pioglitazone also reduced high-sensitivity C-reactive protein (hs-CRP) levels, a marker of subclinical infl ammation and increased cardiovascular risk 21 , whereas orlistat and metformin had no effect 20 . In a more recent large randomized study (n = 149), orlistat combined with lifestyle modifi cation (caloric restriction and increased physical activity) for 16 weeks induced similar reductions in weight with orlistat and lifestyle modifi cation combined with oral contraceptive pills (OCP, ethinyl estradiol 20 mcg/1 mg norethindrone acetate) and greater than OCP alone (6.2, 6.4 and 1.0%, respectively).…”

“…19 In a post-hoc analysis of 2 randomized studies (n = 50), orlistat 120 mg tid reduced weight by 5.7% whereas metformin 500 mg tid and pioglitazone 45 mg od had no effect. 20 Orlistat and pioglitazone yielded similar improvements in markers of IR whereas metformin did not affect IR. 20 The 3 agents induced comparable reductions in the free androgen index but none affected the lipid profi le.…”

“…20 Orlistat and pioglitazone yielded similar improvements in markers of IR whereas metformin did not affect IR. 20 The 3 agents induced comparable reductions in the free androgen index but none affected the lipid profi le. 20 Pioglitazone also reduced high-sensitivity C-reactive protein (hs-CRP) levels, a marker of subclinical infl ammation and increased cardiovascular risk 21 , whereas orlistat and metformin had no effect 20 .…”

Cannabinoids in Gynecological Diseases

“…Dawson et al [91] recently reported that a weight-reducing therapy with the CB 1 antagonist rimonabant in obese women with PCOS resulted in a reduction of alanine aminotransferase, accompanied by a reduction of insulin resistance. In contrast, it has been reported that the amount of both vascular endothelial growth factor and interleukin-8, which play a crucial role in inflammation, are paradoxically increased upon rimonabant treatment of obese women with POCS, which may compensate the benefit associated with weight loss [98].…”

“…These include fertility disorders like polycystic ovary syndrome (PCOS), endometriosis, and gynecological cancers [91-93]. …”