Abdulmaged M. Traish

Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer.

Expression of nuclear factor-kappaB (NF-kappaB)/Rel transcription factors has recently been found to promote cell survival, inhibiting the induction of apoptosis. In most cells other than B lymphocytes, NF-kappaB/Rel is inactive, sequestered in the cytoplasm. For example, nuclear extracts from two human untransformed breast epithelial cell lines expressed only very low levels of NF-kappaB. Unexpectedly, nuclear extracts from two human breast tumor cell lines displayed significant levels of NF-kappaB/Rel. Direct inhibition of this NF-kappaB/ Rel activity in breast cancer cells induced apoptosis. High levels of NF-kappaB/Rel binding were also observed in carcinogen-induced primary rat mammary tumors, whereas only expectedly low levels were seen in normal rat mammary glands. Furthermore, multiple human breast cancer specimens contained significant levels of nuclear NF-kappaB/Rel subunits. Thus, aberrant nuclear expression of NF-kappaB/Rel is associated with breast cancer. Given the role of NF-kappaB/Rel factors in cell survival, this aberrant activity may play a role in tumor progression, and represents a possible therapeutic target in the treatment of these tumors.

Shifting the Paradigm of Testosterone and Prostate Cancer: The Saturation Model and the Limits of Androgen-Dependent Growth

CONTEXT The traditional belief that prostate cancer (PCa) growth is dependent on serum testosterone (T) level has been challenged by recent negative studies in noncastrated men. OBJECTIVE To provide an improved framework for understanding the relationship of PCa to serum T level that is consistent with current evidence and is based on established biochemical principles of androgen action within the prostate. EVIDENCE ACQUISITION A literature search was performed of publications dating from 1941 to 2008 that addressed experimental and clinical effects of androgens on prostate growth. Review of studies investigating the prostatic effects of manipulation of androgen concentrations in human and animal studies, and in PCa cell lines. EVIDENCE SYNTHESIS Prostate growth is exquisitely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels. This pattern is consistent with the observation that androgens exert their prostatic effects primarily via binding to the androgen receptor (AR), and that maximal androgen-AR binding is achieved at serum T concentrations well below the physiologic range. A Saturation Model is proposed that accounts for the seemingly contradictory results in human PCa studies. Changes in serum T concentrations below the point of maximal androgen-AR binding will elicit substantial changes in PCa growth, as seen with castration, or with T administration to previously castrated men. In contrast, once maximal androgen-AR binding is reached the presence of additional androgen produces little further effect. CONCLUSIONS The evidence clearly indicates that there is a limit to the ability of androgens to stimulate PCa growth. A Saturation Model based on androgen-AR binding provides a satisfactory conceptual framework to account for the dramatic effects seen with castration as well as the minor impact of T administration in noncastrated men.

The Dark Side of Testosterone Deficiency: I. Metabolic Syndrome and Erectile Dysfunction

The metabolic syndrome (MetS) is considered the most important public health threat of the 21st century. This syndrome is characterized by a cluster of cardiovascular risk factors including increased central abdominal obesity, elevated triglycerides, reduced high-density lipoprotein, high blood pressure, increased fasting glucose, and hyperinsulinemia. These factors increase the risk of cardiovascular disease (CVD) and/or type 2 diabetes. Although the etiology of this syndrome is thought to stem from obesity and physical inactivity, the extent of interactions of the individual MetS components with one another remains poorly defined. Obesity, diabetes, hypogonadism, and specific hormone and metabolic profiles have been implicated in the pathophysiology of CVD. The evolving role of androgens in MetS and CVD is of paramount importance. Reduced androgen levels associated with hypogonadism or androgen deprivation therapy increase cardiovascular risk factors and produce marked adverse effects on cardiovascular function. MetS has been associated with hypogonadism and erectile dysfunction (ED), and MetS may be considered a risk factor for ED. It is suggested that MetS, diabetes, and CVD will increase in the upcoming decades. Thus, it is critically important to develop a better understanding of how obesity, diabetes and hypogonadism contribute to androgen deficiency and the various pathophysiologic states of vascular disease. In this review we discuss the current literature pertaining to androgen deficiency, MetS, and ED, because the relationship of these factors is of scientific and clinical importance. Specifically, we will focus on exploring the relationships between hypogonadism, obesity, MetS, and ED.

