Biomedical subjects

Suresh C Sikka

Publications and source records attributed to Suresh C Sikka.

At least 19 recordsLinked to original sources

PubMed2006

Semen and sperm reference ranges for men 45 years of age and older.

The most widely used reference values for human semen and sperm variables were developed by the World Health Organization (WHO) to help assess the fertility status of men interested in reproduction (typically a younger population). In this retrospective analysis, data from a large population of men aged 45 years or older were analyzed to derive semen and sperm reference ranges for an older population. Baseline semen samples were obtained from 1174 men with no or mild erectile dysfunction (ED) during the screening phase of two clinical trials evaluating the effects of a drug on human spermatogenesis. The median values and 95% reference ranges for 4 measured semen and sperm parameters (semen volume, sperm concentration, sperm motility, and sperm morphology) and 1 derived parameter (total sperm count) were calculated for the population and by age quartile. These references ranges were compared to established WHO reference values. Associations between the semen and sperm parameters and smoking status, alcohol use, and serum hormone concentrations were also analyzed. The mean age was 52.9 years (range: 45-80). Median semen volume, sperm motility, and sperm morphology parameters declined significantly with age. Only 46% of study subjects had baseline values for semen and sperm parameters that met or surpassed all the WHO reference values. This is the first study to statistically derive semen reference ranges from a large population of men aged 45 years or older. The observation that less than half the men in this study met all 4 WHO reference values for measured semen and sperm parameters underscores the need for age-specific reference ranges.

Aging↗

PubMed2006

Oxidant stress and blood pressure responses to angiotensin II administration in rats fed varying salt diets.

To examine the hypothesis that NAD(P)H oxidase (Nox)-derived superoxide generation is involved in the development of angiotensin II (ANG II)-induced hypertension, we evaluated the responses to ANG II infusion (65 ng/min; osmotic mini-pump) for 2 weeks in rats treated with or without apocynin (APO) (inhibitor of Nox subunits assembly) in drinking water (12 mmol/L). Rats were grouped according to their diets with varying salt content (normal salt [NS], 0.4%; high salt [HS], 8%; low salt [LS], 0.03%) given during the 2-week experimental period. The variation in salt intake did not alter mean arterial pressure (MAP, recorded via pre-implanted arterial catheter) but showed proportionate levels in urinary excretion rate of Isoprostaglandin(2alpha) (U(ISO)V; NS, 179 +/- 26; HS, 294 +/- 38; LS, 125 +/- 7 ng/kg/24 h). Treatment with ANG II increased MAP proportional to salt intake (NS, 126 +/- 3 to 160 +/- 5; HS, 116 +/- 4 to 184 +/- 5; LS, 125 +/- 1 to 154 +/- 5 mm Hg). However, ANG II increased U(ISO)V only in NS rats (250 +/- 19 ng/kg/24 h) but not in HS or LS rats. In response to ANG II, Nox subunits protein expression increased in HS but not in the NS or LS rats. Apocynin treatment partially ameliorated these changes in Nox proteins in HS rats but did not alter ANG II-induced increases in MAP or U(ISO)V. These data suggest that Nox activation may not be the sole factor or alternatively, that a constitutively active isoform of Nox is involved in oxidative stress mechanism that is associated with dietary salt or ANG II-induced hypertension.

Acetophenones↗

PubMed2006

Reactive oxygen species as an independent marker of male factor infertility.

