ABDULMAGED M. TRAISH
From the Departments of Biochemistry and Urology, Boston University School of Medicine, Boston, Massachusetts.
|Correspondence to: Dr Abdulmaged M. Traish, Professor of Biochemistry and Urology, Director, Laboratories for Sexual Medicine, Institute for Sexual Medicine, Boston University School of Medicine, Center for Advanced Biomedical Research, 700 Albany St, W607, Boston, MA 02118 (e-mail: [email protected]).|
|Received for publication June 13, 2008; accepted for publication September 17, 2008.|
Androgens are essential for development, growth, and maintenanceof penile structure, and regulate erectile physiology by multiplemechanisms. Here we provide a concise overview of the basicresearch findings pertaining to androgen modulation of erectiletissue architecture and physiology. A significant body of evidenceexists pointing to a critical role of androgens in erectilephysiology. Studies in animal models have provided fundamental knowledge on the role of androgens in modulating tissue architectureand cellular, molecular, and physiological mechanisms. Basedon data from our laboratory and those reported by others, webelieve that androgens play a pivotal role in maintaining thestructure and function of the peripheral penile nerve network,the structural integrity of the corpora cavernosa, the tunicaalbuginea, and the endothelium of the cavernous spaces. Further, androgens play an important role in regulating the differentiationof precursor cells into trabecular smooth muscle. In this review,we will focus our discussion on findings pertaining to therole of androgens in regulating penile tissue architecturalelements in modulating penile function. This knowledge hasa profound impact on the potential use of androgens in the clinicalsetting to treat patients with erectile dysfunction.
Corporeal veno-occlusive dysfunction is an important cause oforganic erectile dysfunction and is characterized by the needfor increased flow rates to maintain erection during clinicalevaluation of erection by intracavernous saline infusion (Hatzichristouet al, 1995, 1999; Nehra et al, 1996, 1998; Udelson et al, 1998; Mulhall et al, 2004). Corporeal veno-occlusive dysfunctionalone or combined with arterial disease is the specific hemodynamicabnormality causing lack of response to intracavernous pharmacotherapy(Rajfer et al, 1988; Mulhall et al, 1997; Aversa et al, 2003;Wespes et al, 2005; Hwang et al, 2006). The existence of concomitantarterial and sinus smooth muscle disease makes veno-occlusivedysfunction often difficult to diagnose and treat.
Although efforts have been made by a number of laboratoriesto define and understand the role of androgens in regulatingthe cellular and molecular basis of erectile function and someprogress has been made, several gaps remain. These includethe role of androgens in the structural and functional integrityof the cavernosal and dorsal nerves, the growth and functionof the smooth muscle, and the function of the endothelium andmaintenance of connective tissue metabolism and attenuationof fibrosis. Here we present a working model of androgen actionin erectile function (Figure 2). Using this framework, wediscuss the role of androgens on penile structural components including 1) peripheral nerves, 2) trabecular smooth muscle,3) differentiation of precursor pluripotent cells into smoothmuscle, 4) vascular endothelium, and 5) tunica albuginea andconnective tissue.
Androgens modulate the structure and function of pelvic ganglia (Meusburger and Keast, 2001; Keast et al, 2002). Giuliano et al (2004) suggested that androgens modulate erectile functionby acting on postganglionic parasympathetic neurons. Armaganet al (2007) showed that androgen deprivation by castrationaltered the structure of the dorsal nerve. This observationis consistent with those made by Baba et al (2000a,b) in whichcastration reduced NADPH staining in the cavernosal and dorsalnerves and testosterone treatment restored these nerve fibersto control levels. Rogers et al (2003) also demonstrated thatcastration altered the structure of the dorsal nerve and resultedin venous leakage. Testosterone treatment immediately following castration prevented venous leakage and restored intracavernosalpressure to values similar to those of intact animals. Interestingly,treatment of castrated animals with vascular endothelial growthfactor (VEGF) restored nerve structure and veno-occlusive function.Because androgens have been shown to regulate VEGF expression(Haggestrom et al, 1999), it is possible that VEGF synthesisin the corpus cavernosum is down-regulated in castrated animalsand testosterone treatment induces VEGF synthesis, thus mediatingthe androgen-dependent effects on corpus cavernosum.
Orchiectomy produced significant reduction in intracavernosalpressure elicited by electrical field stimulation of the pelvicnerve. This was reversed by testosterone replacement, suggestingthat testosterone plays an important role in the peripheralnerve network regulating penile erection (Simpson and Marshal, 1908; Müller et al, 1988; Heaton and Varrin, 1994; Mills et al, 1994; Bivalacqua et al, 1998; Traish et al, 1999; Palese et al, 2003; Suzuki et al, 2007). Further, Suzuki et al (2007) demonstratedthat, in contrast to the erectile responses elicited by electricalstimulation of the cavernosal nerve, which were reduced butwere not eliminated in castrated animals, erectile responseselicited by electrical stimulation of the medial preoptic areawere eliminated following castration and were fully restoredafter testosterone replacement.
