A prospective, randomized, placebo-controlled trial of on-Demand vs. nightly sildenafil citrate as assessed by Rigiscan and the international index of erectile function.

Multiple studies have evaluated the use of PDE5 inhibitors in penile rehabilitation following nerve-sparing prostatectomy. These studies have evaluated the use of various pharmacologic agents as well as various approaches to treatment (on-demand vs. rehabilitative). Most of these studies relied on self-reported outcomes to determine efficacy of the therapy which could allow response bias to affect their results. The aim of this study was to evaluate the effects of nightly sildenafil citrate therapy during penile rehabilitation, using nocturnal penile rigidity (RigiScan(™), Gotop Medical, Inc., St. Paul, MN, USA) in addition to the IIEF-EF. Patients with localized prostate cancer and normal erectile function prior to nsRP were randomized to take either nightly 50 mg sildenafil citrate or placebo starting the night following surgery. Both groups were allowed on-demand sildenafil citrate. Erectile function was evaluated at 2 weeks, 3, 6, 9 and 12 months post-operatively, with a final assessment made at 13 months, following a 1 month drug washout. At all time points, self-reported (IIEF-EF) and objective (RigiScan(™)) measures were obtained and evaluated. About 74 of 97 randomized patients completed the study. On completion, 40% of patients in each group had normal erectile function based on RigiScan(™) (p = 1.0). Additionally, no statistical differences were seen using the IIEF-EF domain (32.4% of placebo, 29% of treatment; p = 0.79). Multivariable analysis showed no significant differences in erectile function based on treatment intervention. Results did show that African-American men in this cohort were at higher risk for lower RigiScan(™) scores over time (OR: 0.48, p = 0.0399). This study demonstrates that nightly sildenafil citrate does not provide a therapeutic benefit for recovery of erectile function post-prostatectomy when compared to on-demand dosing using both self-reported as well as objective measures. Differences in objective recovery parameters based on patients' race/ethnicity warrant further investigation.

Erectile dysfunction.

A better understanding of penile physiology and pathophysiology has revolutionized the diagnosis and treatment of erectile dysfunction in the past decade. This article summarizes the current knowledge and presents a patient's goal-directed approach to the evaluation and treatment of erectile dysfunction.

Self-administration in the pharmacological treatment of impotence.

Recent innovative research into the physiology and pharmacology of erection and the introduction of intracavernous injection of vasoactive agents have revolutionised our approach to the diagnosis and treatment of impotence. A thorough understanding of the rationale, indications, precautions and potential complications of intracavernous self-injection is essential for successful management. The commonly used drugs for injection are papaverine, either alone or in combination with phentolamine, and alprostadil (prostaglandin E1). The major adverse effects include priapism, prolonged erection, and fibrosis of the erectile tissue. With the proper technique and appropriate dosage, this is a safe, minimally invasive, and highly effective treatment.

Analysis and mapping of plastin phosphorylation.

Plastins (fimbrins) are a family of three tissue-specific actin-binding proteins. Both L- and T-plastin have been shown to be involved in cytoskeletal reorganization in signal-transduction pathways. Phosphorylation of the leukocyte-specific L-plastin plays important roles in regulating L-plastin function and leukocyte activation. We created L-plastin mutants, changing each of the Ser-5 and Ser-7 residues to alanine. Expression of either mutant in WI38VA13 fibroblasts did not result in phosphorylation. The transfected wildtype L-plastin was phosphorylated in WI38VA13, but its two-dimensional gel pattern suggested that it was phosphorylated on one residue, whereas the endogenous L-plastin in leukocytes was likely phosphorylated on two residues. The nonleukocyte-specific T-plastin, which has an equivalent Ser-7 residue, was not phosphorylated in T-plastin-expressing fibroblasts or in transfected leukocytes. Expression of CK-IIalpha, the catalytic subunit of casein kinase II, resulted in changes of the protein expression profile in leukocytes but not the phosphorylation status of L- or T-plastin. Phorbol myristate acetate induced L-plastin phosphorylation in both leukocytes and fibroblasts, lending support to the view that protein kinase C is the likely candidate kinase for L-plastin phosphorylation.