OBJECTIVE: To determine the abnormal patterns of reactive oxygen species (ROS) production in male factor infertility (MFI) patients and to define the ROS reference values in such patients. DESIGN: A retrospective study. SETTING: Male infertility clinic at a tertiary healthcare center. PATIENT(S): We examined 132 MFI patients (all normal sperm parameters, n = 24, and all abnormal sperm parameters, n = 38) and 34 healthy donors. INTERVENTION(S): Routine semen analysis, measurement of ROS. MAIN OUTCOME MEASURE(S): Sperm parameters, ROS levels (10(4) cpm/20 x 10(6) sperm). RESULT(S): Normal, healthy donors had significantly higher (P<.0001) sperm concentration, motility, and morphology compared with all MFI patients. Univariate analysis indicated a significant association between MFI and log (ROS + 1) (odds ratio [OR] = 3.84), besides sperm parameters and age. A multivariate model using logistic regression analysis also indicated an independent association of log ROS with MFI (OR = 4.25). The ROS cutoff values of 1.2-1.4 had a sensitivity of 0.70-0.78 with a corresponding specificity of 0.82. However, at a cutoff point of 1.2, the OR was 68.6, which increased with an increase in the cutoff. CONCLUSION(S): High ROS is an independent marker of MFI, irrespective of whether these patients have normal or abnormal semen parameters. We suggest the inclusion of ROS measurement as part of idiopathic infertility evaluation. Treatment with antioxidants may be beneficial in such patients.

Adult↗

PubMed2006

Effects of acute treatment with tamsulosin versus alfuzosin on ejaculatory function in normal volunteers.

PURPOSE: The frequency of ejaculatory dysfunction in men varies among the alpha-blockers used in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia. We assessed the effect of acute administration of tamsulosin, alfuzosin and placebo on ejaculate volume and sperm concentration in post-ejaculate urine, and addressed the mechanism of action of tamsulosin and alfuzosin on ejaculation. MATERIALS AND METHODS: Using a randomized, 3-way crossover design, the effects of 5 days of treatment with 0.8 mg tamsulosin daily, 10 mg alfuzosin daily and placebo on ejaculation in healthy adult men were compared. The primary end points of the study were ejaculate volume and sperm concentration in post-ejaculate urine on each treatment. To aid in clinical interpretation of primary efficacy end points, each primary end point was transformed into a binary outcome, that is subjects with a greater than 20% decrease in ejaculate volume and subjects with a greater than 20% increase in sperm concentration in post-ejaculate urine. RESULTS: In healthy volunteers who completed the study (48), tamsulosin resulted in significantly decreased ejaculate volume (-2.4 +/- 0.17 ml) compared to alfuzosin (+0.3 +/- 0.18 ml, p < 0.0001 vs tamsulosin) or placebo (+0.4 +/- 0.18 ml, p < 0.0001 vs tamsulosin, p = nonsignificant vs alfuzosin). Among completers the incidence of more than 20% decreased ejaculate volume was significantly greater with tamsulosin (89.6%) compared to alfuzosin (20.8%, p < 0.0001 vs tamsulosin) or placebo (12.5%, p < 0.0001 vs tamsulosin, p = nonsignificant vs alfuzosin). While on tamsulosin 35.4% of 48 completers had complete lack of ejaculation (anejaculation) and no subjects experienced anejaculation while on alfuzosin or placebo. CONCLUSIONS: On 0.8 mg tamsulosin daily ejaculatory function in subjects was marked by decreased ejaculate volume in almost 90% of subjects and anejaculation in approximately 35% of participants. These ejaculatory disorders with tamsulosin were not attributed to retrograde ejaculation. In contrast, anejaculation was not observed in any subjects in the alfuzosin or placebo groups.

Adrenergic alpha-Antagonists↗

PubMed2006

Single-blind, multicenter, placebo controlled, parallel study to assess the safety and efficacy of intralesional interferon alpha-2B for minimally invasive treatment for Peyronie's disease.