Androgens Maintain Penile Trabecular Smooth Muscle Structure and Function
Considerable evidence exists suggesting that penile trabecularsmooth muscle plays an integral role in regulating erectilefunction (Saenz de Tejada, 2002). The exact nature of themolecular and structural alterations that occur in the smoothmuscle subsequent to androgen deficiency, however, remains unknown.
Androgen deprivation in animal models, by surgical or medicalcastration, produced significant reduction in trabecular smoothmuscle content, and increased deposition of extracellular connectivetissue matrix (Traish et al, 1999). This change in tissuearchitecture is associated with reduction in intracavernosal pressure in response to pelvic nerve stimulation (Simpson and Marshal, 1908; Müller et al, 1988; Takahashi et al, 1991; Heaton and Varrin, 1994; Mills et al, 1994; Bivalacqua et al, 1998; Traish et al,1999, 2003; Palese et al, 2003; Suzuki et al, 2007). Furthermore,ultrastructural studies in tissue from castrated animals documentedthat trabecular smooth muscle appeared disorganized, with large numbers of cytoplasmic vacuoles and decreased amounts of cytoplasmic myofilaments (Persson et al, 1989; Traish and Kim, 2005;Traish and Guay, 2006; Traish et al, 2007). The loss of smoothmuscle resulting from androgen deprivation is attributed toan increase in programmed cell death, connective tissue deposition,and adipocyte differentiation from precursor cells (Shabsigh et al, 1998; Traish et al, 2005). Some notable alterations in penile tissuestructural features reported in patients with erectile dysfunctionwere smooth muscle atrophy and accumulation of extracellularmatrix, comprised primarily of collagen fibrils.
The smooth muscle content of the corpora cavernosa relativeto the connective tissue, assessed histologically with specificstaining, is defined as the smooth muscle to connective tissueratio. A decrease in the trabecular smooth muscle content concomitantwith increased deposition of connective tissue matrix is expectedto produce tissue fibrosis and ultimately erectile dysfunction.The severity of symptoms and clinical findings in men with erectiledysfunction was correlated with reduced tissue content of corporalsmooth muscle (Nehra et al, 1996, 1998; Wespes et al, 1997, 1998). In tissue from men with ED, the smooth muscle exhibitedaltered morphology concomitant with sparse glycogen particlesand aggregated mitochondria found throughout the cells. The nuclei displayed pleomorphic shape and the cell-cell contactswere decreased or eliminated. These studies suggested thatincreased collagen content (eg, connective tissue) concomitantwith a compensatory decline in trabecular smooth muscle contentalters penile fibroelastic properties, reduces compliance,and results in reduced penile blood flow, producing erectile dysfunction (Persson et al, 1989; Mersdorf et al, 1991).
Androgens Regulate Differentiation of Pluripotent Precursor Cells Into Trabecular Smooth Muscle
Androgen deprivation in the animal model resulted in accumulationof adipocytes in penile tissues, particularly in the subtunicalregion (Traish et al, 2005). Testosterone replacement restorednormal cavernosal histological appearance. The observed tissuealterations were associated with decreased intracavernosal pressurefollowing pelvic nerve stimulation. We and others have notedthe accumulation of adipocytes in penile tissue of diabeticanimals (Traish and Kim 2005; Kovanecz et al, 2006). Because diabetes is associated with decreased androgen circulation,it is likely that such accumulation of adipocytes is causedby loss of androgen control of cellular differentiation. Similarly,treatment of male animals with bisphenol A, which is knownto possess estrogenic activity, also resulted in accumulationof adipocytes in the corpora cavernosa (Moon et al, 2001, 2004).This suggests that estrogens may antagonize androgen actionin the corpus cavernosum and result in differentiation of precursorpluripotent cells into adipocytes. Goyal et al (2005a,b; 2007a,b) have elegantly demonstrated that treatment of 2-day-old animalswith estrogens resulted in reduced plasma testosterone levelsand accumulation of adipocytes in the corpora cavernosa ofthe mature animal. Bhasin et al (2003) suggested that androgens regulate differentiation of pluripotent cells into smooth muscleand inhibit differentiation into adipocytes. This hypothesiswas further supported by the findings of Singh et al (2003, 2006), who demonstrated that differentiation of pluripotentcells into smooth muscle and inhibition of adipogenesis areandrogen-dependent. We postulated that accumulation of adipocytesin the interface between the tunica albuginea and the cavernosal bodies might contribute to corporo-occlusive dysfunction.
