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Biomedical subjects

Irwin Goldstein

Publications and source records attributed to Irwin Goldstein.

At least 19 recordsLinked to original sources
PubMed2006

Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat.

BACKGROUND: Tamoxifen, a selective estrogen receptor modulator with both estrogenic and anti-estrogenic activity, is widely used as adjuvant therapy in breast cancer patients. Treatment with tamoxifen is associated with sexual side effects, such as increased vaginal dryness and pain/discomfort during sexual activity. There have been limited investigations of the effect of tamoxifen on estrogen-dependent peripheral genital arousal responses. The objective of this study was to investigate the effects of tamoxifen on vaginal physiology in the rat. METHODS: Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy. After 2 weeks, sham-operated rats were implanted with subcutaneous osmotic infusion pumps containing vehicle (control) or tamoxifen (150 microg/day). Ovariectomized rats were similarly infused with vehicle. After an additional 2 weeks, vaginal blood flow responses to pelvic nerve stimulation were measured by laser Doppler flowmetry and vaginal tissue was collected for histological and biochemical assay. RESULTS: Tamoxifen treatment did not change plasma estradiol concentrations relative to control animals, while ovariectomized rats exhibited a 60% decrease in plasma estradiol. Tamoxifen treatment caused a significant decrease in mean uterine weight, but did not alter mean vaginal weight. Vaginal blood flow was significantly decreased in tamoxifen-infused rats compared to controls. Similar to ovariectomized animals, estrogen receptor binding was increased and arginase enzyme activity was decreased in tamoxifen-infused rats. However, different from control and ovariectomized animals, the vaginal epithelium in tamoxifen-infused rats appeared highly mucified. Periodic acid-Schiff staining confirmed a greater production of carbohydrate-rich compounds (e.g. mucin, glycogen) by the vaginal epithelium of tamoxifen-infused rats. CONCLUSION: The observations suggest that tamoxifen exerts both anti-estrogenic and pro-estrogenic effects in the vagina. These physiological alterations may eventually lead to vaginal atrophy and compromise sexual function.

Journal Article↗
PubMed2006

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

BACKGROUND: Diabetes 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 (ERalpha) and androgen receptor (AR) expression. RESULTS: In 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 ERalpha and AR in nuclear extracts of vaginal tissue from diabetic animals. CONCLUSION: In ovariectomized (estrogen deficient) animals, previous reports from our lab and others have documented changes in blood flow, tissue structure, ERalpha, 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.

Animals↗
PubMed2006

Dose-response relationship between testosterone and erectile function: evidence for the existence of a critical threshold.

Androgens play an important role in erectile function. However, the dose-response relationship between plasma testosterone levels and penile erection remains unclear. Intact (sham operated) or bilaterally orchiectomized, mature male Sprague-Dawley rats were used. Two weeks after surgery, rats were infused continuously with either vehicle (polyethyleneglycol) or varying doses of testosterone (44, 88, 220, or 440 mug/day) for 14 days using subcutaneous osmotic infusion pumps (study 1). In a separate study, 4 weeks after surgery, rats were infused with a lower range of testosterone doses (11, 22, or 44 mug/day) for 14 days (study 2). In the first study, intact rats had a mean plasma testosterone concentration of 0.56 +/- 0.12 ng/mL ( approximately 1.9 nM), as determined by standard radioimmunoassay. In the second study, a more sensitive enzyme-linked immunoassay was used to measure the lower testosterone levels. Using this assay, intact rats had a mean plasma testosterone concentration of 2.02 +/- 0.59 ng/mL. Intracavernosal pressure measurements indicated that orchiectomy resulted in a significant reduction in erectile function, when compared to intact animals, whereas testosterone infusion restored erectile function to varying degrees. Erectile function was maintained by a wide range of systemic testosterone levels as low as 10%-12% of normal physiological plasma concentrations. Below these concentrations, erectile function was significantly and positively correlated with testosterone plasma levels in a dose-dependent manner. Interestingly, prostate tissue mass was positively correlated to plasma testosterone levels across all concentrations examined. Protein expression of neural nitric oxide synthase (nNOS) and phosphodiesterase type 5 (PDE 5) was reduced in penile tissue from orchiectomized animals and increased in testosterone-infused animals, as assessed by Western blot analyses. We suggest that testosterone at levels approaching one-tenth normal physiological plasma concentration may represent a threshold value, below which erectile function declines in a dose-dependent fashion. However, different androgen-dependent tissues may exhibit varying sensitivities to circulating testosterone with regard to growth and function.