PURPOSE: We investigated the efficacy and safety of intralesional interferon alpha-2b for the treatment of Peyronie's disease. MATERIALS AND METHODS: A total of 117 consecutive patients with a mean age of 55.1 years who had Peyronie's disease were enrolled in a single-blind, multicenter, placebo controlled, parallel study to determine the efficacy and safety of intralesional interferon alpha-2b therapy (Schering, Kenilworth, New Jersey), including 62 who received placebo and 55 who received interferon alpha-2b. Saline (10 ml) in controls and interferon alpha-2b (5 x 10(6) U) were administered biweekly for 12 weeks. Each patient was evaluated for penile curvature, plaque size and density, penile pain, erectile function and penile hemodynamics before and after study completion. Improvement in these parameters was statistically compared between the groups. RESULTS: A total of 53 patients in the control arm and 50 in the interferon alpha-2b arm completed the study. Improvement in penile curvature, plaque size and density, and pain resolution was significantly greater in patients treated with interferon alpha-2b vs placebo. The increase in mean International Index of Erectile Function scores was not significantly different between the groups. Penile blood flow improvement was observed in interferon alpha-2b treated patients but not in those who received placebo. The decrease in the number of penile vascular pathologies was significantly higher in interferon alpha-2b cases. Side effects, mostly flu-like symptoms, which were frequently noted in patients on interferon alpha-2b, were mild to moderate in degree and of short duration. CONCLUSIONS: This single-blind, multicenter, placebo controlled, parallel study demonstrates that intralesional interferon alpha-2b at a dose of 5 x 10(6) units biweekly for 12 weeks is effective and safe as minimally invasive therapy for Peyronie's disease.

Adult↗

PubMed2006

Seminal characteristics and sexual behavior in men of different age groups: is there an aging effect?

AIM: To assess the seminal characteristics as well as the sexual behavior of men of various age groups to establish the presence of an aging effect on those characteristics. METHODS: Semen samples were collected from men (n = 792) undergoing in vitro fertilization or intrauterine insemination in cases of female factor infertility only. Samples were collected using a seminal collection device at intercourse and evaluated manually according to World Health Organization (WHO) standards. Men were divided into four groups according to their ages: (i) 20-30, (ii) 31-40, (iii) 41-50 and (iv) 51-60 years, and their seminal characteristics and responses to a sexual behavior questionnaire were compared. RESULTS: The data showed statistically significant differences in the seminal characteristics tested, most notably in the sperm concentration, motility, grade of motility, hypo-osmotic swelling and normal sperm morphology. Furthermore, the decline in normal sperm morphology with age was more pronounced when using strict criteria rather than WHO standards. There were also differences in total sperm count, total motile sperm and total functional sperm fraction (assessed by both WHO and strict criteria). Significant differences were also observed in the sexual behavior patterns in older men in terms of the number of years they have been trying to conceive, sexual frequency and sexual satisfaction. CONCLUSION: The data clearly illustrate an aging effect on semen characteristics and sexual behavior in men as they age. It is suggested that the aging effect be taken into consideration when proposing normal standard values for semen characteristics in routine semen analysis as outlined by WHO standards.

Adult↗

PubMed2005

Gene therapy for erectile dysfunction.

The past decade has seen an explosion of new information on the physiology of penile erection, pathophysiology of erectile dysfunction (ED), and development of new oral agents (e.g., three PDE5 inhibitors) to manage ED. Although all three selective PDE5 inhibitors are effective in the majority of ED cases, these oral medications have failed in certain disease states, such as diabetic ED, postprostatectomy ED, and severe veno-occlusive dysfunction. Only about 50% to 60% of these cases benefit from PDE5 inhibitor therapy, prompting the development of new approaches, including gene-based therapies for the treatment of ED. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Initially, gene therapy has been reserved for the treatment of life-threatening disorders including cancer, hereditary and acquired diseases. However, gene therapy is an attractive therapeutic possibility for the treatment of ED. Evolution of nitric oxide (NO), a small gaseous, lipophilic signaling molecule that is produced by nitric oxide synthase (NOS) activates guanylate cyclase (GC), resulting in increased cyclic guanosine monophosphate (cGMP) production, plays a significant role in our understanding of cavernosal smooth muscle physiology. Many gene therapy strategies have focused on the NO/GS/cGMP pathway. All three NOS isoforms, endothelial NOS (eNOS), neuronal NOS (nNOS), and iNOS have been used for gene therapy in order to modulate erectile response. Various viral and nonviral vectors have been used to date for the transfer of genetic material to the target cell or tissues with various degrees of success. Recently, second generation or "gutless" (helper-dependent) adenovirus vectors have been developed in order to reduce cellular toxicity and immune response, while increasing efficient gene therapy. Varieties of other gene therapy trials have also been undertaken for the treatment of ED and are the focus of this review.

