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 (ERα) 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 ERα 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, 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

ROLE OF TESTOSTERONE IN THE TREATMENT OF ED

Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome

A critical analysis of the role of testosterone in erectile function: From pathophysiology to treatment - A systematic review

Context: Androgen modulation of erectile function (EF) is widely accepted. However, the use of testosterone replacement therapy (TRT) in men with erectile dysfunction (ED) has generated an unprecedented debate. Objective: To summarize the relevant data on the incidence, diagnosis, and management of ED coexisting with hypogonadism and to develop a pathophysiology-based treatment algorithm. Evidence acquisition: We reviewed the relevant medical literature, with a particular emphasis on original molecular studies, prospective observational data, and randomized controlled trials performed in the past 20 yr. Evidence synthesis: Testosterone modulates nearly every component involved in EF, from pelvic ganglions to smooth muscle and the endothelial cells of the corpora cavernosa. It also regulates the timing of the erectile process as a function of sexual desire, coordinating penile erection with sex. Epidemiologic studies confirm the significant overlap of hypogonadism and ED; however, most guidelines do not consider the differential diagnosis of hypogonadism or the relevance of subclinical disease. Various clinical tools can help the physician to assess and restore androgen levels in men with ED. Special attention is given to fertility-sparing treatments, due to the increasing number of older men desiring fatherhood. The simultaneous use of phosphodiesterase type 5 inhibitors (PDE5-Is) and TRT has recently been questioned. Originally proposed as a salvage therapy for nonresponders to PDE5-Is, this approach has been inappropriately transformed into a combination therapy. Clinical data are consistent when reinterpreted in the proper framework, whereas molecular evidence remains controversial. Conclusions: A body of molecular and clinical evidence supports the use of TRT in hypogonadal patients with ED, although the benefit-risk ratio is uncertain in advanced age. Critical appraisal of this evidence enabled the development of a pathophysiology-oriented algorithm designed to avoid inappropriate treatments and support whether to start with TRT, PDE5-I only, or both. Apparently divergent findings are reconciled when TRT is correctly indicated. An improved diagnosis and individualized management is desirable in light of the many available options. © 2013 European Association of Urology

Immunodetection of nmt55/p54(nrb) isoforms in human breast cancer

BACKGROUND: We previously identified and characterized a novel 55 kDa nuclear protein, termed nmt55/p54(nrb), whose expression was decreased in a subset of human breast tumors. The objective of this study was to determine if this reduced expression in human breast tumors was attributed to the regulation of mRNA transcription or the presence of altered forms of this protein. RESULTS: Northern blot analysis and ribonuclease protection assay indicated that nmt55/p54(nrb) mRNA is expressed at varying levels in estrogen receptor positive (ER+) and estrogen receptor negative (ER-) human breast tumors suggesting that reduced expression of nmt55/p54(nrb) protein in ER- tumors was not due to transcriptional regulation. To determine if multiple protein isoforms are expressed in breast cancer, we utilized Western blot and immunohistochemical analyses, which revealed the expression of an nmt55/p54(nrb) protein isoform in a subset of ER+ tumors. This subset of ER+ human breast tumors expressed an altered form of nmt55/p54(nrb) that was undetectable with an amino-terminal specific antibody suggesting that this isoform contains alterations or modifications within the amino terminal domain. CONCLUSIONS: Our study indicates that nmt55/p54(nrb) protein is post-transcriptionally regulated in human breast tumors leading to reduced expression in ER- tumors and the expression of an amino terminal altered isoform in a subset of ER+ tumors. The potential involvement of nmt55/p54(nrb) in RNA binding and pre-mRNA splicing may be important for normal cell growth and function; thus, loss or alteration of protein structure may contribute to tumor growth and progression

Obesity and Erectile Dysfunction: Is Androgen Deficiency the Common Link?

Obesity is associated with increased risk of erectile dysfunction (ED); however, the underlying causes of ED in obese individuals remain poorly defined. The aim of this review is to discuss the evidence available on the relationship between obesity and ED. A search of published studies in PubMed from 1970 through 2009 was conducted, and relevant articles were evaluated and discussed. Visceral obesity is a public health threat, and is associated with increased risk of diabetes, vascular disease, endothelial dysfunction, and ED. Plasma testosterone levels are reduced in obesity, further contributing to an increased risk of vascular pathology in obesity. The recognition of the relationship between obesity, reduced testosterone levels, and ED has paved the way for new approaches to manage and treat obese, hypogonadal patients with ED. Obesity profoundly and adversely impacts overall health and, in particular, vascular health, by increasing proinflammatory factors, altering endothelial function and the androgen endocrine milieu, thus increasing the risk of ED. KEYWORDS: obesity, dyslipidemia, testosterone, hypogonadism, diabetes, endothelial dysfunction, vascular disease, metabolic syndrome, erectile dysfunction INTRODUCTION Obesity is a major public health concern worldwide. The adverse health consequences of obesity include diabetes, vascular diseases, atherosclerosis, and erectile dysfunction (ED). The prevalence of obesity has increased significantly over the past several decades. Ogden et al. Erectile function depends on the health of the central and peripheral nervous systems, the vascular bed of erectile tissue, and the hormonal milieu of the individual (reviewed in 677 and increase dyslipidemia, all of which contribute to the pathophysiology of ED. In this review, we evaluate the relationship between obesity and ED, and discuss the hypothesis that obesity-related androgen deficiency may be a common link in these two pathophysiological states FIGURE 1. OBESITY AND ED A host of clinical studies suggest a link between obesity and ED Based on the information in the studies cited above, it is clear that obesity is a risk factor for ED. ED is thought to be a warning sign for vascular disease, and a potential marker for atherosclerosis, endothelial dysfunction, and cardiovascular disease (CVD) Interestingly, Esposito et al. "The incidence of impotence (mild to severe) occurred in 52% of men aged between 40 and 70 years, and the higher probability of ED after adjusting for age correlated with…the metabolic syndrome. The same cohorts of men were studied after an average of 8.8 years, and the data showed that …BMI significantly predicted the risk of developing ED. Of the 154 patients who were overweight, 41% had moderate or complete ED, which was significantly more than that of leaner patients after controlling for other risk factors…Physical activity was also associated with ED with sedentary men posing the highest risk." While many studies have reported a link between obesity and ED, some studies have not observed such a relationship. For example, in the MMAS, there was no association between BMI and ED at baseline Many studies have linked obesity with endothelial dysfunction and subsequent ED. Endothelial dysfunction negatively influences endothelial-derived NO, which is critical for endothelium-dependent vasodilation While obesity represents a risk factor for ED, exercise and obesity interventions have been shown to have a beneficial impact on ED OBESITY AND ANDROGEN DEFICIENCY A considerable number of studies show that obesity is associated with androgen deficiency Obesity is associated with low serum T levels[61] as well as reduced SHBG (sex hormone-binding globuline) level

Obesity and Erectile Dysfunction: Is Androgen Deficiency the Common Link?

Obesity is associated with increased risk of erectile dysfunction (ED); however, the underlying causes of ED in obese individuals remain poorly defined. The aim of this review is to discuss the evidence available on the relationship between obesity and ED. A search of published studies in PubMed from 1970 through 2009 was conducted, and relevant articles were evaluated and discussed