Ricardo Munarriz

Pharmacotherapy for erectile dysfunction.

INTRODUCTION Pharmacotherapy is the usual initial therapy for most men with erectile dysfunction. AIM To review the current data relating to the efficacy, tolerability and safety of drugs used in the treatment of men with erectile dysfunction. METHODS A critical review of the literature relating to the use of pharmacotherapeutic agents was undertaken by a committee of eight experts from five countries, building on prior reviews. MAIN OUTCOME MEASURES Expert opinion and recommendations were based on grading of evidence-based literature, internal committee dialogue, open presentation, and debate. RESULTS Almost all currently available evidence relates to sildenafil, tadalafil, and vardenafil. Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for most men with erectile dysfunction who do not have a specific contraindication to their use. There is no evidence of significant differences in efficacy, safety, and tolerability between the PDE5 inhibitors and apomorphine. Intracavernosal injection therapy with alprostadil should be offered to patients as second line therapy for erectile dysfunction. Intraurethral alprostadil is a less effective treatment than intracavernosal alprostadil for the treatment of men with erectile dysfunction. CONCLUSIONS PDE5 inhibitors are effective, safe, and well-tolerated therapies for the treatment of men with erectile dysfunction. Apomorphine, intracavernosal injection therapy with alprostadil, and intraurethral alprostadil are all effective and well-tolerated treatments for men with erectile dysfunction. We recommend some standardization of the assessment of psychosocial outcomes within clinical trials in the field of erectile dysfunction.

Women's sexual dysfunction: a pathophysiological review

A. SALONIA, R.M. MUNARRIZ*, R. NASPRO, R.E. NAPPI†, A. BRIGANTI, R. CHIONNA‡, F. FEDERGHINI†, V. MIRONE¶, P. RIGATTI, I. GOLDSTEIN* and F. MONTORSI Departments of Urology, University Vita-Salute San Raffaele, Milan, Italy, and *Boston University School of Medicine, Boston, MA, USA, and ¶University Federico II, Naples, Italy, and Departments of Obstetrics/Gynaecology, †IRCCS S. Matteo, University of Pavia, Pavia, and ‡University VitaSalute San Raffaele, Milan, Italy

Blunt Trauma: The Pathophysiology of Hemodynamic Injury Leading to Erectile Dysfunction

A 9 1/2-year pharmaco-cavernosometry/pharmaco-cavernosography and pharmaco-arteriography study was performed in 131 men with persistent changes in erectile function following blunt pelvic or perineal trauma. The goal was to determine the incidence of hemodynamic impairment, and to characterize the location and pattern of abnormal venous drainage. Corporeal veno-occlusive dysfunction was identified in 62% of the cases and cavernous artery insufficiency in 70%. Pharmaco-cavernosography revealed abnormal venous drainage confined to the proximal corpora in 91% of the cases. Patients with pelvic trauma had significantly more abnormal sites of venous drainage (3 or more sites in 61%) and more severe degrees to which venous structures filled with contrast medium (23% had 3+ degree of luminal filling) than did patients with perineal trauma (61% had 1 or 2 sites of venous drainage and 92% had 1+ or 2+ degree of luminal filling). Pharmaco-arteriography revealed site specific arterial occlusive lesions consistent with the site of impact. Traumatic vasculogenic impotence is hypothesized as being the result of direct impact injury to the fixed proximal corpora and its arterial inflow bed. The exerted perineal impact force is estimated to range from 50 to 500 pounds, depending on the weight of the individual, height of the fall, speed at contact and surface hardness. Traumatic veno-occlusive dysfunction is theorized to be the consequence of focal intracavernous wound repair and permanent focal alterations in erectile tissue compliance. Traumatic vasculogenic impotence afflicts an estimated 600,000 American men of whom 250,000 have sports-related injuries. Future consideration should be given to the development of appropriate protective perineal equipment.

Role of androgens in female genital sexual arousal: receptor expression, structure, and function

OBJECTIVE In women, androgens modulate the physiological function of many reproductive and sexual organs, including the ovaries, uterus, vagina, oviducts, clitoris, and mammary gland. In this article, we review the mechanisms of androgen action and discuss new data on the effects of androgens in vaginal and clitoral tissues. MAIN OUTCOME MEASURE(S) In this study, we characterized the androgen receptor expression in rabbit vaginal tissues from control and ovariectomized animals treated with or without androgen replacement therapy. We investigated the effects of androgen deprivation and replacement on the expression and activity of nitric oxide synthase and arginase and on vaginal smooth muscle contractility. RESULT(S) Androgens enhanced nitric oxide synthase activity and down-regulated arginase activity in proximal vagina. Estrogens down-regulated nitric oxide synthase activity and increased arginase activity in distal vagina. Androgens facilitated vaginal smooth muscle relaxation to electric field stimulation and vasoactive intestinal polypeptide, whereas estrogens attenuated vaginal tissue relaxation to electric field stimulation and to vasoactive intestinal polypeptide. CONCLUSION(S) These observations suggest that androgens may play an important role in modulating the physiology of vaginal tissue and contribute to female genital sexual arousal.