Brain-Derived Neurotrophic Factor↗

PubMed2005

Characterization of oxidative stress status by evaluation of reactive oxygen species levels in whole semen and isolated spermatozoa.

We defined the basal levels of reactive oxygen species (ROS) in normal donors in neat (whole unprocessed) semen specimens, and in mature and immature spermatozoa isolated by a double-density gradient technique. In addition, we demonstrated that the ROS levels were significantly lower in neat semen compared with washed spermatozoa. The reference values of ROS in neat semen and mature spermatozoa can be used to define the pathologic levels of ROS in infertile men and may guide in therapeutic interventions.

Adult↗

PubMed2005

Impact of sperm morphology on DNA damage caused by oxidative stress induced by beta-nicotinamide adenine dinucleotide phosphate.

OBJECTIVE: To investigate the role of DNA damage induced by beta-nicotinamide adenine dinucleotide phosphate (NADPH) in human spermatozoa. DESIGN: Prospective controlled study. SETTING: Male infertility clinic at the Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio. PATIENT(S): Twenty-eight men undergoing infertility screening. INTERVENTION(S): Chemiluminescence assay and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) assay coupled flow cytometry after incubating mature and immature sperm separated by density gradient with 5 mM NADPH for 0, 3, and 24 hours. MAIN OUTCOME MEASURE(S): Reactive oxygen species (ROS) generation (10(6) counted photons per minute/10(6) sperm) and percentage of spermatozoa with fragmented DNA. RESULT(S): Immature sperm from teratozoospermic semen samples were characterized by a statistically significant presence of cytoplasmic residues in the mid-piece when compared with mature normozoospermic samples. Increased ROS production was observed in spermatozoa rich in cytoplasmic residues that showed a statistically significant positive correlation with sperm DNA damage in a time-dependent manner. CONCLUSION(S): Immature sperm contain high nicotinamide adenine dinucleotide phosphate (NADPH) in cytoplasmic droplets, but it has not yet been clear whether abnormal sperm morphology plays any role in sperm DNA damage induced by oxidative stress. Our data support the role of NAPDH in ROS-mediated sperm DNA damage and suggest that abnormal sperm morphology combined with elevated ROS production may serve as a useful indicator of potential damage to sperm DNA.

DNA Damage↗

PubMed2005

The relationship between the type of penile abnormality and penile vascular status in patients with peyronie's disease.

PURPOSE: We evaluated penile vascular status using penile duplex Doppler ultrasound (PDDU) according to the type of abnormality in men with Peyronie's disease (PD). MATERIALS AND METHODS: A total of 523 patients with PD were evaluated retrospectively. Each patient underwent PDDU following injections of 10 to 15 mug prostaglandin E1 intracavernously with accompanying visual sexual stimulation to evaluate penile blood flow. Abnormalities were divided into 7 groups. Objective evaluation of penile curvature was done with a protractor during maximum erection. Specific criteria were used to categorize patients into varying definitions of vascular status. The results were compared statistically among groups. RESULTS: Mean patient age +/- SEM was 54.2 +/- 1.5 years. The most frequently noted type of curvature was dorsal (43.5% of cases), followed by lateral (24.8%). Mean peak systolic velocity in the ventrolateral group was the highest, while the lowest peak systolic velocity was noted in the hourglass abnormality group. The hourglass group had the highest rate of pure arterial insufficiency, while veno-occlusive dysfunction was seen most commonly in the ventral curvature group. The ventrolateral group showed the most normal vascular status parameters. CONCLUSIONS: This study demonstrates there is a relationship between the type of curvature and penile hemodynamics. Although patients with PD in the hourglass abnormality group were the youngest, this abnormality was associated with the poorest penile vascular status. Patients with ventrolateral curvature had the best penile hemodynamics in our series. PDDU findings may direct the treating physician to different treatment options.

