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Tadalafil and Steroid Hormones Interactions in Adipose, Bone and Prostate Tissues: Focus on Translational Perspectives - PMC
Tadalafil is a selective phosphodiesterase type-5 (PDE5) inhibitor that is approved for the treatment of men with erectile dysfunction (ED) and/or benign prostate hyperplasia (BPH) -associated symptoms. Besides its classical actions on PDE5 within ...
pmc.ncbi.nlm.nih.gov
Tadalafil and Adipose Tissue: Clinical and Preclinical Observations
Serendipity, a clinical observation coming from our pilot study, suggested that the administration of tadalafil in men with ED was associated with an increase of the serum testosterone/estradiol (T/E2) ratio, mainly due to a significant reduction of E2 levels [4]. In that pilot study, where both lean and obese subjects were investigated, no clear-cut explanation for the observed serum E2 decrease was found or why this effect might have occurred. Even if a possible variation of the ARO activity was hypothesized, in that moment, any potential effects of PDE5i on ARO were unexplored. So, on the basis of our previous pilot study, we successively investigated the potential role of chronic tadalafil administration in men affected by ED and metabolic disorders, and we demonstrated its ability to improve insulin secretion and reduce visceral fat mass [10]. Similar observations have been reported by other published clinical studies [13] and by clinical trials actually registered on ClinicalTrials.gov which investigate the possible role of tadalafil on metabolism and body composition disorders (Table 1). Importantly, successive preclinical studies confirmed our clinical observation in men [9,14]. In a mouse model of diet-induced, insulin-resistant, chronic treatment with the PDE5i sildenafil caused a significant improvement in insulin sensitivity [14]. This result was promptly investigated in a successive animal study by controlling the expression and activity of PDE5 in different cell lines of rabbit adipose tissue (i.e., visceral vs. subcutaneous) in different metabolic conditions. This study demonstrated that tadalafil counteracted high fat, diet-associated visceral adipose tissue alterations by restoring insulin sensitivity and prompting preadipocytes differentiation towards a metabolically healthy phenotype where brown, fat-specific genes (such as uncoupling protein-1) are mostly expressed [9]. Apart from clinical and preclinical observations, controversial data confirming a role for PDE5 in adipocyte biology in vitro have been reported [3]. On the basis of our previous clinical observations, as confirmed by successive preclinical data, we subsequently found for the first time that PDE5 mRNA is present in human adipocytes and that selective PDE5 inhibition significantly stimulated ARO mRNA expression in mature adipocytes in vitro upon short-time exposure with a parallel increase in E2 concentrations in the supernatant [3]. E2 is synthesized by cytochrome P450-ARO, which converts androgens into estrogens; indeed, changes at the level of estrogen biosynthesis are closely related to modifications in the transcription of ARO and may exert an important role in the prevention of cardiovascular and metabolic disease [3]. These findings showed, for the first time, that acute PDE5 inhibition was able to increase ARO mRNA expression, which should reflect positive, anti-adipogenic effects. Finally, another study confirmed that even human skeletal muscle cells are a target tissue of tadalafil, and experimental data support its pharmacological actions on modulating glucose metabolism through a direct control on insulin signaling, on improving sex hormones profile and body composition, and on ARO expression, as well as on increasing exercise capacity due to its cardiovascular and vasodilatory effects, as demonstrated by in vitro and in vivo studies [12]. However, to date, neither the molecular mechanisms underlining the interactions between tadalafil, steroid hormones and skeletal muscle metabolism and differentiation are clear, nor are the mechanisms by which PDE5i might positively influence hormone metabolism and physical activity. These clinical and preclinical results led us to conclude that, at least in theory, a dose-dependent, tadalafil-related stimulation of ARO activity could positively modulate the serum T/E2 ratio in vivo during chronic treatment with tadalafil, and this might represent a possible mechanism influencing fat-mass content and its hormonal functions [3]. Thus, we can speculate that the stimulation of the NO/cGMP signal transduction system through a PDE5 blockade can provide a new, effective and reliable ‘target’ for deranged adipose tissue pathways, suggesting its potential role in the treatment of some forms of abdominal fat accumulation and mild obesity (Figure 1).
