HIGHLIGHT ON THE MALE SEXUAL FUNCTION/DYSFUNCTION PAPERS PRESENTED AT THE ESSM/ISSM-2008 JOINT MEETING
Muammer Kendirci, MD
2nd Urology Department, Sisli Etfal Training and Research Hospital, 34377, Istanbul, Turkey
E-mail: mkendirci@superonline.com
The joint meeting of the 13th World Congress of the International Society for Sexual Medicine (ISSM) and 11th Congress of the European Society for Sexual Medicine (ESSM) held in Brussels was very productive. Among a total of 436 works, 89 were podium, 102 were moderated and 245 were unmoderated presentations. Studies on female sexual function and dysfunction were 10% and male sexual function and dysfunction were 90% of all presentations. Among 393 works on male sexual function and dysfunction, 42 (11%) were focused on basic science. Since many studies have demonstrated the pathophysiological links between erectile dysfunction (ED) and the neuro-vascular abnormalities, including cavernous nerve injury, diabetes mellitus, atherosclerosis, hypertension, coronary artery disease, dislipidemia and smoking, the researchers have focused on augmenting molecular mechanisms altered by these abnormalities.
Diabetes & ED
Basic science studies have previously shown the deleterious affects of diabetes on various pathways of erectile mechanisms. Castela et al. from Portugal investigated alterations in cavernosal angiogenic gene expression profiles in cavernosal tissues of diabetic and non-diabetic rats using RNA isolation studies. These investigators found a reduction in the expression of several genes, such as the regulator of apoptosis, oxidative stress, cell proliferation, and adhesion in cavernosal tissues of diabetic animals, suggesting deregulation of potential angiogenic molecules and pathways in diabetic cavernosal tissues which results in impaired vascular and erectile functions.
Previous studies have shown the involvement of Rho/Rho-kinase system in the several steps of apoptotic pathway in diabetes-related ED. Park et al. from Korea examined the effects of chronic treatment of Rho-kinase inhibitor (fasudil, 30 mg/kg) and insulin, on the corporal apoptosis and erectile function in streptozotocin-induced diabetic rats. The authors found that both oral fasudil and subcutaneous insulin treatments for 4 weeks prevented corporal apopitosis by effectively reversing increased phosphorylation of MYPT-1 and decreased phosphorylation of PTEN and Akt observed in the diabetic group. These investigators concluded that Rho-kinase inhibitor fasudil might have a role in preventing diabates-related apoptosis in animals by suppression of PTEN and Akt phosphorylation.
Previous studies have shown thromboxane A2 to be upregulated in diabetes. Villalba et al. from Denmark and Spain investigated the contribution of calcium influx, the roles of protein kinase C (PKC) and Rho-kinase in penile vasoconstriction evoked by activation of the thromboxane receptors. Segments of the dorsal penile artery from adult male Wistar rats were used for in vitro studies and immunoblot analysis. The authors found that the thromboxane analogue U46619 concentration dependently increased both intracellular calcium concentration and tension in dorsal penile arteries. In addition, they showed that the Rho-kinase inhibitor Y27632 evoked concentration-dependent relaxations in arteries contracted with U46619. The inhibition of PKC as well as the combined inhibition of PKC and Rho-kinase attenuated U46619 contractions and phosphorylation of myosin light chain in rat penile arteries. The activation of the thromboxane receptors led to activation of PKC and RhoK signaling pathways followed by enhanced Ca2+ sensitivity of the contractile apparatus. This study demonstrated the potential therapeutic role of controlling thromboxane receptors in diabetes-related ED.
Metformin is known as an oral biguanide insulin-sensitizing agent that activates eNOS by targeting AMP-activated protein kinase (AMPK). Song et al. from Korea investigated whether metformin activates eNOS in the penile tissues of genetically obese rats. They measured phospho-eNOS levels and eNOS expression profiles in the obese rats following 3-day-treatment with oral metformin. Although short-term application of metformin did not change visceral fat mass and serum leptin levels in genetically obese rats, these investigators found that metformin treatment increased eNOS expression and phospho-eNOS levels accompanied with an increase of phospho-AMPK levels in the penis. However, the effects of long-term use of metformin and other antidiabetic drugs need to be further elucidated.
