Chronic treatment with sildenafil stimulates Leydig cell and testosterone secretion

Abstract

The phosphodiesterase type 5 (PDE5) inhibitor, Sildenafil, is a novel, oral treatment approach for pulmonary hypertension. As Leydig cells present PDE5, this study was conducted to investigate the effects of the chronic treatment with Sildenafil (25 mg/kg) on male Swiss Webster mice steroidogenesis. After a 4-week long experimental design, Leydig cells were analysed by morphological and immunocytochemical procedures. Serum testosterone was assayed by radioimmunoassay. Leydig cells presented noteworthy ultrastructural alterations, such as a vesicular smooth endoplasmic reticulum, large vacuoles scattered through the cytoplasm, enlarged mitochondria with discontinue cristaes and whorle membranes with vesicles at the periphery, which are typical characteristics of an activated steroid-secreting cell. Important immunocytochemical labelling for steroidogenic acute regulatory protein, cytochrome P450 side-chain cleavage enzyme and testosterone were detected in isolated Leydig cells. In addition, Sildenafil-treated mice showed significant increased levels of total testosterone. The results obtained in the present study are consistent with the hypothesis that the accumulation of cyclic guanosine monophosphate by PDE5 inhibition could be involved in the androgen biosynthesis stimulation. Important clinical implications of hormonal disorders should be taken into account for patients with pulmonary hypertension.

Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial

“…Prolonged PDE5i in rats stimulates Leydig cell steroidogenesis, through a coordinate stimulatory effect of cAMP and cGMP (31). Both of these messengers act synergistically and converge on steroidogenic acute regulatory protein to enhance testosterone production (31,32).…”

Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway

“…The intracellular level of cGMP is controlled by cGMP-selective phosphodiesterases (PDEs), expressed in Leydig cells (1,2,20,33) and inhibition of Leydig cell PDE5 in vitro, were accompanied by elevations of cGMP and testosterone production (1). Additionally, in mice, chronic inhibition PDE5 caused ultrastructural changes characteristic for secretory active Leydig cells (31).…”

A sensitive and selective LC-MS/MS analysis coupled with an online sample enrichment technique for H295R steroidogenesis assay and its application in the investigation of the effect of sildenafil on steroidogenesis

“…Moreover, the changes in the testosterone level in experimental animals treated with sildenafil were controversial in previous studies [21][22][23][24]. Janjic et al [21] demonstrated that the serum testosterone level was increased in male adult rats at 60 and 120 min after the oral administration of sildenafil (1.25 mg/kg), which was a transient rise.…”

“…The effect of sildenafil on testosterone production was investigated in a few previous studies [21][22][23][24], whereas that on the 17β-estradiol level has been little studied. Moreover, the changes in the testosterone level in experimental animals treated with sildenafil were controversial in previous studies [21][22][23][24].…”