OnLine First 2013

[Michael Scally MD]

Plumelle D, Lombard E, Nicolay A, Portugal H. Influence of diet and sample collection time on 77 laboratory tests on healthy adults. Clin Biochem. Influence of diet and sample collection time on 77 laboratory tests on healthy adults

OBJECTIVES: We studied the effect of a standardized breakfast or lunch before blood sampling on 77 analytes.

DESIGN AND METHODS: The mean difference between assays from 20 healthy adults was calculated on blood samples taken before and after food intake. Significant differences were tested using two-tailed student t-test and compared to the acceptable limits derived from analytical and intraindividual biological variation.

RESULTS: Most of the analytes investigated were not significantly affected by food intake. Six of them were influenced by breakfast or lunch: triglycerides, glucose, creatinine, C-peptide and insulin were significantly upregulated, whereas testosterone was downregulated. Fourteen parameters were more influenced by time of sampling than by meals: nine decreased during the day (total bilirubin, BNP, myoglobin, cortisol, TSH, C-telopeptide, prolactin, ACTH, uric acid) and two increased (white blood cells, neutrophils). Three parameters showed levels that were similar at 9:00am and 5:00pm but their lowest level at 12:30pm (inorganic phosphorus, osteocalcin, PTH).

CONCLUSIONS: Fasting is necessary for some laboratory tests. Clinicians should be aware of variations due to sampling time before ordering non-fasting tests, and in the subsequent interpretation of results.

 

[Michael Scally MD]

McCabe MP, Althof SE. A Systematic Review of the Psychosocial Outcomes Associated with Erectile Dysfunction: Does the Impact of Erectile Dysfunction Extend Beyond a Man's Inability to Have Sex? The Journal of Sexual Medicine. A Systematic Review of the Psychosocial Outcomes Associated with Erectile Dysfunction: Does the Impact of Erectile Dysfunction Extend Beyond a Man's Inability to Have Sex? - McCabe - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Aim - The aim of this study was to report and analyze the published data from randomized controlled trials (RCTs) for (i) the psychosocial outcomes associated with erectile dysfunction (ED) before treatment with a phosphodiesterase type 5 (PDE5) inhibitor; and (ii) the change in psychosocial outcomes after the use of a PDE5 inhibitor in men with ED.

Methods - The method used was a prospectively designed systematic literature review of publications reported in MEDLINE via PubMed, EMBASE, the Cochrane Library, Science Citation Index Expanded, and PsychINFO from January 1, 1995 to May 14, 2012.

Main Outcome Measures - The main outcome measures were scores on psychosocial measures in men who were treated for ED with a PDE5 inhibitor before and after treatment.

Results - A total of 1,714 publications were retrieved; 1,674 publications were excluded because they did not meet the design requirements of the review, and 40 publications (32 RCTs) were retained. Before treatment, men who participated in clinical trials reported relatively good quality of life and overall relationships, but poor sexual relationships and sexual satisfaction, diminished confidence, low self-esteem, and symptoms of depression. After treatment, there were significant improvements from baseline in most of these measures, except for overall life satisfaction and overall relationship satisfaction.

Conclusions - ED and the treatment of ED are associated with substantially broader aspects of a man's life than just erectile functioning. This review demonstrates the importance of evaluating the psychosocial factors associated with ED and its treatment, and the importance of using standardized scales to conduct this evaluation. Further research is needed to better understand the mechanisms underlying the reciprocal relationships among physical and psychological functioning in men with ED.

 

[Michael Scally MD]

Xu L, Au Yeung SL, Kavikondala S, Leung GM, Shooling CM. Testosterone concentrations in young healthy US versus Chinese men. American Journal of Human Biology. Testosterone concentrations in young healthy US versus Chinese men - Xu - 2013 - American Journal of Human Biology - Wiley Online Library

Background - Previous small studies examining differences in testosterone concentrations by ethnicity found mixed results for Caucasians and Chinese men, which might be confounded by age differences and living standards. The aim of the present study is to examine the differences in total, free, and bioavailable testosterone concentrations between healthy young men from the United States (US) and from the most economically developed part of China, i.e., Hong Kong (HK).