Differential regulation of human T-plastin gene in leukocytes and non-leukocytes: identification of the promoter, enhancer, and CpG island.

Plastins (fimbrins) are a family of actin-bundling proteins conserved from yeast to humans. In humans, three tissue-specific plastin isoforms have been identified. The T isoform (T-plastin) is unique in that it is expressed in all tissues except leukocytes. To investigate how the T-plastin gene is differentially regulated in leukocytes and non-leukocytes, we isolated a genomic clone that included 9 kb of the upstream flanking region, 0.1 kb of the first exon, and 5.9 kb of the first intron. From this clone, we obtained a continuous sequence of 5535 bp, including 3138 bp of the upstream flanking region, the first exon, and 2286 bp of the first intron. A cluster of four transcription initiation sites was located by S1 mapping. A region spanning these sites and extending 1.4 kb into the first intron had the characteristics of a CpG island. Three CG-containing restriction sites within this island were analyzed and found all or variably methylated in four T-plastin-negative leukemia cell lines. In contrast, the same sites were not methylated in three T-plastin-expressing cell lines or in a sample of normal blood lymphocytes. A basal promoter was located 250 bp upstream from the transciption initiation sites. It comprised a CCAAT box, an Sp1 motif, and four AP2 motifs. No TATA or Inr sequence was found. The basal promoter exhibited weak activity when assayed in fibrosarcoma cells. Stronger promoter activities were found in the presence of the SV40 enhancer or a T-plastin enhancer located some 500 bp from the basal promoter. In T-plastin-negative leukemia cells, the T-plastin basal promoter could be activated by the SV40 enhancer but not by the T-plastin enhancer. DNA footprinting identified the T-plastin enhancer as two inverted symmetric octamers (AGATAACCTC and GAGGTCAGCT) separated by 17 nucleotides.

Upregulation of L-plastin gene by testosterone in breast and prostate cancer cells: identification of three cooperative androgen receptor-binding sequences.

L-Plastin is normally a leukocyte-specific actin-binding protein; it is also expressed in the majority of human cancer cell lines that are derived from many types of solid tumors. We have previously reported the isolation of the L-plastin gene promoter, in which we identified several potential steroid receptor-binding sequences. We now obtained evidence that L-plastin gene expression was positively regulated by testosterone in androgen receptor (AR)-positive prostate and breast cancer cells. DNase I footprint analysis identified three AR-binding elements (ARE) located in a 545-bp region approximately 1.1 kb upstream from the transcription initiation site. However, each of these three AREs exhibited very little testosterone/AR-responsive enhancer activities toward a test promoter (of the thymidine kinase gene) when tested in MCF-7 breast cancer cells. Their testosterone/AR responsiveness became evident only when two or three of them were combined. In PC-3 prostate cancer cells, cooperation among L-plastin AREs was still evident although individually they had moderate levels of testosterone/AR responsiveness. Thus, the three L-plastin AREs, despite their imperfect sequences compared with the consensus ARE, could cooperate with each other to become a potent testosterone/AR-responsive unit, which was likely responsible for the inducibility of the L-plastin gene by testosterone.

Drug-induced male sexual dysfunction. An update.

Impotence, defined as the consistent inability to maintain an erect penis of sufficient rigidity for sexual intercourse, has been estimated to affect 10 million American men. An age dependence has been shown to exist, with 25% of men over age 65 affected. A large body of clinical experience and published reports in the literature link many commonly prescribed drugs with sexual dysfunction. Drugs can affect sexual function at a variety of points such as inhibition of ejaculation or sedation/depression leading to reduced libido. Antihypertensive drugs have been most commonly associated with impotence. There have been reports of sexual dysfunction with almost all classes of antipsychotics, but little clinical investigation has been performed. Other drugs associated with sexual dysfunction include digoxin, clofibrate, cimetidine and various hormonal agents and antineoplastics. An important first step in approaching all impotent patients is the taking of a detailed medical, surgical, sexual and drug/substance abuse history. The least invasive form of therapy should be employed. Recent studies have shown intracavernous injections of alprostadil (prostaglandin E1) to be safe and effective for long term use. Vacuum constriction devices may also be of help. Better and more durable prostheses are now available should other treatment be unsuccessful.

