Testosterone Partially Ameliorates Metabolic Profile and Erectile Responsiveness to PDE5 Inhibitors in an Animal Model of Male Metabolic Syndrome

Abstract

Introduction Metabolic syndrome (MetS) is a clustering of cardio-metabolic risk factors (hyperglycemia, hypertension, dyslipidemia, visceral fat accumulation) that is also associated with hypogonadism and erectile dysfunction (ED). Aim To clarify the relationships among MetS, hypogonadism, and ED, we developed an animal model of MetS. Methods Male rabbits fed a high-fat diet (HFD), with or without testosterone (T) supplementation, were compared with control rabbits (fed a standard chow) and with rabbits made hypogonadal by a single injection of a long-acting GnRH-analog, triptorelin. Main Outcome Measures Evaluation of metabolic disturbances (plasma glucose, cholesterol, triglycerides, testosterone, LH, FSH level, glucose tolerance, mean arterial pressure, visceral fat accumulation), and corpora cavernosa (CC) relaxant capacity (in vitro contractility study) in HFD animals as compared with control, GnRH analog-treated rabbits, and T-supplemented HFD rabbits. Results HFD rabbits showed all the features of MetS. HFD induced hypogonadotropic hypogonadism is characterized by a reduction of plasma T, FSH, LH levels, testis and seminal vesicles weight, and testicular steroidogenic enzymes. Such a phenotype is similar to that induced by triptorelin administration. A reduced GnRH immunopositivity in hypothalamus suggests a central origin of HFD-related hypogonadism. HFD also induced penile alterations, as demonstrated by a reduction of acetylcholine-and electrical field stimulation-induced CC relaxation, hyper-responsiveness to the NO donor, SNP, and unresponsiveness to PDE5 inhibitors. Similar penile alterations were observed in triptorelin treated rabbit. In HFD, as well as in triptorelin treated rabbits, PDE5 and eNOS mRNA expression quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) were significantly decreased. T administration prevented almost all penile alterations observed in HFD rabbits. T treatment dramatically reduced HFD-induced visceral obesity, partially ameliorating also the metabolic profile. Conclusion We have developed an animal model of MetS associated with hypogonadotropic hypogonadism and penile alterations including unresponsiveness to PDE5 inhibitors. T supplementation was able to partially revert HFD-induced phenotype.

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

“…The MetS rabbit model has been obtained by feeding adult male rabbits a high fat diet (HFD; n = 48) for 12 weeks, as previously described (Filippi et al, 2009). A first subgroup of HFD rabbits (n = 28) was treated with intramuscular injections of testosterone (30 mg/ kg/week), as previously described (Filippi et al, 2009;Vignozzi et al, 2012a).…”

“…A first subgroup of HFD rabbits (n = 28) was treated with intramuscular injections of testosterone (30 mg/ kg/week), as previously described (Filippi et al, 2009;Vignozzi et al, 2012a). A second subset of HFD rabbits (n = 18) was treated with the FXR agonist OCA (10 mg/kg/day for 5 days a week, by oral gavage), as previously described ).…”

“…The current study addressed this issue by taking advantage of a non-genomic, high fat diet (HFD)-induced, animal model of MetS that closely resembles the human MetS phenotype (Filippi et al, 2009;Vignozzi et al, 2011Vignozzi et al, , 2012aManeschi et al, 2012;Maneschi et al, 2013). This model is characterized by hyperglycaemia, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, hypertension, increased visceral fat mass, hypogonadotropic hypogonadism, lower urinary tract (LUT) abnormalities (Vignozzi et al, 2012a), penile alterations (Filippi et al, 2009;Vignozzi et al, 2011) and NASH .…”

“…This model is characterized by hyperglycaemia, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, hypertension, increased visceral fat mass, hypogonadotropic hypogonadism, lower urinary tract (LUT) abnormalities (Vignozzi et al, 2012a), penile alterations (Filippi et al, 2009;Vignozzi et al, 2011) and NASH . The primary goal of our analysis was to evaluate the relationship between liver pathology and penile dysfunction in the course of HFD-induced MetS.…”

“…The data indicate that MetS-induced NASH plays an active role in the pathogenesis of ED in HFD rabbits, likely via TNFa. We have recently demonstrated that both testosterone (T; Filippi et al, 2009;Maneschi et al, 2012) or obeticholic acid (OCA; Vignozzi et al, 2011;Maneschi et al, 2013) supplementation to HFD rabbits were able to normalize not only several MetS features, including visceral adipose tissue dysfunction and insulin resistance, but also HFD-induced penile alterations, including hypo-responsiveness to acetylcholine (Ach). Hence, here, we tested whether these treatments can ameliorate also HFD-induced liver alterations, as well as TNFa circulating level.…”