Methods - Cross-sectional analysis based on 365 young men from the Third National Health and Nutrition examination Survey (NHANES III) in the US and 299 Chinese men recruited from university students. All participants were aged from 18 to 29 years. Main outcome measures were total testosterone (TT) and calculated bioavailable testosterone (Bio T) and free testosterone (FT).

Results - In both US and Chinese men, TT, FT, and Bio T concentration peaked at 20–24 years of age, at 23.19, 0.49, and 12.23 nmol/l in US men, and 20.72, 0.48 and 12.59 nmol/l in Chinese men, respectively. Among those aged 18–24 years, after adjusting for age, US men had higher TT (mean, 95% confidence interval: 21.64, 21.31–21.99 versus 20.20, 20.12–20.28 nmol/l), but not FT (0.47, 0.47–0.48 versus 0.47, 0.47–0.47 nmol/l) or Bio T (11.90, 11.83–11.97 versus 12.39, 12.35–12.42 nmol/l) than Chinese men.

Conclusions - TT, but not FT or Bio T concentrations are lower in young healthy Chinese men than US men. These differences apparent in young men may be important in understanding different patterns of diseases between Western and Asian populations.

 

[Michael Scally MD]

Aung K, Lorenzo C, Hinojosa MA, Haffner SM. Risk of Developing Diabetes and Cardiovascular Disease in Metabolically Unhealthy Normal-Weight and Metabolically Healthy Obese Individuals. Journal of Clinical Endocrinology & Metabolism. Risk of Developing Diabetes and Cardiovascular Disease in Metabolically Unhealthy Normal-Weight and Metabolically Healthy Obese Individuals

Context: The risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (DM) associated with obesity appears to be influenced by the coexistence of other metabolic abnormalities.

Objective: We examined the risk of developing CVD and DM in metabolically healthy obese (MHO) and metabolically unhealthy normal weight (MUH-NW) individuals.

Design and Setting: We analyzed prospective data of the San Antonio Heart Study, a population-based study among Mexican Americans and non-Hispanic whites (median follow-up, 7.4 y).

Participants: Incident DM and CVD were assessed in 2814 and 3700 participants aged 25 to 64 years, respectively.

Main Measures: MHO was defined as obesity (body mass index ? 30 kg/m2) with no more than one metabolic abnormality, and MUH-NW was defined as body mass index <25 kg/m2 with two or more abnormalities.

Results: In logistic regression models, BMI was associated with incident DM after controlling for demographics, family history of DM, and fasting glucose (odds ratio × 1 SD, 1.7 [1.5–2.0]). Both MUH-NW and MHO individuals had an increased DM risk (2.5 [1.1–5.6] and 3.9 [2.0–7.4], respectively). Similarly, BMI was related to incident CVD after adjusting for demographics and Framingham risk score (1.3 [1.1–1.6]). Incident CVD was also increased in MUH-NW and MHO individuals (2.9 [1.3–6.4] and 3.9 [1.9–7.8], respectively). Results were consistent across gender and ethnic categories.

Conclusion: The risk of developing DM and CVD is increased in MUH-NW and MHO individuals. Screening for obesity and other metabolic abnormalities should be routinely performed in clinical practice to institute appropriate preventive measures.

 

[Michael Scally MD]

Yeap BB, Alfonso H, Chubb SAP, et al. In Older Men an Optimal Plasma Testosterone Is Associated With Reduced All-Cause Mortality and Higher Dihydrotestosterone With Reduced Ischemic Heart Disease Mortality, While Estradiol Levels Do Not Predict Mortality. Journal of Clinical Endocrinology & Metabolism. In Older Men an Optimal Plasma Testosterone Is Associated With Reduced All-Cause Mortality and Higher Dihydrotestosterone With Reduced Ischemic Heart Disease Mortality, While Estradiol Levels Do Not Predict Mortality

Context: Testosterone (T) levels decline with age and lower T has been associated with increased mortality in aging men. However, the associations of its metabolites, dihydrotestosterone (DHT) and estradiol (E2), with mortality are poorly defined.

Objective: We assessed associations of T, DHT, and E2 with all-cause and ischemic heart disease (IHD) mortality in older men.

Participants: Participants were community-dwelling men aged 70 to 89 years who were residing in Perth, Western Australia.