Dislipidemia & ED
Previous reports on dislipidemia have demonstrated a pathophysiologic link between the consumption of high-fat diet and ED caused by the impairment in endothelial function. Tomado et al. from Portugal evaluated atherosclerotic effects of high-fat diet on the corpus cavernosum of male adult Wistar rats and its implication for ED progression. These investigators also investigated the benefit of caloric restriction on endothelial dysfunction. The authors found increased adipocytes close to the vascular spaces of the penis in high-fat-diet rats but a decrease with caloric restriction. These investigators also found using angiopoietins’ expressions (Ang1 and Ang2) that some of the high-fat-diet-induced changes in the endothelium of the rat penis might effectively be reversed by caloric restriction. This study might further the contribution of lifestyle modifications on reversing ED.
Another study by Maio et al. from Canada also investigated the role of caloric restriction on age-related decline in erectile function and accumulation of visceral adipose tissue. After 20-week-period, they found that either moderate or aggressive caloric restriction resulted in decreased accumulation of visceral adipose tissue and age-related decline in erectile function compared to obese rats. Like previous presentation, this one also suggests the benefit of lifestyle modification on erectile function.
Accumulating data have shown the impairment of NO formation in hypercholesterolemia in animals. Murat et al. from Turkey investigated the time when endothelial and erectile dysfunction occur in an animal model of hypercholesterolemia using in vitro and in vivo studies. They performed endothelium-dependent organ bath studies and in vivo erectile function measurements in response to cavernous nerve stimulation at 72 hours, 2 weeks and 8 weeks. These investigators found that intracavernous pressure might be diminished as early as 72 hours in hypercholesterolemia. They concluded that hypercholesterolemia in rats caused time-dependent decline in endothelial and erectile dysfunction evidenced by in vitro and in vivo evaluations.
Arteriogenic ED
Abe et al. from Japan investigated the affect of ischemia on the penis using a rabbit model of bilateral internal iliac artery ligation. They classified the rabbits into 3 groups according to the duration of arterial ligation as; 3 days, 1 week and 4 weeks. Endothelium-dependent and -independent relaxation responses were evaluated in organ bath studies and eNOS mRNA expression was analyzed using RT-PCR. These investigators found that eNOS expression and endothelium-dependent relaxation responses were affected at the early periods after arterial ligation (3 days and 1 week) but not the late periods (4 weeks) after the ligation. This study concluded that endothelial dysfunction in the penis occurred at the early ischemic stage after arterial ligation, but penile endothelium might get recovered from the affect of arterial ischemia at the long-term.
Exercise
Clinical studies have documented the benefit of regular exercise on erectile function. Özbek et al. from Turkey investigated if regular exercise in aged rats could improve ED. They trained aged rats to swim for 30 minutes a day and 5 days a week for a total of 8 weeks. These investigators assessed eNOS/nNOS activities using immunhistochemistry and blood testosterone levels. They found significantly increased levels of blood testosterone in regularly exercised-aged rats compared to control aged rats. They also documented significantly increased eNOS/nNOS immunoreactivity in aged rats with regular exercise. These data may provide molecular basis for the benefit of regular exercise on erectile function.
Cavernous nerve injury
Bivalacqua et al. from the Baltimore investigated the candidate genes involved in injury and the expression of the neural stem cell marker, Nestin. After either a sham procedure or bilateral cavernous nerve-crush injury, they isolated major pelvic ganglion (MPG) and removed 48 hours and 14 days after the procedures. These authors identified more than 2.000 genes that were differentially induced and repressed at both time-points tested post-injury. They also showed the neural stem cell marker, Nestin to be increased 4-fold at 48 hours but no change at 14 days after cavernous nerve-crush injury. These data suggest that Nestin might be involved in early differentiation of nerves after cavernous nerve injury.