Animals↗
PubMed2006

Successful use of electroconvulsive therapy in 2 cases of persistent sexual arousal syndrome and bipolar disorder.

We present 2 patients with bipolar disorder and persistent sexual arousal syndrome (PSAS). Because they were refractory to several trials of antidepressants and mood stabilizers, electroconvulsive therapy (ECT) was prescribed. They underwent a course of ECT with remission of both their depressive and their PSAS symptoms. They have remained on maintenance ECT with good results. Although the etiology of PSAS is unknown and its relationship to bipolar disorder is unclear, the successful resolution of PSAS with ECT is of clinical and theoretical interest.

Bipolar Disorder↗
PubMed2006

Management of ischemic priapism with high-dose intracavernosal phenylephrine: from bench to bedside.

INTRODUCTION: Ischemic priapism is associated with cavernosal acidosis, which decreases the efficacy of adrenergic agonists. We determined the effect of acidosis on ligand dissociation from adrenergic receptors and assessed the efficacy of high-dose phenylephrine in treating patients with acute ischemic priapism. METHODS: Dissociation rates of [3H]prazosin were determined at pH 7.2 and 6.9 in membrane preparations of rabbit penile cavernosal tissue. Vital signs were recorded from patients before injection, and at 1 minute and 5 minutes after injection of high-dose phenylephrine (1,000 mg q 5 minutes) for 17 consecutive cases of iatrogenic ischemic priapism that occurred after vascular assessment. We also provide two case reports of prolonged ischemic priapism successfully managed with high-dose phenylephrine. RESULTS: Dissociation rates of [3H]prazosin were greater at pH 6.9 (K (-1) = 0.23/minute) than at pH 7.2 (K (-1) = 0.10/minute), suggesting decreased receptor affinity at acidic pH. Intracavernosal therapy with high-dose phenylephrine (mean dose 2,059 +/- 807 microg) was 100% effective with no adverse events or significant changes in vital signs. In addition, two patients with ischemic priapism for > or =36 hours were successfully treated with high-dose intracavernosal phenylephrine (mean dose 45,000 microg) without any adverse event. Both patients are currently potent. CONCLUSIONS: Acidic pH may decrease the binding affinity of adrenergic ligands to their receptors. Phenylephrine at doses higher than previously reported may be necessary to overcome this decreased affinity in acidosis associated with ischemic priapism. High-dose intracavernosal phenylephrine administration is safe and effective in the management of ischemic priapism. Continuous cardiovascular monitoring is advised.

Acute Disease↗
PubMed2006

Impact of oral contraceptives on sex hormone-binding globulin and androgen levels: a retrospective study in women with sexual dysfunction.

INTRODUCTION: Oral contraceptives (OCs) have been the preferred method of birth control because of their high rate of effectiveness. OC use, however, has been associated with women's sexual health complaints and androgen insufficiency. OC use is associated with a decrease of androgen ovarian synthesis and an increase in the production of sex hormone-binding globulin (SHBG). There have been limited studies assessing SHBG values after discontinuation of OC use. AIM: To retrospectively investigate SHBG levels before and after discontinuation of OC use. MAIN OUTCOME MEASURE: Sex hormone-binding globulin values were compared at baseline, while on the OC, and well beyond the 7-day half-life of SHBG at 49-120 (mean 80) days and >120 (mean 196) days after discontinuation of OCs. METHODS: A total of 124 premenopausal women with sexual health complaints for >6 months met inclusion/exclusion criteria. Three groups of women were defined: (i) "Continued-Users" (N = 62; mean age 32 years) had been on OCs for >6 months and continued taking them; (ii) "Discontinued-Users" (N = 39; mean age 33 years) had been on OCs for >6 months and discontinued them; and (iii) "Never-Users" (N = 23; mean age 36 years) had never taken OCs. RESULTS: Sex hormone-binding globulin values in the "Continued-Users" were four times higher than those in the "Never-User" group (mean 157 +/- 13 nmol/L vs. 41 +/- 4 nmol/L; P < 0.0001). Despite a decrease in SHBG values after discontinuation of OC use, SHBG levels in "Discontinued-Users" remained elevated in comparison with "Never-Users" (N = 26; P < 0.0001 for >120 days). CONCLUSION: In women with sexual dysfunction, SHBG changes in "Discontinued-Users" did not decrease to values consistent with "Never-Users." Long-term sexual, metabolic, and mental health consequences might result as a consequence of chronic SHBG elevation. Does prolonged exposure to the synthetic estrogens of OCs induce gene imprinting and increased gene expression of SHBG in the liver in some women? Prospective research is needed.