Main Outcome Measures: Plasma total T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning samples collected in 2001 to 2004 from 3690 men. Deaths to December 2010 were ascertained by data linkage.

Results: There were 974 deaths (26.4%), including 325 of IHD. Men who died had lower baseline T (12.8 ± 5.1 vs 13.2 ± 4.8 nmol/L [mean ± SD], P = .013), DHT (1.4 ± 0.7 vs 1.5 ± 0.7 nmol/L, P = .002), and E2 (71.6 ± 29.3 vs 74.0 ± 29.0 pmol/L, P = .022). After allowance for other risk factors, T and DHT were associated with all-cause mortality (T: quartile [Q] Q2:Q1, adjusted hazard ratio

---

= 0.82, P = .033; Q3:Q1, HR = 0.78, P = .010; Q4:Q1, HR = 0.86, P > .05; DHT: Q3:Q1, HR = 0.76, P = .003; Q4:Q1, HR = 0.84, P > .05). Higher DHT was associated with lower IHD mortality (Q3:Q1, HR = 0.58, P= .002; Q4:Q1, HR = 0.69, P = .026). E2 was not associated with either all-cause or IHD mortality.

Conclusions: Optimal androgen levels are a biomarker for survival because older men with midrange levels of T and DHT had the lowest death rates from any cause, whereas those with higher DHT had lower IHD mortality. Further investigations of the biological basis for these associations including randomized trials of T supplementation are needed.

 

[Michael Scally MD]

Nagata N, Furuya K, Oguro N, et al. Lead Evaluation of Tetrahydroquinolines as Nonsteroidal Selective Androgen Receptor Modulators for the Treatment of Osteoporosis. ChemMedChem. http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201300348/abstract

Tetrahydroquinoline (THQ) was deemed to be a suitable scaffold for our nonsteroidal selective androgen receptor modulator (SARM) concept. We adapted the strategy of switching the antagonist function of cyano-group-containing THQ (CN-THQ) to the agonist function and optimized CN-THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a para-substituted aromatic ring attached through an amide linker. The long-tail THQ derivative 6-acetamido-N-(2-(8-cyano-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl)-2-m ethylpropyl)nicotinamide (1 d), which bears a para-acetamide-substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between 1 d and helix 12 of the AR could maintain the structure of the AR in its agonist form; indeed, 1 d displays strong AR agonistic activity. Furthermore, 1 d showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model.

 

[Michael Scally MD]

Al-Niaimi F, Lyon CC. Acute Kidney Injury Due to Interaction of Methyl-1-testosterone with Ciclosporin Metabolism in a Patient with Severe Atopic Dermatitis. Dermatol Ther (Heidelb). Acute Kidney Injury Due to Interaction of Methyl-1-testosterone with Ciclosporin Metabolism in a Patient with Severe Atopic Dermatitis - Online First - Springer

Ciclosporin is widely used in a number of inflammatory disorders and has the potential for drug interactions. We report here a case of acute kidney injury due to the interaction of ciclosporin with methyl-1-testosterone. This has not been previously reported and it is relevant as methyl-1-testosterone can be purchased online. Physicians should be aware of any over the counter or online purchased "supplements" and consider possible drug interactions.

 

[Michael Scally MD]

Costanzo PR, Suarez SM, Scaglia HE, Zylbersztein C, Litwak LE, Knoblovits P. Evaluation of the hypothalamic-pituitary-gonadal axis in eugonadal men with type 2 diabetes mellitus. Andrology. Evaluation of the hypothalamic-pituitary-gonadal axis in eugonadal men with type 2 diabetes mellitus - Costanzo - 2013 - Andrology - Wiley Online Library