Investigative Urology: PGE sub 1 Suppresses the Induction of Collagen Synthesis by Transforming Growth Factor-beta sub 1 in Human Corpus Cavernosum Smooth Muscle

Collagen synthesis has been examined in primary cultures of human corpus cavernosum smooth muscle cells (HCCSMC), the major mesenchymal cell type of the corpus cavernosum. These cultures were grown from human surgical specimens and characterized by morphological and biochemical characteristics. These cells express mRNA for transforming growth factor-beta 1 (TGF-beta 1), a major regulator of extracellular matrix synthesis, as well as all three subtypes of TGF-beta receptors. Human corpus cavernosum smooth muscle cells primarily synthesize types I and III fibrillar collagen. Treatment of HCCSMC with exogenous TGF-beta 1 (80 pM.) induced a 2.5- to 4.5-fold increase in the synthesis of types I and III collagen and resulted in detectable levels of type V/XI collagen. Treatment of HCCSMC with the eicosanoid PGE1 in combination with TGF-beta 1 suppressed the induction of collagen synthesis by TGF-beta 1 in a dose-dependent manner with concomitant decreases in types I, III and V/XI collagen. The expression of TGF-beta 1 mRNA as well as types I and II TGF-beta receptors was induced by exogenous TGF-beta 1. Transforming growth factor-beta 1 mRNA induction was suppressed by PGE1. These data suggest that prostaglandins and TGF-beta 1 may play a key role in modulation of collagen synthesis in the corpus cavernosum, and in the regulation of fibrosis of the corpus cavernosum.

Estradiol-induced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase.

Phosphorylation of Ser118 of human estrogen receptor α (ER) enhances ER-mediated transcription and is induced by hormone binding and by activation of the mitogen-activated protein kinase (MAPK) pathway. We discovered that phosphorylation of Ser118 reduces the electrophoretic mobility of the ER. Using this mobility shift as an assay, we determined the in vivo stoichiometry and kinetics of Ser118 phosphorylation in response to estradiol, ICI 182,780, epidermal growth factor (EGF), and phorbol 12-myristate 13-acetate (PMA). In human breast cancer MCF-7 cells, estradiol induced a steady state phosphorylation of Ser118 within 20 min with a stoichiometry of 0.67 mol of phosphate/mol of ER. Estradiol did not activate p42/p44 MAPK, and basal p42/p44 MAPK activity was not sufficient to account for phosphorylation of Ser118 in response to estradiol. In contrast, both EGF and PMA induced a rapid, transient phosphorylation of Ser118 with a stoichiometry of ∼0.25, and the onset of Ser118 phosphorylation correlated with the onset of p42/p44 MAPK activation by these agents. Either the EGF- or PMA-induced Ser118 phosphorylation could be inhibited without influencing estradiol-induced Ser118phosphorylation. The data suggest that a kinase other than p42/p44 MAPK is involved in the estradiol-induced Ser118phosphorylation. We propose that the hormone-induced change in ER conformation exposes Ser118 for phosphorylation by a constitutively active kinase.

The dark side of testosterone deficiency: III. Cardiovascular disease.

A considerable body of evidence exists suggesting that androgen deficiency contributes to the onset, progression, or both of cardiovascular disease (CVD). The aim of this review is to evaluate the relationships between testosterone (T) deficiency and risk factors of CVD and to discuss the implications of androgen deficiency in men with cardiovascular risk factors. The relationship between androgen deficiency and endothelial function, lipid profiles, inflammatory responses, altered vascular smooth muscle reactivity, and hypertension are discussed with regard to CVD. A comprehensive literature search was carried out with the use of Pub Med from 1980 through 2009, and relevant articles pertinent to androgen deficiency and vascular disease were evaluated and discussed. Low T, whether attributed to hypogonadism or androgen deprivation therapy, in men with prostate carcinoma, produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low-density lipoprotein, increased production of proinflammatory factors, and increased thickness of the arterial wall and contributes to endothelial dysfunction. Testosterone supplementation restores arterial vasoreactivity; reduces proinflammatory cytokines, total cholesterol, and triglyceride levels; and improves endothelial function but also might reduce high-density lipoprotein levels. Testosterone is an anabolic hormone with a wide range of beneficial effects on mens health. The therapeutic role of T in mens health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for CVD, androgen replacement therapy could potentially reduce CVD risk in hypogonadal men. It should be emphasized, however, that androgen replacement therapy should be done with very thorough and careful monitoring for prostate diseases.

Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients.

INTRODUCTION 5α-reductase inhibitors (5α-RIs), finasteride and dutasteride, have been approved for treatment of lower urinary tract symptoms, due to benign prostatic hyperplasia, with marked clinical efficacy. Finasteride is also approved for treatment of hair loss (androgenetic alopecia). Although the adverse side effects of these agents are thought to be minimal, the magnitude of adverse effects on sexual function, gynecomastia, depression, and quality of life remains ill-defined. AIM The goal of this review is to discuss 5α-RIs therapy, the potential persistent side effects, and the possible mechanisms responsible for these undesirable effects. METHODS We examined data reported in various clinical studies from the available literature concerning the side effects of finasteride and dutasteride. MAIN OUTCOME MEASURES Data reported in the literature were reviewed and discussed. Results.  Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship. CONCLUSIONS We suggest discussion with patients on the potential sexual side effects of 5α-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia.

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.

Arginase-boronic acid complex highlights a physiological role in erectile function.

The crystal structure of the complex between the binuclear manganese metalloenzyme arginase and the boronic acid analog of L-arginine, 2(S)-amino-6-boronohexanoic acid (ABH), has been determined at 1.7 Å resolution from a crystal perfectly twinned by hemihedry. ABH binds as the tetrahedral boronate anion, with one hydroxyl oxygen symmetrically bridging the binuclear manganese cluster and a second hydroxyl oxygen coordinating to Mn2+A. This binding mode mimics the transition state of a metal-activated hydroxide mechanism. This transition state structure differs from that occurring in NO biosynthesis, thereby explaining why ABH does not inhibit NO synthase. We also show that arginase activity is present in the penis. Accordingly, the tight binding and specificity of ABH allows us to probe the physiological role of arginase in modulating the NO-dependent smooth muscle relaxation required for erection. Strikingly, ABH causes significant enhancement of nonadrenergic, noncholinergic nerve-mediated relaxation of penile corpus cavernosum smooth muscle, suggesting that arginase inhibition sustains L-arginine concentrations for NO synthase activity. Therefore, human penile arginase is a potential target for therapeutic intervention in the treatment of erectile dysfunction.

Dehydroepiandrosterone (DHEA)—A Precursor Steroid or an Active Hormone in Human Physiology (CME)

INTRODUCTION The circulation of large amounts of dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEA-S) suggests a physiological role in human physiology. In the central nervous system, DHEA is considered a neurosteroid with a wide range of functions. AIM The goal of this review is to discuss metabolism, biochemical, and physiological mechanism of DHEA action and the potential role of DHEA in aging and in ameliorating a host of pathological conditions, associated with aging. METHODS We examined preclinical and clinical data reported in various studies from the available literature concerning the effects of DHEA in normal and pathological conditions. MAIN OUTCOME MEASURES Data reported in the literature were analyzed, reviewed, and discussed. RESULTS DHEA mediates its action via multiple signaling pathways involving specific membrane receptors and via transformation into androgen and estrogen derivatives (e.g., androgens, estrogens, 7α and 7β DHEA, and 7α and 7β epiandrosterone derivatives) acting through their specific receptors. These pathways include: nitric oxide synthase activation, modulation of γ-amino butyric acid receptors, N-methyl D-aspartate, receptors sigma receptors (Sigma-1), differential expression of inflammatory factors, adhesion molecules and reactive oxygen species, among others. Clinical and epidemiological studies suggested that low DHEA levels might be associated with ischemic heart disease, endothelial dysfunction, atherosclerosis, bone loss, inflammatory diseases, and sexual dysfunction. Most importantly, no significant adverse or negative side effects of DHEA were reported in clinical studies of men and women. CONCLUSIONS DHEA modulates endothelial function, reduces inflammation, improves insulin sensitivity, blood flow, cellular immunity, body composition, bone metabolism, sexual function, and physical strength in frailty and provides neuroprotection, improves cognitive function, and memory enhancement. DHEA possesses pleiotropic effects and reduced levels of DHEA and DHEA-S may be associated with a host of pathologies; however, the clinical efficacy of DHEA supplementation in ameliorating patho-physiological symptoms remains to be evaluated.