In addition to testosterone, various endocrine hormones may be involved in erectile function. Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant steroid hormone in humans which is reported to play a multifunctional protective role in cellular well-being.2 The Massachusetts Male Aging Study (MMAS) revealed that out of 17 investigated hormones only DHEA-S exhibited a significant correlation with ED.3 Additionally, estradiol and prolactin have been reported to affect erectile function. However, the role of these sex hormones in the erectile function of men with normal testosterone levels remains unclear.
In the present study, first, we evaluated the relationship between sex hormone levels and ED in community-dwelling men without hypoandrogenism. Second, we investigated the correlation between DHEA-S and estradiol levels and well-known risk factors for ED, including low-grade systemic inflammation, endothelial dysfunction, and advanced glycation end-products (AGEs) accumulation.
This cross-sectional study included 398 community-dwelling men without hypoandrogenism. ED was assessed using the 5-item International Index of Erectile Function (IIEF-5). The participants were categorized into the non-ED (IIEF-5 score ≥ 22) and ED (IIEF-5 score ≤ 21) groups. Serum total testosterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin levels were measured using a chemiluminescent immunoassay. Serum DHEA-S level was measured using a chemiluminescent enzyme immunoassay. Hypoandrogenism was defined as a serum total testosterone level ≤ 250 ng/dL. The accumulation of skin AGEs can be assessed non-invasively by measuring skin autofluorescence. Multivariable logistic regression analyses were performed to identify significant factors associated with ED.
The median age of the study participants and their IIEF-5 scores were 53 years and 17, respectively. Among the 398 men, 66 (17%) and 332 (83%) were classified into the non-ED and ED groups, respectively.
Spearman’s rank correlation test revealed that serum total testosterone and prolactin levels did not exhibit a significant correlation with IIEF-5 scores (ρ = −0.057, P = 0.258; ρ = 0.033, P = 0.509; respectively). Serum DHEA-S levels were positively and significantly correlated with IIEF-5 scores (ρ = 0.524, P < 0.001), whereas serum estradiol, LH, and FSH levels were negatively and significantly correlated with IIEF-5 scores (ρ = −0.133, P = 0.008; ρ = −0.409, P < 0.001; and ρ = −0.435, P < 0.001; respectively).
In the univariable analyses, age, hypertension, dyslipidemia, renal function, and brachial-ankle pulse wave velocity were significantly associated with ED. In the multivariable analyses adjusted for these confounding variables, serum DHEA-S and estradiol levels were significantly associated with ED (odds ratio [OR]: 0.996, P = 0.030; OR: 1.082, P = 0.002; respectively), whereas serum total testosterone, LH, FSH, and prolactin levels did not demonstrate significant association.
In the multiple linear regression analyses, after adjusting for age, none of neutrophil-to-lymphocyte ratio, serum von Willebrand factor, and plasminogen activator inhibitor-1 (PAI-1) levels, and skin AGEs levels did not demonstrate significant correlation with serum DHEA-S and estradiol levels.
Serum total testosterone levels were not associated with ED in men with normal testosterone levels in the present study. However, the reasons for these negative results remain unclear. Endothelial dysfunction is believed to be one of the mechanisms by which hypoandrogenism causes ED. Additional our analysis revealed that serum testosterone levels exhibited negative and significant correlation with serum PAI-1 levels, a well-known endothelial dysfunction marker, after adjusting for age, hypertension, and diabetes mellitus. However, lower testosterone levels had no effect on ED in the present study. Since the pathogenic mechanisms linking low testosterone levels with ED are complex, further studies are necessary to elucidate the role of testosterone in erectile function in men with normal testosterone levels.4
In the present study, serum DHEA-S levels were significantly associated with ED in men without hypoandrogenism. Since DHEA has its own receptors on vascular endothelial cells,5 both DHEA and DHEA-S have various biological functions besides being precursors of testosterone and estradiol.6 DHEA has been reported to activate potassium channels via the activation of soluble guanylate cyclase and trigger nitric oxide synthesis through G-protein-dependent activation and stabilization of endothelial nitric oxide synthase, independent of androgen receptors.7 Besides its effect as a modulator of endothelial function, DHEA has a multifunctional protective effect in many aspects of cellular well-being,2 including the improvement of insulin sensitivity, reduction of fibrinolysis suppressor, and antiatherosclerotic and antioxidative effects.8-10 However, the present study failed to demonstrate a significant correlation between DHEA-S levels and well-known risk factors for ED, including systemic inflammation, endothelial dysfunction, and AGEs accumulation. Because its precise physiological function remains unknown, further research is required to establish a link between erectile function and DHEA-S in men without hypoandrogenism.
Although the present study has several limitations, we demonstrated that testosterone had no effect on ED in men with normal testosterone levels, whereas serum DHEA-S and estradiol levels were significantly associated with ED. These results broaden our understanding of the etiology of ED in men without hypoandrogenism.
Written by: Naoki Fujita, MD, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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