Men with type 2 diabetes mellitus (DM2) have lower testosterone levels and a higher prevalence of hypogonadism. It still remains unclear the mechanism by which there is a relationship between hypogonadism and DM2. The objective was to evaluate the hypothalamic-pituitary-gonadal axis at different levels in eugonadal patients with DM2. Fourteen patients with DM2 (DM2 group) and 15 subjects without DM2 (normal glucose tolerance test) as control group (CG) were included. We assessed: (i) fasting glucose, insulin, Homeostasis Model Assessment (HOMA); (ii) luteinizing hormone (LH) pulsatility through blood collections every 10 min for 4 h; (iii) gonadotropin-releasing hormone (GnRH) test: basal LH and 30, 60 and 90 min after 100 mug of i.v. GnRH; (iv) human chorionic gonadotropin (hCG) test: basal total testosterone (TT), bioavailable testosterone (BT), free to (FT), estradiol (E2), bioavailable E2 (BE2) and sex hormone-binding globulin (SHBG) and 72 h post 5000 IU of i.m. hCG. There were no differences in age, body mass index and waist circumference between groups. Glucose was higher in the DM2 group vs. CG: 131.1 +/- 25.5 vs. 99.1 +/- 13.6 mg/dL, p = 0.0005. There were no difference in basal insulin, HOMA, TT, BT, FT, E2, BE2, SHBG and LH levels between groups. The DM2 group had lower LH pulse frequency vs. CG: 0.8 +/- 0.8 vs. 1.5 +/- 0.5 pulses, p = 0.009. Differences in LH pulse amplitude were not found. A negative correlation was found between the number of LH pulses and glucose, r: -0.39, p = 0.03. There were no differences in the response of LH to GnRH between groups nor in the response of sexual steroids and SHBG to hCG. Patients with DM2 showed lower hypothalamic pulse frequency without changes in the pituitary response to GnRH nor testicular response to hCG. Glucose levels negatively correlated with the number of LH pulses which suggests a negative effect of hyperglycaemia in the hypothalamic secretion of GnRH.

 

[Michael Scally MD]

Chowdhuri S, Bascom A, Mohan D, Diamond MP, Badr MS. Testosterone Conversion Blockade Increases Breathing Stability in Healthy Men during NREM Sleep. Sleep 2013;36(12):1793-8. http://www.journalsleep.org/ViewAbstract.aspx?pid=29214

STUDY OBJECTIVES: Gender differences in the prevalence of sleep apnea/hypopnea syndrome may be mediated via male sex hormones. Our objective was to determine the exact pathway for a testosterone-mediated increased propensity for central sleep apnea via blockade of the 5alpha-reductase pathway of testosterone conversion by finasteride.

DESIGN: Randomization to oral finasteride vs. sham, single-center study.

SETTING: Sleep research laboratory.

PARTICIPANTS: Fourteen healthy young males without sleep apnea.

INTERVENTION: Hypocapnia was induced via brief nasal noninvasive positive pressure ventilation during stable NREM sleep. Cessation of mechanical ventilation resulted in hypocapnic central apnea or hypopnea.

MEASUREMENTS AND RESULTS: The apnea threshold (AT) was defined as the end-tidal CO2 (PETCO2) that demarcated the central apnea closest to the eupneic PETCO2. The CO2 reserve was defined as the difference in PETCO2 between eupnea and AT. The apneic threshold and CO2 reserve were measured at baseline and repeated after at a minimum of 1 month. Administration of finasteride resulted in decreased serum dihydrotestosterone. In the finasteride group, the eupneic ventilatory parameters were unchanged; however, the AT was decreased (38.9 +/- 0.6 mm Hg vs.37.7 +/- 0.9 mm Hg, P = 0.02) and the CO2 reserve was increased (-2.5 +/- 0.3 mm Hg vs. -3.8 +/- 0.5 mm Hg, P = 0.003) at follow-up, with a significantly lower hypocapnic ventilatory response, thus indicating increased breathing stability during sleep. No significant changes were noted in the sham group on follow-up study.

CONCLUSIONS: Inhibition of testosterone action via the 5alpha-reductase pathway may be effective in alleviating breathing instability during sleep, presenting an opportunity for novel therapy for central sleep apnea in selected populations.

 

[Michael Scally MD]

Jasuja R, Costello JC, Singh R, et al. Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy. Aging Cell. Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy - Jasuja - 2013 - Aging Cell - Wiley Online Library

Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone's adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone's promyogenic effects are mediated through upregulation of follistatin.

We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights.

To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed.

Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without ?-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone's effects on prostate, but did not affect testosterone's anabolic effects on muscle.

Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy.