Possible role of Na+‐K+‐ATPase in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide

1 This study was designed to determine the role of sodium‐potassium adenosine triphosphatase (Na+‐K+‐ATPase) in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide (NO). In addition, we determined if the modulation of Na+‐K+‐ATPase activity by NO is dependent on the increases in intracellular cyclic GMP concentration. 2 The effect of NO donors, sodium‐nitroprusside (SNP) and S‐nitroso‐glutathione (S‐NO‐Glu), and a permeable cyclic GMP analogue, 8‐bromo‐cyclic GMP, on Na+‐K+‐ATPase activity (measured as ouabain‐sensitive 86Rb‐uptake) was studied in human cultured corpus cavernosum smooth muscle cells (HCCSMC). In addition, the effect of the cyclic GMP lowering agent, methylene blue, on NO‐induced increase in Na+‐K+‐ATPase activity was studied. 3 SNP (1 μm) caused time‐dependent increases in ouabain‐sensitive Rb‐uptake (33–72%) over 2–20 min in HCCSMC. The stimulation of ouabain‐sensitive Rb‐uptake by SNP was concentration‐dependent (30 and 102% with 0.1 and 1 μm SNP, respectively). Similarly, significant increases in ouabain‐sensitive Rb‐uptake were obtained with 1 and 10 μm S‐NO‐Glu. In contrast, incubation of HCCSMC with 8‐bromo‐cyclic GMP (100 μm) did not increase ouabain‐sensitive Rb‐uptake. 4 S‐NO‐Glu induced‐increase in intracellular cyclic GMP synthesis, but not the increase in ouabain‐sensitive Rb‐uptake, was completely inhibited by methylene blue in HCCSMC. 5 The Na+‐K+‐ATPase inhibitor, ouabain, caused a concentration‐dependent increase in tension (0.5 to 2 fold) in tissues contracted with 15 mM KCL. SNP and S‐NO‐Glu caused a concentration‐dependent relaxation (concentration required to cause half maximal relaxation (ED50) = 0.04 and 0.2 μm, respectively) of HCC strips contracted with 15 mM K+. Ouabain (0.1 to 10 μm) inhibited the response to SNP and S‐NO‐Glu by shifting the concentration‐response curves to the right and preventing full smooth muscle relaxation. 6 These results indicate that the activity of Na+‐K+‐ATPase modulates the contractility of HCC smooth muscle, and that NO stimulates Na+‐K+‐ATPase activity in HCCSMC independently of its ability to increase the intracellular cyclic GMP concentration. They also suggest that stimulation of Na+‐K+‐ATPase activity plays an important role in NO‐induced relaxation of HCC smooth muscle

Effects of ovariectomy and steroid hormones on vaginal smooth muscle contractility

The role of steroid hormones in regulating vaginal smooth muscle contractility was investigated. Rabbits were kept intact or ovariectomized. After 2 weeks, animals were continuously infused with vehicle or supraphysiological levels of testosterone (100 μg/day), or estradiol (200 μg/day), for an additional 2 weeks. The distal vaginal tissue was used to assess contractility in organ baths and changes in tissue structure were assessed by histology. Ovariectomized animals infused with vehicle exhibited significant atrophy of the muscularis and decreased epithelial height, resulting in thinning of the vaginal wall. Estradiol infusion increased epithelial height, comparable to that of intact animals, but only partially restored the muscularis layer. In contrast, testosterone infusion completely restored the muscularis layer, but only partially restored the epithelial height. In vaginal tissue strips contracted with norepinephrine and treated with bretylium, electrical field stimulation (EFS) caused frequency-dependent relaxation that was slightly attenuated with vehicle, significantly inhibited with estradiol and significantly enhanced with testosterone. VIP-induced relaxation was slightly attenuated in tissues from vehicle and estradiol-infused groups, but was enhanced in tissues from testosterone-infused animals. Contraction elicited by EFS or exogenous norepinephrine was not significantly altered with ovariectomy or steroid hormone infusion when data were normalized to potassium contraction. However, the tissue from testosterone-infused animals developed significantly greater contractile force to norepinephrine. These observations suggest that steroid hormones may be important regulators of vaginal tissue structure and contractility.