Previous studies have shown rationale to use PDE-5 inhibitors for preserving erectile function after cavernous nerve injury. Although the mechanism of action has not been fully elucidated, these drugs seem to protect cavernosal smooth muscle and endothelial integrity. Müller et al. from MSKKC investigated the effect of sildenafil on gene expression in a cavernous nerve injury model in rats. Using RNA extraction and intracavernosal pressure measurements, these authors identified three specific genes that were changed by nerve injury, but restored by sildenafil treatment. These investigators suggested that these genes were predominantly in the realm of apoptosis, neurotrophism and endothelial function. This study may help to explain pathophysiologic mechanisms for injury-related ED.
Basic science studies have previously identified the presence of angiotensin-II receptors (AT-II) in the penis. AT-II seems to modulate cavernosal smooth muscle contraction. It is also suggested to activate latent TGF-ß via thrombospondin-1 (TSP-1), resulting in cavernosal fibrosis. Cangüven et al. from Johns Hopkins investigated the effect of losartan, AT-II antagonist, on erectile function in the bilateral cavernous nerve injury model. These authors found that both doses of losartan significantly attenuated expression of TSP-1, pSMAD2 and fibronectin and upregulated total pSMAD2 after cavernous nerve injury. They concluded that losartan might preserve erectile function after cavernous nerve injury, possibly through down-regulating fibrotic activators in the penis.
Gene or Cell-based studies
In order to identify molecular markers for erectile function following a successful gene treatment or pharmacotherapy, Calenda et al. from Albert Einstein injected rats intracorporally with pVAX-hSlo or pSMAA-hSlo, or a control plasmid (pVAX). One week after injections, they performed in vivo measurements of erectile function in response to cavernous nerve stimulation and gene expression by microarray analysis and quantitative RT-PCR. They found animals treated with vectors expressing hSlo had significantly improved erectile function compared to controls. Parallels to the in vivo results, they documented that Vcsa1, which was previously shown to be down-regulated with ED, as one of the genes most changed in expression. When tadalafil was administered to retired breeder rats to improve ED, a 4-fold increase was found in levels of the Vcsa1 transcript in corpora cavernosa compared to untreated control. These data suggest Vcsa1 as marker for the restoration of erectile function following both gene transfer and pharmacotherapy.
Melman et al. from New York investigated if smooth muscle-specific gene transfer with the human Maxi-K channel could improve erectile function to the same manner and degree as a non-specific CMV promoter in common causes of ED, aging and atherosclerosis, in two different species, rats and monkeys. Experiments were conducted with varying doses of the human max-K channel encoded by the hSlo gene in which a novel plasmid containing the mouse smooth muscle ?-actin promoter was employed. They found in aged rats and atherosclerotic monkeys that smooth-muscle specific gene transfer with the human maxi-K channel showed significantly improved erectile function compared to control. Gene transfer with this novel plasmid containing smooth muscle ?-actin promoter may add benefit of a tissue-specific effect compared to non-specific promoters.
In a cavernous nerve injury model in rats, Bella et al. from UCLA investigated the effect of autologous, non cell-line-induced, adult adipose tissue-derived stem cells (ADSCs) in restoring ED. They injected ADSC into major pelvic ganglia (MPG) and site of crush-injury, corpora cavernosa only, and a combination of both sites to augment erectile function following cavernous nerve injury. At 5 weeks post-injury, they found best ICP measurements in rats treated with ADSCs transplantation into MPG/crush-injury site combined with intracavernous injection. They also documented significant penile gene expression increases for IGF after ADSC treatment. BDNF and eNOS were found to be down-regulated and neurturin expression increased in all 3 ADSC treatment groups. These data demonstrated that ADSC transplantation restores erectile function in rats with cavernous nerve-crush injury. These authors suggested ADSC worked best when injected into both MPG/site of nerve-crush and corpora cavernosa.
SuperEnzyme is a newly engineered protein with COX-2 and prostacyclin synthase activities that convers arachidonic acid directly to prostacyclin (PGI2), a potent smooth muscle relaxant. Yuan et al. from Houston (abstract #MP-067) investigated the effect of adenoviral SuperEnzyme gene transfer into corpora cavernosa after bilateral cavernous nerve-crush injury in rats. Although the parameters assessed were limited, they found restoration of erectile function in nerve-injured rats after adenoviral SuperEnzyme transfer into the penis as evidenced by in vivo measurements.