Diabetes Mellitus↗

PubMed2005

The impact of intralesional interferon alpha-2b injection therapy on penile hemodynamics in men with Peyronie's disease.

INTRODUCTION: Penile duplex Doppler ultrasound (PDDU) is currently the preferred method for the functional evaluation of penile hemodynamics. PDDU may be used to monitor objectively changes in penile vascular parameters in men who undergo treatment for Peyronie's disease (PD), including intralesional interferon alpha-2b (IFN alpha-2b). AIM: To investigate the impact of intralesional IFN alpha-2b therapy for PD on penile hemodynamics by using PDDU and to assess the objective role of PDDU in monitoring treatment outcomes. MATERIALS AND METHODS: Thirty-nine patients (20 in the placebo and 19 in the IFN alpha-2b treatment arm) were enrolled in this prospective, placebo-controlled, parallel study. Patients received either 10 mL saline or 5 x 10(6) units of IFN alpha-2b intralesional injections every other week for a total of six injections. Patients in each group were evaluated at baseline and after completion of treatment regarding changes in penile hemodynamic parameters, penile curvature, plaque size and density, pain on erection, and erectile function. Specific published criteria were used for PDDU measurements. Outcomes were statistically compared between each group by using Mann-Whitney U and chi-square tests. RESULTS: The mean age of the patients and the duration of PD were similar in both groups. The improvement in penile blood flow was significantly greater in IFN alpha-2b-treated patients than those in the placebo group. The number with the nonvascular classification increased significantly in the IFN alpha-2b arm from 31.5% to 57.8%. Additionally, improvements in penile curvature, plaque size and density, and pain on erection were better in the IFN alpha-2b group compared with the control. No significant improvement was observed in the erectile function domain in either group. CONCLUSION: This study reveals that intralesional IFN alpha-2b injections have a significant benefit on penile hemodynamic parameters. Moreover, intralesional IFN alpha-2b is an effective, minimally invasive treatment for PD, and PDDU is a useful adjunct to monitor objectively changes in penile vascular parameters. interferon alpha-2b injection therapy on penile hemodynamics in men with Peyronie's disease.

Adult↗

PubMed2005

T-type (alpha1G) low voltage-activated calcium channel interactions with nitric oxide-cyclic guanosine monophosphate pathway and regulation of calcium homeostasis in human cavernosal cells.

INTRODUCTION: Nitric oxide-cyclic guanosine monophosphate (NO-cGMP)-mediated relaxation of cavernosal smooth muscle during erection is accompanied by a decrease in intracellular calcium concentrations ([Ca2+](i)). However, it is not known whether and how an increase in [Ca2+](i) is responsible for (i) initiating smooth muscle contraction/detumescence following relaxation; and (ii) maintaining the penis in a flaccid state under nonstimulating conditions. AIM: To elucidate (i) the mechanism(s) of [Ca2+](i) homeostasis regulation in human cavernosal smooth muscle cells (HCSMC); and (ii) how NO-cGMP interacts with such [Ca2+](i) homeostasis. METHODS: We evaluated the expression and function of both T-type and L-type Ca2+ channels in HCSMC by employing selective probes/inhibitors using various cellular and molecular techniques (e.g., reverse transcriptase and real-time polymerase chain reaction, cell proliferation assay, fura-2 Ca2+ fluorescence spectroscopy, enzyme-linked immuno-absorbent assay (ELISA)). MAIN OUTCOME MEASURE: We have demonstrated for the first time significant interactions of NO-cGMP with the T-type (alpha1G) Ca2+ channel in HCSMC. RESULTS: Our results suggest that in addition to NO-induced rapid and transient decrease in [Ca2+](i) that results in smooth muscle relaxation, NO-cGMP also enhanced mRNA expression of the T-type (alpha1G) Ca2+ channel resulting in delayed elevation of [Ca2+](i). This could be abolished by a selective T-channel blocker, NNC 55-0396. Another unique finding of this study is that dose-dependent HCSMC proliferation in vitro by NO is associated with the activation of the T-type (alpha1G) Ca2+ channel that regulates [Ca2+](i) homeostasis in these cells. CONCLUSIONS: Human cavernosal cells express T-type (alpha1G) Ca2+ channels that are involved in maintaining [Ca2+](i) homeostasis and regulation of NO-cGMP-induced smooth muscle relaxation-contraction responsible for penile erection, flaccidity, and tonicity. Targeting these Ca2+ channels may (i) associate various comorbidities with the onset of erectile dysfunction; (ii) provide a biochemical basis for differences between therapeutic profiles of various phosphodiesterase type 5 inhibitors, especially in nonresponders to current therapy; and (iii) provide biochemical basis in understanding mechanism(s) of drug tolerance.