Adult↗
PubMed2006

Differential regulation of the expression of estrogen, progesterone, and androgen receptors by sex steroid hormones in the vagina: immunohistochemical studies.

OBJECTIVE: Significant structural changes occur in the rat vagina in response to sex steroid hormone deprivation and replacement. However, the mechanism by which these changes occur is not clearly understood and our current hypothesis is that these effects are mediated, at least in part, by the expression of sex steroid hormone receptors. The goal of this study was to assess changes in steroid hormone receptor expression and distribution in response to sex steroid hormone deprivation and administration. METHODS: Female rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or hormone combinations. Using immunohistochemistry, hormone receptor distribution was assessed in all layers of the vaginal wall. RESULTS: After ovariectomy, estrogen receptor alpha (ERalpha) was up-regulated and progesterone receptor (PR) was down-regulated. Estradiol replacement restored these ovariectomy-induced changes, and this effect was dose-dependent. Androgen receptor (AR) expression was unaffected by ovariectomy or estradiol replacement. However, testosterone treatment resulted in increased AR density in the muscularis. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. CONCLUSION: Estradiol down-regulated ERalpha and up-regulated PR expression in the vagina, suggesting this may be a mechanism to prevent continued proliferation of the epithelium by surges of estradiol during the estrous cycle.

Animals↗
PubMed2006

Comparing vardenafil and sildenafil in the treatment of men with erectile dysfunction and risk factors for cardiovascular disease: a randomized, double-blind, pooled crossover study.

INTRODUCTION: Data from head-to-head clinical trials of phosphodiesterase type 5 (PDE5) inhibitors are scarce, making it difficult for clinicians to differentiate among these agents to select the most appropriate treatment for their patients with erectile dysfunction (ED). AIM: This randomized, double-blind, crossover head-to-head clinical trial compared patient preference, efficacy, and safety of vardenafil and sildenafil in men with ED and diabetes, hypertension, and/or hyperlipidemia. METHODS: Prospective analysis was performed on two studies in which 1,057 men were randomized to vardenafil 20 mg (N = 530) or sildenafil 100 mg (2 x 50 mg encapsulated tablets) (N = 527) for 4 weeks. Following a 1-week washout, patients switched treatment for 4 weeks. MAIN OUTCOME MEASURES: Patients were asked about overall preference: "Overall, which medication do you prefer?", plus 11 other preference questions relating to their ED treatment. Efficacy assessments after each treatment period included the erectile function (EF) domain score of the International Index of Erectile Function (IIEF); Sexual Encounter Profile (SEP) diary questions SEP2 and SEP3; Global Assessment Question (GAQ); and Treatment Satisfaction Scale (TSS). Data regarding adverse events were collected throughout the study. RESULTS: A total of 931 men (mean age 57.9 years) were included in the intent-to-treat (ITT) population. Non-inferiority of vardenafil over sildenafil was achieved for overall preference (vardenafil 38.9%; sildenafil 34.5%; and no preference 26.6%). Additionally, the change from baseline in the EF domain score of the IIEF achieved nominal significance for vardenafil over sildenafil (10.00 vs. 9.40; P = 0.0052). Patients also had a higher percentage of positive responses for vardenafil for SEP2, SEP3, GAQ, and 12 of 19 questions on the TSS. Both drugs were well tolerated. CONCLUSIONS: This randomized, double-blind, head-to-head trial in ED patients with cardiovascular risk factors demonstrated noninferiority of vardenafil for overall preference. Vardenafil achieved nominal statistical superiority over sildenafil for several frequently used efficacy measures. Both drugs were well tolerated.

Adult↗
PubMed2006

Vulvodynia: a state-of-the-art consensus on definitions, diagnosis and management.

Vulvodynia is a chronic pain syndrome affecting up to 18% of the female population. Despite its high prevalence and associated distress, the etiology, diagnosis and clinical management of the disorder have not been clearly delineated. This "white paper" describes the findings and recommendations of a consensus conference panel based on a comprehensive review of the published literature on vulvodynia in addition to expert presentations on research findings and clinical management approaches. The consensus panel also identified key topics and issues forfurther research, including the role of inflammatory mechanisms and genetic factors and psychosexual contributors.

Biomedical Research↗
PubMed2005

Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference).