 

[Michael Scally MD]

Zhao J, Jiang C, Lam TH, et al. Genetically predicted testosterone and cardiovascular risk factors in men: a Mendelian randomization analysis in the Guangzhou Biobank Cohort Study. Int J Epidemiol. Genetically predicted testosterone and cardiovascular risk factors in men: a Mendelian randomization analysis in the Guangzhou Biobank Cohort Study

BACKGROUND: Observationally lower testosterone is associated with an unhealthier cardiovascular (CVD) risk profile, but this association is open to confounding and reverse causality. The authors examined the association of testosterone with well-established cardiovascular disease (CVD) risk factors (blood pressure, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL)cholesterol and fasting glucose) and the Framingham score using a Mendelian randomization analysis with a separate-sample instrumental variable estimator.

METHODS: To minimize reverse causality, a genetic score predicting testosterone was developed in 289 young Chinese men from Hong Kong, based on three selected testosterone-related single nucleotide polymorphisms (rs10046, rs1008805 and rs1256031). Multivariable censored and linear regressions were used to examine the association of genetically predicted testosterone levels with CVD risk factors and Framingham score among 4212 older Chinese men from the Guangzhou Biobank Cohort Study.

RESULTS: Predicted testosterone was unrelated to systolic blood pressure [-0.11 mmHg, 95% confidence interval (CI) -0.70 to 0.48], diastolic blood pressure (0.04 mmHg, 95% CI -0.27 to 0.36), fasting glucose (0.02 mmol/l, 95% CI -0.02 to 0.06) or Framingham score (0.02, 95% CI -0.0001 to 0.03) but associated with higher LDL-cholesterol (0.02 mmol/l, 95% CI 0.01 to 0.04) and lower HDL-cholesterol (-0.01 mmol/l, 95% CI -0.02 to -0.001), after adjustment for potential confounders (age, education, smoking status, use of alcohol and body mass index).

CONCLUSIONS: Our findings did not corroborate observed protective effects of testosterone on cardiovascular risk factors or risk of ischaemic heart disease among men, but raises the possibility that higher testosterone may be associated with an unhealthier lipid profile.

 

[Michael Scally MD]

Brioche T, Kireev RA, Cuesta S, et al. Growth Hormone Replacement Therapy Prevents Sarcopenia by a Dual Mechanism: Improvement of Protein Balance and of Antioxidant Defenses. J Gerontol A Biol Sci Med Sci. Growth Hormone Replacement Therapy Prevents Sarcopenia by a Dual Mechanism: Improvement of Protein Balance and of Antioxidant Defenses

The aim of our study was to elucidate the role of growth hormone (GH) replacement therapy in three of the main mechanisms involved in sarcopenia: alterations in mitochondrial biogenesis, increase in oxidative stress, and alterations in protein balance. We used young and old Wistar rats that received either placebo or low doses of GH to reach normal insulin-like growth factor-1 values observed in the young group. We found an increase in lean body mass and plasma and hepatic insulin-like growth factor-1 levels in the old animals treated with GH. We also found a lowering of age-associated oxidative damage and an induction of antioxidant enzymes in the skeletal muscle of the treated animals. GH replacement therapy resulted in an increase in the skeletal muscle protein synthesis and mitochondrial biogenesis pathways. This was paralleled by a lowering of inhibitory factors in skeletal muscle regeneration and in protein degradation. GH replacement therapy prevents sarcopenia by acting as a double-edged sword, antioxidant and hypertrophic.

 

[Michael Scally MD]

Iyengar A, Sheppard D. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer. Case Rep Hematol. 2013:615189. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer

A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO) level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no spontaneous erythroid colonies were demonstrated.

Erythrocytosis is common reason for referral to a hematologist. The myeloproliferative disorder, polycythemia vera, and the rare congenital polycythemias represent primary erythrocytosis. Common secondary causes include smoking, obstructive sleep apnea, and other pulmonary diseases. Erythrocytosis is well described with certain classes of drugs, including androgens. We hypothesize that exemestane contributed to the development of erythrocytosis in our patient.

To our knowledge, erythrocytosis has not been previously described in association with aromatase inhibitors. These drugs prevent the conversion of androstenedione and testosterone to estrogen; thus the physiologic mechanisms may be similar to those responsible for erythrocytosis seen with exogenous androgens. These mechanisms are not well understood, but may include altered iron metabolism by a reduction in hepcidin levels.