Biology of female sexual function

Although the psychosocial and relationship aspects of female sexuality have been extensively investigated, studies concerning the anatomy, physiology and pathophysiology of female sexual function and dysfunction are limited. The paucity of biologic data may be attributed to a lack of reliable experimental models and tools for investigating female sexual function and to limited funding, which is critical for developing experimental approaches. Research efforts by several investigators in different laboratories have been establishing experimental models needed for investigating the physiologic mechanisms involved in the genital arousal response of sexual function. These experimental models have permitted assessment of genital hemodynamics, vaginal lubrication, regulation of genital smooth muscle contractility and signaling pathways, providing preliminary information about the role of neurotransmitters and sex steroid hormones in sexual function. Further research is needed to define the neurotransmitters responsible for vaginal smooth muscle relaxation and the role of sex steroid hormones and their receptors in modulating genital hemodynamics, smooth muscle contractility, and neurotransmitter receptor expression. Finally, a global and integral understanding of the biologic aspects of female sexual function requires investigation of the vascular, neurologic (central and peripheral), and structural components of this extremely complex physiologic process.

Role of the nitric oxide-cyclic GMP pathway in regulation of vaginal blood flow

The regulatory role of nitric oxide (NO) in vaginal perfusion remains unclear. We used specific inhibitors of enzymes in the NO-cyclic GMP (NO-cGMP) pathway and investigated their effects on vaginal blood flow in the rabbit. NO synthase (NOS) activity was similar in both the proximal and distal rabbit vagina; whereas, arginase activity was 3.4-fold higher in the distal vagina. Intravenous administration of the NOS inhibitor L-NAME resulted in a 66% reduction in genital tissue oxyhemoglobin and a 53% reduction in vaginal blood flow. This attenuation occurred despite a 20–30% increase in systemic arterial pressure. The arginase inhibitor ABH caused a 2.1-fold increase in genital tissue oxyhemoglobin and 34% increase in vaginal blood flow. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one and the phosphodiesterase type 5 inhibitor sildenafil caused in a 37% reduction and a 44% increase in vaginal blood flow, respectively. These observations suggest that the NO-cGMP pathway is an important regulator of vaginal hemodynamics.

Serum androgen levels in healthy premenopausal women with and without sexual dysfunction: part B: reduced serum androgen levels in healthy premenopausal women with complaints of sexual dysfunction

Androgen insufficiency has been associated with decreased libido and arousal in postmenopausal women, but rarely has been evaluated in healthy premenopausal women. In all, 32 healthy premenopausal women were enrolled in this study, 18 with one or more complaints of sexual dysfunction and 14 without. Assays of ovarian and adrenal androgens were measured before and after ACTH stimulation. The women with complaints of sexual dysfunction had significantly lower adrenal androgens than did the control women. There were no differences in the basal ovarian androgens or cortisol levels. After ACTH, both groups stimulated cortisol as well as adrenal and ovarian androgens. In conclusion, premenopausal women with complaints of sexual dysfunction had lower adrenal androgen precursors and testosterone than age-matched control women without such complaints. Further study is required to determine how lower adrenal androgens contribute to female sexual dysfunction.

Streptozotocin-induced diabetes in the rat is associated with changes in vaginal hemodynamics, morphology and biochemical markers

BackgroundDiabetes is associated with declining sexual function in women. However, the effects of diabetes on genital tissue structure, innervation and function remains poorly characterized. In control and streptozotocin-treated female rats, we investigated the effects of diabetes on vaginal blood flow, tissue morphology, and expression of arginase I, endothelial nitric oxide synthase (eNOS) and cGMP-dependent protein kinase (PKG), key enzymes that regulate smooth muscle relaxation. We further related these changes with estrogen receptor alpha (ERα) and androgen receptor (AR) expression.ResultsIn addition to significantly elevated blood glucose levels, diabetic rats had decreased mean body weight, lower levels of plasma estradiol, and higher plasma testosterone concentration, compared to age-matched controls. Eight weeks after administration of buffer (control) or 65 mg/kg of streptozotocin (diabetic), the vaginal blood flow response to pelvic nerve stimulation was significantly reduced in diabetic rats. Histological examination of vaginal tissue from diabetic animals showed reduced epithelial thickness and atrophy of the muscularis layer. Diabetic animals also had reduced vaginal levels of eNOS and arginase I, but elevated levels of PKG, as assessed by Western blot analyses. These alterations were accompanied by a reduction in both ERα and AR in nuclear extracts of vaginal tissue from diabetic animals.ConclusionIn ovariectomized (estrogen deficient) animals, previous reports from our lab and others have documented changes in blood flow, tissue structure, ERα, arginase I and eNOS that parallel those observed in diabetic rats. We hypothesize that diabetes may lead to multiple disruptions in sex steroid hormone synthesis, metabolism and action. These pathological events may cause dramatic changes in tissue structure and key enzymes that regulate cell growth and smooth muscle contractility, ultimately affecting the genital response during sexual arousal.