Recent studies have highlighted the relation between erectile dysfunction (ED) and cardiovascular disease. In particular, the role of endothelial dysfunction and nitric oxide in ED and atherosclerotic disease has been elucidated. Given the large number of men receiving medical treatment for ED, concerns regarding the risk for sexual activity triggering acute cardiovascular events and potential risks of adverse or unanticipated drug interactions need to be addressed. A risk stratification algorithm was developed by the First Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. Patients were assigned to 3 categories: low, intermediate (including those requiring further evaluation), and high risk. This consensus study from the Second Princeton Consensus Conference corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED. The panel reviewed recent safety and drug interaction data for 3 phosphodiesterase (PDE)-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. Increasing evidence supports the role of lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease. Special management recommendations for patients taking PDE-5 inhibitors who present at the emergency department and other emergency medical situations are described. Finally, further research on the role of PDE-5 inhibition in treating patients with other medical or cardiovascular disorders is recommended.

Cardiovascular Diseases↗
PubMed2005

Differential effects of estradiol, progesterone, and testosterone on vaginal structural integrity.

Ovarian steroids are known to be important in maintaining vaginal tissue, and evidence is mounting that imbalances in the hormonal milieu contribute to vaginal pathophysiology. To date, limited data are available on the effects of hormone deprivation and replacement on vaginal tissue morphology and vaginal innervation. The goal of this study was to assess the dynamic changes in vaginal tissue structure in response to sex steroid hormone deprivation and administration. Female Sprague-Dawley rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or a combination of estradiol plus testosterone or progesterone. Histological techniques, including stereological analysis and immunohistochemistry for localization of neuronal markers, were used. Ovariectomy produced a significant decrease in epithelial height that was restored with estradiol replacement. Interestingly, a subphysiological dose of estradiol resulted in hyperplasia of the vaginal epithelium and nonvascular smooth muscle. Neither testosterone nor progesterone had a significant effect on epithelial height or muscularis thickness. However, testosterone treatment resulted in a significant increase in small adrenergic nerve fibers. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. This study demonstrates that estradiol and testosterone have differential effects on vaginal tissue parameters and that ovarian hormones are critical for the maintenance of genital tissue structure. Present observations also suggest that combined replacement regimens may be required for an optimal physiological response.

Animals↗
PubMed2005

Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference).

Recent studies have highlighted the relation between erectile dysfunction (ED) and cardiovascular disease. In particular, the role of endothelial dysfunction and nitric oxide in ED and atherosclerotic disease has been elucidated. Given the large number of men receiving medical treatment for ED, concerns regarding the risk for sexual activity triggering acute cardiovascular events and potential risks of adverse or unanticipated drug interactions need to be addressed. A risk stratification algorithm was developed by the First Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. Patients were assigned to 3 categories: low, intermediate (including those requiring further evaluation), and high risk. This consensus study from the Second Princeton Consensus Conference corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED. The panel reviewed recent safety and drug interaction data for 3 phosphodiesterase (PDE)-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. Increasing evidence supports the role of lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease. Special management recommendations for patients taking PDE-5 inhibitors who present at the emergency department and other emergency medical situations are described. Finally, further research on the role of PDE-5 inhibition in treating patients with other medical or cardiovascular disorders is recommended.

Age Distribution↗
PubMed2005

Genital duplex Doppler ultrasonography before and after sexual stimulation in women with sexual dysfunction: gray scale, volumetric, and hemodynamic findings.

OBJECTIVE: To report gray scale, volumetric, and duplex ultrasound data before and after sexual stimulation in a large population of women with sexual dysfunction. DESIGN: Retrospective review of women with sexual dysfunction. SETTING: An academic center. PATIENT(S): Pre- and postmenopausal women with sexual dysfunction. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): This is an Institutional Review Board-approved retrospective study of 142 women who underwent duplex Doppler ultrasound (DDU) arousal testing for sexual dysfunction. RESULT(S): This study revealed that DDU was able to record morphologic, volumetric (clitoral and corpora spongiosa diameters), and hemodynamic (peak systolic and end-diastolic) changes in women with sexual dysfunction before and after sexual stimulation. Resistive index measurements, which are indicative of veno-occlusive function, did not significantly change before and after arousal in both the clitoris and corpora spongiosa. We also found a correlation between genital diameter and genital end-diastolic velocity value. Gray scale scanning revealed tunical thickening or plaque in several patients who sustained blunt perineal trauma. CONCLUSION(S): The role of DDU in the management of women with sexual dysfunction remains to be determined; however, end-diastolic velocity values suggest that this parameter has an important physiologic implication as a direct determinant of genital engorgement.

Adult↗