Extravaginal torsion of spermatic cord in adult.

A twenty-six-year-old man with no history of testicular trauma presented with both extra- and intravaginal torsion of the spermatic cord. This phenomenon is extremely rare in the adult, having been reported only twice before.

Improved hemodynamic response after long-term intracavernous injection for impotence.

OBJECTIVE: To investigate the phenomenon of spontaneous erections in patients on long-term intracavernous injection therapy. METHODS: We undertook an objective assessment of the penile circulation of 35 patients; 21 used prostaglandin E1 (PGE1) alone and 14 used a combination of papaverine, phentolamine, and PGE1. All underwent duplex ultrasonography before initiation of home self-injection and again after a mean of thirty-one months of treatment (most patients performed injections once or twice a week). RESULTS: The diameter of the cavernosal arteries did not change significantly after treatment. However, the mean peak flow velocity increased highly significantly (P < 0.001): 17.9 cm/second in the right cavernous artery and 21.2 cm/second on the left before treatment; 24 cm/second on the right and 29 cm/second on the left after treatment. More than one third (13 of 35 patients [35%]) achieved functional erection without injection at least some of the time, giving clinical support to the sonographic findings. CONCLUSIONS: We suggest that the combination of vasodilatory drugs and sexual stimulation may act to improve sinusoidal and penile arteriolar smooth muscle function.

Peyronie's disease: a modified treatment.

We evaluated 93 patients with complaints of sexual dysfunction and evidence of Peyronie's disease. Duplex ultrasonography (10-MHz probe and 4.5-MHz pulsed Doppler test) in 87 enabled definition of their penile vascular response to an intracorporeal injection of a vasoactive agent. Vascular disease was present in 70 percent of the study population. Forty-four patients had a surgical procedure. Nineteen had plications using a simultaneous pharmacological erection, 3 had dermal grafts, and 3 with severe vascular disease had primary placement of a prosthesis. One patient underwent a single Nesbit procedure. In 18 patients, we incised the plaque and grafted a segment of the deep dorsal vein, using the expertise gained from penile venous surgery. In the vein-grafted patients, rapid return of suppleness of the penile shaft, use of only a single incision, and use of the patient's own tissue, with the possible beneficial effect of endothelial-derived substances (nitric oxide) decreasing the risk of hematoma below the graft, support our belief that this modified technique may be superior to those presently in common use.

Potential preservation of potency after radical prostatectomy.

Radical prostatectomy often is followed by erectile dysfunction. Various etiologies have been postulated--vascular, psychologic, or neurologic. Recently, we were able to isolate the cavernous nerves of the prostatic plexus, which innervate the erectile tissue of the corpora cavernosa, for electroerection in dogs. Acute and chronic experiments were then performed to examine the relationship between erectile impotence and radical prostatectomy. We conclude that erectile impotence after total prostatectomy is a result of injury to the cavernous nerves and that potency can be preserved if these nerves are identified and salvaged during surgery.

Cavernous vein arterialization for vasculogenic impotence. An animal model.

We designed acute and chronic animal models to evaluate a new procedure of arterialization of the cavernous vein. In the acute study, arteriogenic impotence was induced in 6 dogs by bilateral ligation of the penile arteries just proximal to the crus of the penis. The cavernous vein and penile artery were anastomosed proximal to the site of ligation, and the pudendal vein was ligated proximally to prevent the diversion of arterial blood away from the penis. Erection was induced either by electrostimulation of the cavernous nerves or by intracavernous injection of papaverine, and the erectile response was studied before and after cavernous vein arterialization. Four dogs were followed up for two months to evaluate the long-term effects of the procedure. Shortly after arterialization of the cavernous vein, the basal flow rate in the internal pudendal artery increased dramatically to almost six times the control rate, and the erectile response to neurostimulation was approximately 85 percent of control. Selective pudendal arteriography at two months confirmed the patency of all arteriovenous anastomoses. However, scanning electron microscopy and histologic examination revealed sinusoidal damage most probably consequent to the chronically elevated arterial flow.