Androgens Maintain Vascular Endothelial Structure and Function
It is well established that the vascular endothelium modulatescorpus cavernosum smooth muscle tone via production of NO andparacrine factors, such as prostaglandins, endothelin, platelet-derivedgrowth factor, and transforming growth factor β1 [TGF-β1] (Moreland, 2000; Bivalacqua et al, 2003, 2005; Solomon et al, 2003;Guay 2005, 2007; Musicki and Burnett, 2007; Watts et al, 2007).Various insults on the endothelium (ie, ischemia, hypoxia,and arteriosclerosis) may produce an increased or decreasedlevel of paracrine factors, which alters the function and growthof smooth muscle cells (Moreland, 2000). A recent study byLu et al (2007) demonstrated that androgen deprivation by castrationor 5-reductase inhibitor treatment produced damage to the endotheliumstructure, as determined by electron microscopy. The endotheliumfrom intact animals exhibited smooth surfaces with regularultrastructural features. The endothelium from castrated animalshad coarse and protuberant surfaces, and appeared to be irregular.The cell-cell contacts were altered and adhesion of red bloodcells to the surface of the endothelium was noted. Administrationof testosterone into castrated animals partially restored endothelialstructural integrity, with few lesions remaining noticeable.The data from this study suggested that androgen deficiencyproduces vascular endothelial damage and that endothelial structuralintegrity is restored by androgen administration. Akishitaet al (2007) reported that, in 187 consecutive male outpatientswho underwent measurement of flow-mediated vasodilation (FMD)of the brachial artery using ultrasonography, total and freetestosterone were significantly correlated with percentage FMD. This correlation was independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus, and smoking, suggestinga protective effect of endogenous testosterone on the endothelium.
The restoration or remodeling of endothelial injury depends,in part, on a pool of premature circulating progenitor cells(PCs) and mature circulating endothelial progenitor cells (EPCs).Foresta et al (2006, 2008) investigated the effects of prolongedtestosterone therapy in men with hypogonadotropic hypogonadismon PCs and EPCs. The authors suggested that hypogonadal patientshad reduced levels of PCs and EPCs and that testosterone therapyresulted in a significant increase in these cells. The authorsconcluded that hypogonadism is associated with reduced numbersof circulating PCs and EPCs. The increase in the proliferation,migration, and colony-formation activity of EPCs induced by androgens is an AR-mediated pathway (Foresta et al, 2008).
We propose that androgen deficiency–induced injury toendothelial cells lining the vascular bed of the penis increasessynthesis and release of TGF-β1, endothelin, and contractileprostanoids, but decreases NO. The outcome of such biologicalinsults to the endothelium would bring about changes in thesmooth muscle phenotype, leading to increased extracellularmatrix deposition (fibrosis), cell atrophy, and an inhibitionof cell growth (hypoplasia). Fibrosis, therefore, may contributeto altered contractility and decreased compliance (as determinedclinically), leading to vasculogenic erectile dysfunction.
Androgens Maintain Tunica Albuginea Structural Integrity and Connective Tissue Matrix Fibroelastic Properties
Shen et al (2003) demonstrated, in castrated animals, a significantreduction in the thickness of the tunica albuginea when comparedwith intact animals. In intact animals, the tunica is richin elastic fibers, and the architecture of such fibers showedtypical regular arrangements. In contrast, the tunica albugineafrom castrated animals showed reduced density of elastic fibersand replacement of these fibers with collagen. The authorsconcluded that androgens are indispensable for maintenanceof normal ultrastructure of penile tunica albuginea.
Androgen ablation by castration in animal models produced amarked increase in the extracellular matrix, with concomitantreduction in smooth muscle to connective tissue ratio by approximately2-fold (Takahashi et al, 1991; Traish et al, 1999, 2003).This reduction in the tissue fibroelastic properties compromisespenile tissue compliance and attenuates penile hemodynamics,resulting in erectile dysfunction (Wespes et al, 1990, 1991;Jevtich, 1991; Nehra et al, 1996). Several studies have suggestedthat androgens modulate the extracellular matrix through expressionof growth factors (Natoli et al, 2005). This, however, needto be further investigated in penile tissue. The decrease in elastic fibers and changes in microscopic features may contributeto erectile dysfunction by impairing the venoocclusive functionof the tunica albuginea (Gentile et al, 1996; Akkus et al, 1997).Recent case studies have corroborated the restoration of erectilefunction in men with erectile dysfunction attributed to venousleakage after androgen treatment (Yassin et al, 2006; Kurbatov et al, 2008a,b). These observations suggest that androgensplay a role in maintaining erectile tissue architecture.
Summary and Conclusions
A significant body of evidence exists, suggesting that androgensregulate the structure and function of penile nerves, vascularendothelium, trabecular smooth muscle, connective tissue matrix,and the tunica albuginea. Further, androgens regulate differentiationof precursor cells into trabecular smooth muscle and inhibitdifferentiation into adipocytes. In humans, androgen deficiencymanifests itself in clinical pathologies, such as 1) inadequate development of the penis and 2) loss of erectile function inpatients with prostate cancer or benign prostatic hyperplasiamanaged with medical or surgical castration or antiandrogentherapy. Androgen supplementation in hypogonadal patients improvessexual function. These clinical observations, together withthe preclinical data, suggest that testosterone restores tissue structural elements and improves penile hemodynamics.
In summary, androgens play a pivotal role in maintaining erectiletissue architecture (Figure 3), and erectile physiology bymodulating penile neural function and structural integrityof the smooth muscle, endothelium, and connective tissue matrix,as well as metabolic and signaling pathways.
This paper is based on a presentation at a Special Symposiumon April 12, 2008, “Therapeutic Strategies for Male Sexualand Hormonal Health,” associated with the American Societyof Andrology Annual Meeting, for which the presenting authorreceived an honorarium.
Dr Traish has consulting and/or financial relationships withBayer AG.
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