Calcium↗

PubMed2004

Human sperm superoxide anion generation and correlation with semen quality in patients with male infertility.

OBJECTIVE: To measure levels of reactive oxygen species (ROS) including H(2)O(2) and O(2)(.-) generation in infertile men and determine whether sperm quality is correlated with levels of ROS triggered by the exogenous reduced form of beta nicotinamide adenine dinucleotide phosphate (NADPH). DESIGN: Prospective study. SETTING: Male infertility clinic at a tertiary healthcare center. PATIENT(S): Eleven infertile men and six healthy donors. INTERVENTION(S): Chemiluminescence assay using luminol and lucigenin as probes before and after incubating sperm samples with 5 mM and 10 mM of NADPH. MAIN OUTCOME MEASURE(S): The ROS generation (10(6) counted photons per minute/10(6) sperm). RESULT(S): Baseline levels of O(2)(.-) generation were significantly higher in the infertile patients than in the healthy donors (r = 0.73, 95% confidence interval [median (25th, 75th percentiles): 0.73 (0.5, 5.5) vs. 0.2 (0.0, 0.5)] when lucigenin was used as the probe. Compared with basal levels, O(2)(.-) generation was significantly higher after coincubation with NADPH (5 mM and 10 mM) in the entire combined study population, and patients only but not donors. The O(2)(.-) generation was negatively correlated with sperm concentration (r = -0.75, 95% CI 0.38-1), motility (r = -0.69, 95% CI 0.28-1), and percentage of normal morphology (r = -0.78, 95% CI 0.36-1). CONCLUSION(S): Spermatozoa from infertile men produce higher levels of O(2)(.-) in the presence of exogenous NADPH compared to healthy donors. The ability of spermatozoa to generate O(2)(.-) increases as the semen quality declines.

Acridines↗

PubMed2004

Relationship between the severity of penile curvature and the presence of comorbidities in men with Peyronie's disease.