 

[Michael Scally MD]

Roberts CK, Chen BH, Pruthi S, Lee ML. Effects of Varying Doses of Testosterone on Atherogenic Markers in Healthy Younger and Older Men. Am J Physiol Regul Integr Comp Physiol. Effects of Varying Doses of Testosterone on Atherogenic Markers in Healthy Younger and Older Men | Regulatory, Integrative and Comparative Physiology

Whether exogenous testosterone is proatherogenic remains controversial. We assessed the effects of graded doses of testosterone on serum markers of oxidative stress, chemotaxis, adhesion and inflammation in healthy younger and older men.

In a double-blind, randomized trial, 121 eugonadal men, (n=61, 18-35 years of age and n=60, 60-75 years of age) were randomized to one of five groups to receive weekly injections of 25, 50, 125, 300, or 600-mg of testosterone enanthate for 20 weeks, respectively, along with a long-acting gonadotropin-releasing hormone (GnRH) agonist. Energy and protein intakes were standardized and no resistance training was allowed.

We measured plasma levels of the atherogenic biomarkers monocyte chemotactic protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1), 8-isoprostane-PGF2alpha (8-iso-PGF2alpha) and high-sensitivity C-reactive protein (hs-CRP) before and after the intervention.

Administration of increasing doses of testosterone led to reduction in total 8-iso-PGF2alpha in the younger (p-trendYounger = 0.01), but not older (p-trendOlder = 0.79) men. No linear associations were observed between testosterone dose and MCP-1, sICAM-1 or hs-CRP (all p-trend >0.20).

In apparently healthy men, over a wide dose range, testosterone did not adversely affect atherogenic biomarkers. Long-term studies are warranted to determine whether testosterone supplementation affects atherosclerosis progression and cardiovascular risk.

 

[Michael Scally MD]

Samavat J, Facchiano E, Cantini G, et al. Osteocalcin increase after bariatric surgery predicts androgen recovery in hypogonadal obese males. Int J Obes (Lond). http://www.nature.com/ijo/journal/vaop/naam/pdf/ijo2013228a.pdf

Objective: Bone modulates testis function through osteocalcin (OCN) production. This paper assesses the association between serum osteocalcin (OCN) and androgen production recovery in morbidly obese males at 9 months after bariatric surgery.

Subjects: A cohort of n=103 obese males with mean+/-s.d. body mass index (BMI) 47.7+/-8.2 Kg/m2, age 42+/-11 years, consisting of n=76 patients undergoing gastric bypass and n=27 in the waiting list for surgery.

Results: At 9 months from surgery, a significant increase was observed in mean+/-SD total (tOCN=10.4+/-10.3 ng/ml, P<0.001) and undercarboxylated osteocalcin (ucOCN=5.4+/-3.7 ng/ml, P<0.001), total (TT, 5.6+/-6.5 nM, P<0.001) and free (cFT, 0.035+/-0.133 nM, P<0.006) testosterone, SHBG (21.2+/-16.7 nM, P<0.001) and decrease in estradiol (E2, -30.1+/-51.9 pM, P<0.001) levels only in operated patients, with a significant reduction in BMI (24%) and waist (20%). A positive correlation existed between tOCN and ucOCN (age-adj:beta=0.692, P<0.001) and their variations (age-adj:beta=0.629, P<0.001) after surgery. Multivariate analysis in operated patients showed a significant positive association between variations in tOCN and TT (age-adj:beta=0.289, P=0.012), SHBG (age-adj:beta=0.326, P=0.005) but not with cFT variation. tOCN, but not LH, variation was the only significant predictive factor of cFT recovery in the hypogonadal (TT<12 nM) operated subjects even after age- and BMI-adjustment (adj:beta=0.582, P<0.05). cFT improvement was significantly higher when considering operated patients with tOCN increase (0.045+/-0.123 vs -0.02+/-0.118 nM, P=0.015), hypogonadism (0.059+/-0.111 vs -0.059+/-0.138 nM, P=0.002) and younger than 35 years (0.102+/-0.108 vs -0.019+/-0.123 nM, P=0.009).

Conclusion: OCN recovery observed after bariatric surgery is significantly associated with cFT improvement independently of BMI variation and age in hypogonadal morbidly obese males.