Anatomy of cavernous nerves distal to prostate: microdissection study in adult male cadavers.

Retrograde and antegrade dissections from the penile hilum to the prostatic area and the glans penis were performed in 4 formalin-preserved adult male cadavers. In addition to the medial branches accompanying the urethra, the lateral branches of the cavernous nerves pierced the urogenital diaphragm 4 to 7 mm from the striated muscles of the external sphincter. At the penile region, multiple communications between the cavernous and dorsal nerves were noted that suggest that either the cavernous nerves use the dorsal nerve as a carrier to the distal portion of the penis or the dorsal nerve may itself contain autonomic fibers. These findings will improve our ability to preserve erectile function during pelvic, urethral, and penile surgery.

Effect of simulated birth trauma on the urinary continence mechanism in the rat.

OBJECTIVES: To examine the effect of simulated birth injury in an animal model as part of a study on the pathogenesis of stress urinary incontinence (SUI) and the urinary continence mechanism. METHODS: A balloon was inflated in the vaginas of rats for 4 hours to simulate prolonged labor. The effect on the continence mechanism was assessed by functional, anatomic, biochemical, and histologic examinations. The functional test consisted of placing chili powder or a clipped whisker into the rat's nostrils to induce sneezing. Anatomic measurement of the genital hiatus was performed with a caliper. Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) were measured to examine the value of muscle injury in predicting incontinence. c-Fos immunostaining in the spinal cord was used as a marker of nerve injury. These data were then correlated with histopathologic examination of the urethra and pelvic floor tissues. RESULTS: Four weeks after simulated birth injury, SUI was noted in 19 of 48 experimental rats. The genital hiatus was significantly wider in incontinent rats. The serum CPK and LDH levels were markedly elevated, but no difference was noted between the continent and incontinent rats. All experimental rats showed many c-Fos immunostaining neurons in the L6 to S1 spinal cord segments, but none was seen in control rats. Histologic study revealed a marked decrease of ganglion cells in the neural plexuses posterolateral to the vagina in experimental rats. After 4 weeks, muscle necrosis and degeneration, irregular shape and size of muscle fibers, and a change in the type I/II ratio were prominent features in the levator ani. In the urethra, we noted a significant decline in urethral wall musculature (both smooth and striated) in incontinent rats. CONCLUSIONS: In this novel rat model, simulated birth injury resulted in SUI in a portion of the animals. Pathologic changes in the urethra, pelvic ganglia, and levator muscles seem to be the contributing factors to SUI.

Pathophysiology of erectile dysfunction.

During the past decade, our knowledge of the hemodynamics, functional anatomy, neurophysiology, and neuropharmacology of erectile function has evolved substantially. The change of smooth muscle tone has emerged as a key factor in erection and detumescence. However, future studies are needed to elucidate the cellular and molecular basis of erectile physiology. With insight into normal physiology we will understand the pathologic process and be able to treat it.

Hemodynamics of canine corpora cavernosa during erection.

Being able to induce erection by electrical stimulation of the cavernous nerves, we studied the hemodynamics of canine penile erection. Simultaneous recording of flow and pressure of the internal pudendal artery as well as pressure within the corpus cavernosum clearly demonstrated that increase of arterial flow preceded corporeal pressure increase. When saline was infused directly into the corpus cavernosum, with the aorta clamped, decreasing venous flow during erection could be demonstrated. Tumescence of the corpus cavernosum was found to be a result of active relaxation of sinusoidal spaces, active arteriolar dilatation, and active venous constriction. At full erection, there was still flow into and out of the corpus cavernosum, although it was reduced to only a fraction of a milliliter per minute.

