Abstract
PurposeFemale sexual response involves a complex interplay between neurophysiological mechanisms and the nitric oxide (NO)-mediated relaxation of clitoris and vagina. The aim of this study was to evaluate sex steroids regulation of the relaxant pathway in vagina, using a validated animal model.MethodsSubgroups of OVX Sprague–Dawley rats were treated with 17β-estradiol, testosterone, or testosterone and letrozole, and compared with a group of intact animals. Masson’s trichrome staining was performed for morphological evaluation of the distal vaginal wall, in vitro contractility studies investigated the effect of OVX and in vivo treatments on vaginal smooth muscle activity. RNA from vaginal tissue was analyzed by semi-quantitative RT-PCR.ResultsImmunohistochemical analysis showed that OVX induced epithelial and smooth muscle structural atrophy, testosterone and testo + letrozole increased the muscle bundles content and organization without affecting the epithelium while 17β-estradiol mediated the opposite effects. In vitro contractility studies were performed on noradrenaline pre-contracted vaginal strips from each experimental group. Acetylcholine (0.001–10 µM) stimulation induced a concentration-dependent relaxation, significantly reduced by NO-synthase inhibitor L-NAME and by guanylate cyclase inhibitor ODQ. OVX resulted in a decreased responsiveness to acetylcholine, restored by testosterone, with or without letrozole, but not by 17β-estradiol. OVX sensitivity to the NO-donor SNP was higher than in the control. Vardenafil, a PDE5 inhibitor, enhanced SNP effect in OVX + testosterone as well as in control, as supported by RNA expression analysis.ConclusionsOur study demonstrates that testosterone improves the NO-mediated smooth muscle vaginal cells relaxation confirming its role in maintaining the integrity of muscular relaxant machinery.
Highlights
Testosterone (T), one of the most potent androgens, makes a quantitative contribution to the circulating sex steroids pool, reaching a level significantly higher than 17β-estradiol (E2), in male and in female [1].The biological activity of T in women has been considered enigmatic and left overlooked for a long time
No changes were observed in the lamina propria, while the smooth muscle bundles in the muscularis appeared smaller and poorly organized after ovariectomy (Fig. 1, panel B)
E2 treatment was able to restore the epithelium thickness, without changing the muscularis content and organization (Fig. 1, panel C), as compared to OVX section. Both T and T + L treatments determined a positive effect on smooth muscle component that appeared increased and better organized, while no effect was evident on the epithelium, as compared to OVX (Fig. 1, panels D and E)
Summary
Testosterone (T), one of the most potent androgens, makes a quantitative contribution to the circulating sex steroids pool, reaching a level significantly higher than 17β-estradiol (E2), in male and in female [1].The biological activity of T in women has been considered enigmatic and left overlooked for a long time. T levels have been positively associated with sexual function in women, and many randomized placebo-controlled trials (RCTs) have shown that T therapy can be an effective treatment for female sexual dysfunction [2]. Several recent studies have investigated the use of intravaginal T in postmenopausal women for the treatment of vulvovaginal atrophy and genitourinary syndrome of menopause (GSM) [2, 6, 7], positing vagina as a new target for T. We recently demonstrated, for the first time, that the enzymatic machinery able to produce androgens— including T and its potent effector dihydrotestosterone (DHT)—is present in the human vagina, substantiating the construct of intracrinology in this organ [8]
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