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ROLE OF TESTOSTERONE IN ERECTILE PHYSIOLOGY AND PATHOPHYSIOLOGY
Abdulmaged M. Traish, and Noel N. K
Departments of Biochemistry and Urology, Boston University School
of Medicine, Boston MA 02118
The role of androgens in maintaining erectile function in humans
remains a controversial and hotly debated issue. An increasing body
of evidence suggests that androgens play an important role in erectile
physiology. In laboratory animal studies, testosterone deprivation
via surgical or medical castration resulted in erectile dysfunction,
in part, due to venous leakage, which was correlated with the loss
of smooth muscle. Animal and human studies suggest that the corporeal
veno-occlusion mechanism is dependent on the relaxation of vascular
smooth muscle of the resistance arteries and the trabeculae. Venous
leakage is a common condition among patients with erectile dysfunction
who do not respond well to various medical management approaches.
This is attributed, in part, to penile arterial insufficiency, smooth
muscle atrophy and imbalance between trabecular smooth muscle content
and connective tissue.
Androgen-deprivation in animals is associated with penile tissue
atrophy concomitant with alterations in the structure and function
of cavernous and dorsal nerves, endothelial morphology and function,
reduction in trabecular smooth muscle content and responsiveness
to vasoactive substances and increased synthesis and deposition
of extracellular connective tissue matrix proteins. Androgen deficiency
also diminishes mRNA, protein expression and enzymatic activities
of nitric oxide synthase isoforms (eNOS & nNOS) and phosphodiesterase
type 5 in penile tissue. The androgen-dependent loss of erectile
response is restored by androgen administration, but not by administration
of phosphodiesterase type-5 inhibitors alone, suggesting that androgens
are critical for maintaining penile tissue health and function.
In more recent studies, we have made the novel observation that androgen
deprivation results in accumulation of fat-containing cells (adipocytes)
in the sub-tunical region of the corpus cavernosum of castrated
adult animals, but not in intact control animals. The origin and
mechanism by which these fat-containing cells arise remains unknown.
Interestingly, fat-containing cells were never observed in the smooth
muscle of the urethra and corpus spongiosum, irrespective of androgen
status. Given the general effects of androgens on inhibiting adipogenesis
in various tissues and cell lines and their ability to maintain
smooth muscle in genital tissue, we suggest that androgens promote
differentiation of precursor vascular stromal cells into smooth
muscle cells, while androgen deficiency promotes differentiation
of the precursor cells into adipocytes and/or facilitates trans-differentiation
of smooth muscle into adipocytes. Thus, the penis is a unique organ
system and provides an experimental model to study the regulation
of smooth muscle cell maintenance and differentiation by androgens.
We further demonstrate that erectile function is maintained by a
wide range of systemic testosterone levels that can be as low as
10-12% of normal physiological plasma concentrations. However, below
these concentrations, erectile function is significantly and positively
correlated with testosterone plasma levels in a dose-dependent manner.
Thus, we suggest that 10% of the normal physiological plasma testosterone
concentration may represent a threshold value, below which erectile
function declines in a dose-dependent fashion.
In summary, we suggest that in the corpus cavernosum, androgens regulate
endothelial and trabecular smooth muscle growth and metabolic function,
the expression and activities of nitric oxide synthases and PDE
5, connective tissue protein synthesis and progenitor cell differentiation.
We conclude that androgen-deficiency produces metabolic and structural
and functional imbalance in the corpus cavernosum with concomitant
alterations in nerve and smooth muscle responses and fibroelastic
properties, resulting in poor tissue compliance and venous leakage,
thus producing erectile dysfunction.
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