Is colchicine effective in Peyronie's disease? A pilot study.

OBJECTIVES: The treatment of Peyronie's disease with oral or topical agents has not been entirely satisfactory. In this pilot study, we hypothesized that colchicine, known to induce collagenase activity and decrease collagen synthesis, might be an ideal agent in the treatment of Peyronie's disease. METHODS: Colchicine was administered orally for 3 to 5 months to a group of 24 previously untreated patients with Peyronie's disease. RESULTS: Peyronie's plaque decreased or disappeared in 12 of the 24 patients, 7 of 9 patients with painful erections reported significant relief, and penile curvature was improved in 7 of 19 cases. Erectile status, narrowing of the penis, and accompanying Dupuytren's contracture did not change in any of the cases. CONCLUSIONS: Although this pilot study shows some promising results of the use of colchicine in the treatment of Peyronie's disease, the ultimate usefulness of this agent will be determined only by a prospective double-blind clinical study.

Free ureteral replacement in rats: regeneration of ureteral wall components in the acellular matrix graft.

OBJECTIVES: To evaluate ureteral replacement by a free homologous graft of acellular matrix in a rat model. METHODS: In 30 male Sprague-Dawley rats, a 0.3 to 0.8-cm midsegment of the left ureter was resected and replaced with an acellular matrix graft of equal length placed on a polyethylene stent. The animals were killed at varying intervals, and the grafted specimens were prepared for light and electron microscopy. RESULTS: In all animals, the acellular matrix graft remained in its original position without evidence of incrustation or infection, and histologic examination showed complete epithelialization and progressive infiltration by vessels. At 10 weeks, smooth muscle fibers were observed; at 12 weeks, nerve fibers were first detected; at 4 months, smooth muscle cells had assumed regular configuration. CONCLUSIONS: The ureteral acellular matrix graft appears to promote the regeneration of all ureteral wall components.

Nitric oxide synthase: a new diagnostic tool for neurogenic impotence.

Cavernosal biopsy specimens obtained from men undergoing penile surgery permitted determination of the diagnostic value of nitric oxide synthase in neurogenic impotence. In biopsy specimens obtained from 25 men, the presence of nitric oxide synthase (NOS), as shown by nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining, was determined in nerve fibers, smooth muscle, and sinusoidal endothelium. Positive staining for NOS correlated significantly (p < or = 0.001) with a clinical history of cavernous nerve integrity. In comparison, staining with protein gene product (PGP 9.5), an excellent general nerve stain, lacked any degree of specificity as an indicator of nerve status. NADPH diaphorase may provide important insight into the cavernous nerve integrity of the patient. This report is the first to describe histologic features of human cavernosal tissue biopsies that will allow the direct diagnosis of neurogenic impotence owing to cavernous nerve damage.

Neuromuscular dysfunction in nonbacterial prostatitis.

Although chronic nonbacterial prostatitis is common, the condition remains poorly understood and refractory to treatment. Another approach, i.e., a urodynamic explanation, seems warranted. The underlying cause of the symptoms may be an inappropriate spasm of of the distal urethra/external sphincteric unit, leading to increased pressure in the prostatic urethra with a resultant reflux of urine into the prostatic ducts. The presence of urine (sterile or infected) could induce ductal and periductal inflammation, which could further aggravate spasm of the involved pelvic musculature, exacerbating the voiding dysfunction. We present 3 patients in whom this sequence of events was documented radiographically and urodynamically. Consequently, treatment involved modulation of the dysfunction of the distal urethra/external sphincteric unit: (1) reeducation by reassurance and biofeedback was the initial line of therapy; (2) pharmacologic manipulation using alpha-blockers (to affect smooth and striated muscle irritability) and striated muscle relaxants was next tried; (3) finally, in unremitting symptoms, we used selective sacral-root electro-stimulation, successfully fatiguing the involved muscles and relieving the voiding dysfunction.