PURPOSE: We investigated the relationship between penile curvature severity and co-morbidities in men with Peyronie's disease (PD) and assessed whether the severity of curvature had an impact on penile vascular status and/or erectile function. MATERIALS AND METHODS: Based on a 10-year period 469 patients with PD were retrospectively evaluated in regard to age at diagnosis, type and degree of penile curvature, erectile dysfunction (ED) and other comorbidities, such as diabetes mellitus, hypertension, serum lipid abnormalities, smoking and ischemic heart disease. To assess penile vascular status all men with PD underwent penile duplex Doppler ultrasound evaluation. The severity of penile curvature was classified using the Kelami system, that is grade 1--curvature 30 degrees or less, grade 2--30 to 60 degrees and grade 3--greater than 60 degrees. RESULTS: Mean patient age was 54.8 +/- 4.3 years (range 18 to 79) and the mean duration of symptoms was 24.8 +/- 13.7 months (range 3 to 120). The most common penile abnormality was dorsal curvature in 47.1% of patients. The most frequently documented co-morbid conditions in association with PD were hypertension in 27.2% of cases, smoking in 25.5%, hypercholesterolemia in 18.3%, diabetes mellitus in 17.2%, hyperlipidemia in 15.7% and a history of penile trauma in 13.2%. There was no relationship between the number or severity of each of these co-morbid conditions and the severity of the penile abnormality. In addition, there was no relationship between the severity of penile curvature and penile vascular status in patients with PD. Moreover, the prevalence of these comorbidities, except smoking and penile trauma history, was significantly higher in patients with PD and concurrent ED than in patients with PD only. CONCLUSIONS: While co-morbid conditions, such as hypertension, smoking, hypercholesterolemia, diabetes mellitus and hyperlipidemia, are commonly seen in patients with PD and may seem to be risk factors for PD, there was no statistical relationship between penile curvature severity and any of these comorbidities. Similarly there was no statistically significant relationship between the severity of curvature and penile vascular status or ED. The fact that the prevalence of associated comorbidities is higher in patients with PD and ED than in patients with PD only indicates that these comorbidities are more likely related to ED than to the pathogenesis of PD.

Adolescent↗

PubMed2004

Stratification of penile vascular pathologies in patients with Peyronie's disease and in men with erectile dysfunction according to age: a comparative study.

PURPOSE: Erectile dysfunction (ED) occurs in 20% to 54% of men with Peyronie's disease (PD). We investigated the role of vascular status in the pathophysiology of ED in patients with PD. MATERIALS AND METHODS: A total of 509 consecutive men with PD (group 1--impotent 259, 1a, and potent 250, 1b, mean age +/- SD 54.6 +/- 4.4 years) and 507 consecutive men with ED only (group 2--mean age 49.4 +/- 12.4 years) underwent penile duplex ultrasonography (PDU). Detailed sexual and medical history, and focused physical examination were performed in all patients. Patients in the 2, groups were stratified according to age (18 to 80 years) and classified according to PDU results (normal vascular status, arterial insufficiency, veno-occlusive dysfunction [VOD] and mixed vascular pathology). RESULTS: VOD was observed in 23.1% and 42.8% of patients in groups 1 and 2, respectively (p <0.05). Although VOD was significantly more common in group 2 (ED alone) than in group 1a (PD plus ED) in the third decade (p <0.05), overall PDU results showed no statistical difference for VOD between these 2 groups (p >0.05). Of note, mixed vascular pathologies were significantly higher in group 1a than in group 2 in the third through fifth decades (p <0.05), while arterial insufficiency was more common in the seventh decade (p <0.05). CONCLUSIONS: While many groups have investigated the vascular causes of ED, the exact etiology of ED in men with PD remains controversial. A possible relationship between ED and VOD in patients with PD has been previously reported. The current PDU study demonstrates that for all ages except 30 to 39 years the prevalence of VOD in patients with PD plus ED is similar to that of patients with ED alone.

Adolescent↗

PubMed2003

Functional androgen receptor confers sensitization of androgen-independent prostate cancer cells to anticancer therapy via caspase activation.

Therapeutic resistance remains an unresolved problem in the clinical management of human prostate cancer (PC). Despite initial positive response to androgen ablation therapy (AAT), virtually all PC patients will relapse due to acquisition of hormone refractory disease and selective outgrowth of tumor cells with multidrug resistance phenotype. We here provide the first experimental evidence that restoring a functional androgen receptor (AR) in the androgen-independent prostate cancer PC3 cells enhances their sensitivity to growth arrest and suppresses their colony-forming ability in response to paclitaxel and gamma-irradiation. Furthermore, functional AR increases the susceptibility of these cells to the apoptotic potentials of therapeutic agents, as evidenced by an increase in caspase activity, annexin V binding, and internucleosomal DNA fragmentation, by inducing caspase activation. The abrogation of the cytotoxic effects by 4-hydroxyflutamide suggests a crucial role for AR activation in enhancing the therapeutic sensitivity of these cells in a ligand-independent fashion. Our data thus demonstrate that a functional AR is a prerequisite for effective therapeutic response and that aberrant expression or blockade by AAT may trigger pathways leading to emergence of PC cells with therapeutic resistance phenotype. Since the mainstay of primary therapy for PC has been AAT by pharmaco-therapeutic or surgical means, this study thus provides a new frontier for revising the AAT therapeutic strategy in conjunction with radiation and/or chemotherapeutic agents.

