Mark C. Lindgren

PD49-11 METABOLIC DYSFUNCTION AND HYPOGONADISM IN A COHORT OF YOUNG, HEALTHY MEN

and neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH) and TUNEL assay expression were measured 72h. Gene expression of nNOS, TH, beta-tubulin, Schwann cells (glial fibrillary acidic protein; GFAP), markers of nerve injury (activating transcription factor 3; ATF3) and regeneration (growth associated protein 43, GAP43) was also measured in irradiated MPGs (n1⁄46/grp). RESULTS: In dissociated MPG neuronal cultures, there was an early increase in neuron length, while branching and nNOS positive neurons decreased (p<0.05). Early radiation caused a 2-fold increase in apoptotic neurons (p<0.05). However, the gene expression of neuronal markers beta-tubulin, nNOS, TH and markers of injury and repair (ATF3, GAP43) were all unchanged. There was a marked increase in the gene expression of Schwann cell marker GFAP 2 weeks post-RT (p<0.001). At 10 weeks post-RT, there was a 20% decrease in neuron length, decreased neuron branching, and 20-30% less nNOS and TH positive neurons (p<0.05). Additionally, there was a 2.5 fold increase in the number of TUNEL positive apoptotic neurons (p<0.05). Gene expression of nNOS, TH, GAP43 and ATF3 were all decreased (p<0.05) while GFAP remained considerably elevated (p<0.005). Interestingly, erectile function was not impaired at either time point following radiation. CONCLUSIONS: This is the first study to characterize the health and regeneration potential of MPG neurons following RT. While this model lead to minimal changes in erectile function, neuronal injury was apparent early post-RT and persisted by increasing over time. The nerves are very susceptible to apoptosis and damage from prostatic RT and additional research is necessary to develop radioprotective strategies for exposed benign periprostatic tissues.

MP60-16 HYPOGONADISM IS ASSOCIATED WITH LOWER SPERM MORPHOLOGY AND LOWER LIVE BIRTH RATES IN MEN WITH UNEXPLAINED INFERTILITY

JC Trussell*, Fayetteville, NY; Robert Coward, Chapel Hill, NC; Nanette Santoro, Denver, CO; Christy Stetter, Allen Kunselman, Hershey, PA; Michael Diamond, Augusta, GA; Karl Hansen, Oklahoma City, OK; Stephen Krawetz, Detroit, MI; Richard Legro, Hershey, PA; James Smith, San Francisco, CA; Anne Steiner, Chapel Hill, NC; Pasquale Patrizio, New Haven, CT; Robert Wild, Oklahoma City, OK; Esther Eisenberg, Rockville, MD; Heping Zhang, New Haven, CT; Mark Lindgren, Oklahoma City, OK

Growth Hormone Secretagogue Treatment in Hypogonadal Men Raises Serum Insulin-Like Growth Factor-1 Levels:

Realizing the reported misuse of human growth hormone (GH), investigation of a safe alternative mechanism for increasing endogenous GH is needed. Several GH secretagogues are available, including GH-releasing peptides (GHRPs) GHRP-2 and GHRP-6, and the GH-releasing hormone analog, sermorelin (SERM). Insulin-like growth factor 1 (IGF-1) serves as a surrogate marker for GH. Here, the effect of GHRP/SERM therapy on IGF-1 levels is evaluated. A retrospective review of medical records was performed for 105 men on testosterone (T) therapy seeking increases in lean body mass and fat loss who were prescribed 100 mcg of GHRP-6, GHRP-2, and SERM three times daily. Compliance with therapy was assessed, and 14 men met strict inclusion criteria. Serum hormone levels of IGF-1, T, free T (FT), estradiol (E), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were evaluated. Mean (SD) age of the cohort was 33.2 (2.9) years, and baseline IGF-1 level was 159.5 (26.7) ng/mL. Mean (SD) duration of continuous GHRP/SERM treatment was 134 (88) days. Mean posttreatment IGF-1 level was 239.0 (54.6) ng/mL (p < .0001). Three of the 14 men were on an aromatase inhibitor and/or tamoxifen prior to treatment and another 4 men were coadministered an aromatase inhibitor and/or tamoxifen during treatment. Inhibition of E production or estrogen receptor blockade resulted in smaller increases in IGF-1 levels. GHRP/SERM therapy increases serum IGF-1 levels with strict compliance to thrice-daily dosing. The results suggest that combination therapy may be beneficial in men with wasting conditions that can improve with increased GH secretion.

