Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction

Abstract

Objectives: Androgens are essential for the development and growth of the penis, and they regulate erectile physiology by multiple mechanisms. Our goal is to provide a concise overview of the basic research and how this knowledge can be translated into a new clinical paradigm for patient management. In addition, this new paradigm may serve as a basis for stimulating constructive debate regarding the use of testosterone in men, and to promote new, innovative basic and clinical research to further understand the underlying mechanisms of androgen action in restoring erectile physiology.

Methods: A literature review was performed utilizing the US National Library of Medicine's PubMed database.

Results: On the basis of evidence derived from laboratory animal studies and clinical data, we postulate that androgen insufficiency disrupts cellular-signaling pathways and produces pathologic alterations in penile tissues, leading to erectile dysfunction. In this review, we discuss androgen-dependent cellular, molecular, and physiologic mechanisms modulating erectile function in the animal model, and the implication of this knowledge in testosterone use in the clinical setting to treat erectile dysfunction. The new clinical paradigm incorporates many of the consensed points of view discussed in traditional consensed algorithms exclusively designed for men with androgen insufficiency. There are, however, novel and innovative differences with this new clinical paradigm. This paradigm represents a fresh effort to provide mandatory and optional management strategies for men with both androgen insufficiency and erectile dysfunction.

Conclusions: The new clinical paradigm is evidence-based and represents one of the first attempts to address a logical management plan for men with concomitant hormonal and sexual health concerns.

Fig. 1

Effect of androgens on rat penile cavernosal nerve structure. Tissue sections of cavernosal nerves from intact (sham-operated) or castrated rats were fixed in glutaraldehyde and stained with toluidine blue to visualize myelinated nerve fibers (magnification = 1000×, oil immersion). Castrated rats infused with vehicle (B) exhibited decreased nerve fiber density and thinner myelin sheaths compared with intact rats (A) or castrated rats infused with testosterone (C). Myelinated nerve fibers can be seen throughout each section and appear as darkened circular or irregularly shaped profiles.

Fig. 2

Potential regulation of nitric oxide synthase (NOS) and phosphodiesterase (type) 5 (PDE5) by androgens. Hypothetical mechanism by which androgens may upregulate both NOS and PDE5 proteins.

Fig. 3

Proposed mechanism of regulation of cellular differentiation by androgens in penile corpus cavernosum. Androgens, through the activation of androgen receptors (ARs), may stimulate stromal precursor cells to differentiate into smooth muscle cells (solid lines/arrows). Normal smooth muscle cell content is predicted to result in abundant amounts of smooth muscle marker proteins (α-actin, desmin, laminin, myosin, vinculin) and decreased levels of adipocyte marker proteins (C/EBPα [CCAAT/enhancer binding protein], PPARγ2 [peroxisome proliferator-activated receptor], and LPL [lipoprotein lipase]). Androgen deprivation may inhibit the smooth muscle differentiation pathway and stimulate differentiation of stromal precursor cells into adipocytes and/or transdifferentiation of smooth muscle cells (dashed lines/arrows). Either of these states is predicted to result in increased levels of adipogenic markers and decreased levels of smooth muscle marker proteins.

Fig. 4

Diagnosis and treatment algorithm for androgen insufficiency and erectile dysfunction.