Androgens↗

PubMed2003

Oxidative stress is associated with increased apoptosis leading to spermatozoa DNA damage in patients with male factor infertility.

OBJECTIVE: To evaluate ejaculated spermatozoa from patients with male factor infertility for the role of cytochrome c and caspases 9 and 3 (the proteins known to mediate apoptosis) and to examine association between semen quality and apoptosis in the presence of oxidative stress. DESIGN: Prospective study. SETTING: Male infertility clinic at a tertiary health care center. PATIENT(S): Semen specimens from 35 patients with idiopathic infertility and 8 normal healthy donors. MAIN OUTCOME MEASURE(S): Levels of ROS, cytochrome c, and caspases 9 and 3 and semen variables. RESULT(S): Compared with normal donors, infertile patients had significantly higher levels (expressed as median [25th and 75th percentiles]) of ROS (4.15 x 10(6) counted photons per minute [cpm] [0.26, 40.16 x 10(6) cpm] vs. 0.06 x 10(6) cpm [0.02, 0.29 x 10(6) cpm]; P<.01), cytochrome c (2.78 [2.21, 43.65 vs. 1.5 [1.25, 2.2]; P<.01)], caspase 9 (2.52 [0.9, 4.28] vs. 6 [4.85, 7.63]; P<.006), and caspase 3 (0.56 [0.32, 1.02] vs. 1.69 [1.66, 2.67]; P<.01). Semen variables (motility, concentration, and morphology) were negatively correlated with caspase 9 and 3 (P<.05). Reactive oxygen species was positively correlated with cytochrome c (r=.43; P<.03), caspase 9 (r=.56; P<.001), and caspase 3 (r=.65;P<.01). CONCLUSION(S): Infertile men have decreased sperm variables induced by higher ROS levels in semen. A positive relationship exists between increased sperm damage by ROS and higher levels of cytochrome c and caspases 9 and 3, which indicate positive apoptosis in patients with male factor infertility.

Apoptosis↗

PubMed2003

Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele.

OBJECTIVE: To examine levels of sperm DNA damage and oxidative stress (OS) in infertile men with varicocele. DESIGN: Prospective controlled study. SETTING: Male infertility clinic, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio. PATIENT(S): Thirty-one infertility patients and 16 fertile controls. INTERVENTION(S): Sperm DNA fragmentation index (DFI), levels of seminal reactive oxygen species (ROS), and total antioxidant capacity (TAC) were assessed using the sperm chromatin structure assay, chemiluminescence assay, and enhanced chemiluminescence assay, respectively. ROS-TAC score was calculated as a measure of OS. MAIN OUTCOME MEASURE(S): Median (interquartile range) DFI and ROS-TAC scores. RESULT(S): Sixteen of the 31 patients had left varicocele [grade I (n = 3), grade II (n = 10), and grade III(n = 3)], and the remaining 15 had normal genital examination. Patients with varicoceles had significantly higher percent DFI than controls (25%, range: 20%-35%; vs. 15%, range: 10%-22%). Patients with varicoceles had significantly lower ROS-TAC scores (21, range: 9.5-31) than the infertile patients with normal genital examination (34, range: 28-42) or the controls (40.3, range: 38-44). CONCLUSION(S): Infertile men with varicoceles showed significantly increased spermatozoal DNA damage that appears to be related to high levels of OS in semen.

Cell Nucleus↗