MP47-05 LOW SERUM TESTOSTERONE IS ASSOCIATED WITH ELEVATIONS IN HIGH-SENSITIVITY CARDIOVASCULAR DISEASE BIOMARKERS

INTRODUCTION AND OBJECTIVES: Significant controversy exists regarding the relationship between serum testosterone (T) levels and cardiovascular risk, with evidence supporting increased risk in men with both low and high T levels. However, few studies have assessed cardiovascular (CV) risk as a function of plasma testosterone (T) level using objective biomarkers. Here we examine the relationship between T levels and a panel of high sensitivity CVD markers. METHODS: 10,041 unique male patients were identified in the database of the Singulex Clinical Laboratory (SCL), which specializes in high sensitivity (hs) CVD biomarker testing using single molecule counting (SMC) technology. Results were evaluated for total T, hscardiac troponin I (cTnI), endothelin-1 (ET), N-terminal pro-B-type natriuretic peptide (NTproBNP), interleukin-6, (IL-6), tumor necrosis factor-a (TNF-a), and interleukin-17A (IL-17A). Patients were grouped by total T concentration and associations with the above biomarkers were determined. RESULTS: Median (interquartile range) age within the cohort was 58 (48-68) years, and serum T level was 421 (305-565) ng/dL; T levels did not change with patient age (p1⁄40.78), but were inversely related with body mass index (BMI) (P<0.0001). An inverse relationship between plasma T level and the number of men with increased CV risk was observed for 6 of 7 cardiovascular markers, including IL-6, cTnI, TNF-a, ET, NTproBNP and leptin (Table 1). In men with T <250 ng/dL, after adjusting for age, BMI, hemoglobin A1c (HbA1c) levels, hsCRP and HDL cholesterol levels, IL-6, ET, NTproBNP, and leptin remained significantly associated with increased CV risk. As plama T levels increased, however, the fraction of men with marker values above the reference range, and therefore considered at increased risk, decreased (Figure 1). CONCLUSIONS: Our findings support prior reports demonstrating increased CV risk in hypogonadal men and argue against the controversial current clinical conclusion that men on testosterone therapy may have an increased incidence of CVD. Source of Funding: AWP and AH are National Institutes of Health (NIH) K12 Scholars supported by a Male Reproductive Health Research Career (MRHR) Development PhysicianScientist Award (HD073917-01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program (to Dolores J. Lamb).

MP76-05 TWICE PER WEEK DOSING OF INTRAMUSCULAR TESTOSTERONE (T) IS ASSOCIATED WITH GREATER RISK OF ERYTHROCYTOSIS

INTRODUCTION AND OBJECTIVES: It is well known that testosterone plays a critical role in regulation of erectile function (EF). Veno-occlusive insufficiency is a causal or accompanying symptom in 20e45% of patients with ED. The conventional therapy of venogenic ED may be useless if unrecognized andogendeficiency. There are limited data shown that testosterone improves EF in hypogonadal patients with veno-occlusive dysfunction. In this multiclinical study we evaluated the results of testosterone therapy (TT) in the hypogonadal patients with corporal venous leakage. METHODS: 49 hypogonadal men with ED and venous leakage from corpora cavernosa, aged 32 e 56 (44 8, 3) non-responded to PDE-5 inhibitors, were examined. Comorbidities included diabetes mellitus (4 pts), arterial hypertension (5 pts), alcohol abuse ( 8pts). Testosterone levels were 2,3 -11,2 (6,8 3,1) nmol/l. After lab tests each patient underwent penile duplex ultrasound for reveling signs of venous deficiency. Arterial inflow was normal at all patients while the end diastolic velocity was >5 ml/sec. All patients underwent the treatment with 1,000 mg testosterone undecanoate on day 1, followed by another injection after 6 weeks and every 3 months thereafter 5 injections totally. Pharmacocavernosography (PCG) (7 pts) or magnetic resonance imaging (MRI) with contrast enhancement (14 pts) were used for visualization of venous leakage pathways prior to TT and after 6 -8 months of TT for the detection of venous leakage decreasing. Design of the investigation: open, prospective, non-control, non-randomize. RESULTS: All patients responded to the therapy and noted the considerable improvement in EF domain (IIEF scores increased to 24,5 0,5) and SD domain (IIEF scores increased to 9 0.3) 41/49 pts (84%) restore satisfactory coitus with monotherapy of testosterone. 8/49 pts (16%) poor responded to monotherapy had satisfactory coitus after combine therapy with PDE-5 inhibitors. After 6 months treatment the control penile duplex ultrasound revealed in 45 pts the end diastolic velocity <5 ml/sec. PCG or MRI was repeated in 12 patients. Compared with baseline investigation, repeat radiological studies after TT showed significant decreasing or even absence of the venous leakage from the corporal bodies. CONCLUSIONS: These results demonstrate that testosterone regulates the veno-occlusive mechanism of erection and improves the EF in hypogonadal patients with venous leakage. The combination of TT with PDE-5 inhibitors will be useful in poor responders to the testosterone monotherapy.