Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: An experimental study in the rabbit

Abstract

a b s t r a c tA pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS-associated cardiovascular disease (CVD). This study was aimed at evaluating the relationship between MetS-induced NASH and penile dysfunction. We used a non-genomic, high fat diet (HFD)-induced, rabbit model of MetS, and treated HFD rabbits with testosterone (T), with the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA), or with the anti-TNFa mAb infliximab. Rabbits fed a regular diet were used as controls. Liver histomorphological and gene expression analysis demonstrated NASH in HFD rabbits. Several genes related to inflammation (including TNFa), activation of stellate cells, fibrosis, and lipid metabolism parameters were negatively associated to maximal acetylcholine (Ach)-induced relaxation in penis. When all these putative liver determinants of penile Ach responsiveness were tested as covariates in a multivariate model, only the association between hepatic TNFa expression and Ach response was confirmed. Accordingly, circulating levels of TNFa were increased 15-fold in HFD rabbits. T and OCA dosing in HFD rabbits both reduced TNFa liver expression and plasma levels, with a parallel increase of penile eNOS expression and responsiveness to Ach. Also neutralization of TNFa with infliximab treatment fully normalized HFD-induced hypo-responsiveness to Ach, as well as responsiveness to vardenafil, a phosphodiesterase type 5 inhibitor. Thus, MetS-induced NASH in HFD rabhttp://dx

The independent association of non‐alcoholic fatty liver disease with lower urinary tract symptoms/benign prostatic hyperplasia and erectile function scores

“…Another effect of NAFLD on ED could be due to IR with enhanced vascular expression of endothelin-b receptors. These receptors contribute to augmented reactive oxygen species production, endothelial dysfunction, and increased vasoconstriction in erectile tissue [40,41]. In the present study, both NAFLD and MetS significantly predicted IIEF-5 scores.…”

Erectile dysfunction

“…However, recent clinical and experimental studies suggest that the association between erectile dysfunction and central obesity is independent from obesity-associated comorbidities and hypogonadism 91 . Although increased levels of tumour necrosis factor (TNF; also known as TNFα) — a cytokine involved in systemic inflammation — could be a mediator of these conditions 92 , further studies are needed to confirm this. Sexual health is impaired by type 1 and type 2 diabetes and even by a pre-diabetic status 93–95 .…”

THERAPY OF ENDOCRINE DISEASE: Testosterone supplementation and body composition: results from a meta-analysis study

“…Studies using androgens other than TS as well as studies with simultaneous treatment with other hormones and drugs were also excluded, unless there was a clearly defined treatment arm that received only T treatment. In addition, since phosphodiesterase type 5 inhibitors (PDE5is) have been reported to play a possible positive influence on metabolic outcome (140,141), trials evaluating the effect of TS as an add-on to PDE5is were excluded from the analysis (see also Table 5). …”