 

[Michael Scally MD]

Jannini EA, Sternbach N, Limoncin E, et al. Health-Related Characteristics and Unmet Needs of Men with Erectile Dysfunction: A Survey in Five European Countries. The Journal of Sexual Medicine. Health-Related Characteristics and Unmet Needs of Men with Erectile Dysfunction: A Survey in Five European Countries - Jannini - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction Data suggest that ED is still an underdiagnosed and undertreated condition. In addition, it seems that men with ED are unsatisfied about their relationship with their physician and with the available drugs.

Aim The study aims to identify health-related characteristics and unmet needs of patients suffering from erectile dysfunction (ED) in big 5 European Union (EU) nations (France, Germany, Italy, Spain, and UK).

Methods Data were collected from the 2011 5EU National Health and Wellness-Survey on a population of 28,511 adult men (mean age: 47.18; SD 16.07) and was focused on men (5,184) who self-reported ED in the past 6 months. In addition, the quality of life (QoL) and work productivity/activity were explored.

Main Outcome Measures Health-related QoL (HRQoL) and work productivity were measured with SF-12v2 and WPAI validated psychometric tools.

Results One in every 20 young men (age 18–39) across 5EU experienced ED in the past 6 months. About half of men (2,702/5,184; [52%]) with ED across all ages did not discuss their condition with their physician. Interestingly, among those men who did discuss their condition with their physician, 68% (1,668/2,465) do not currently use medication. These findings were more evident in the age group of 18–39 years. Only 48% (2,465/5,184) had a closer relationship with their physician, suggesting that this quality of relationship may be unsatisfactory. Compared with controls, ED patients have a significantly higher intrapsychic and relational psychopathological comorbid burden and relevant decreasing in HRQoL, with a significantly higher impairment on work productivity/activity.

Conclusion Data suggest that there is a need for a new therapeutic paradigm in ED treatment which images the achievement of a new alliance between physician and patient. Hence, alternative drug delivery strategies may reduce the psychological and social impact of this disease.

 

[Michael Scally MD]

Lašait? L, ?eponis J, Preikša RT, Žilaitien? B. Impaired emotional state, quality of life and cognitive functions in young hypogonadal men. Andrologia. Impaired emotional state, quality of life and cognitive functions in young hypogonadal men - La[]ait? - 2013 - Andrologia - Wiley Online Library

The study aimed to analyse emotional state, quality of life and cognitive functions in young hypogonadal men. Thirty-four males with hypogonadism (age 29.1 ± 10.5 years) and 34 age-matched healthy males (age 30.5 ± 11.0 years) were recruited.

Their emotional state was evaluated by Profile of Mood States, quality of life – by WHO Brief Quality of Life Questionnaire – and cognitive functioning – by Trail Making Test and Digit Span Test of Wechsler Adult Intelligence Scale.

It was found that young men with hypogonadism had higher depression-dejection (13.1 ± 8.8 versus 7.4 ± 5.9, P = 0.003), fatigue-inertia (10.0 ± 5.8 versus 7.0 ± 4.9, P = 0.030), confusion-bewilderment (5.1 ± 4.6 versus 2.3 ± 3.1, P = 0.004) and lower vigour-activity (14.3 ± 5.1 versus 17.7 ± 4.3, P = 0.008) levels than age- and sex-matched controls. Quality of life psychological (13.1 ± 2.8 versus 15.1 ± 1.9, P = 0.005) and social (13.6 ± 2.4 versus 15.7 ± 2.0, P < 0.001) domains were significantly worse in men with hypogonadism than in controls.

Cognitive functions were significantly worse (P < 0.001) in men with hypogonadism than in controls, showing worse executive function, attention, visual scanning abilities and psychomotor speed. A significant correlation was found between testosterone concentration and quality of life psychological domain. Cognitive functioning scores were significantly related with FT4 concentration.

It is concluded that young hypogonadal patients have impaired emotional state and quality of life, but the most severe impairment was found in cognitive functioning.

 

[Michael Scally MD]

Pye SR, Huhtaniemi IT, Finn JD, et al. Late-Onset Hypogonadism and Mortality in Aging Men. Journal of Clinical Endocrinology & Metabolism. Late-Onset Hypogonadism and Mortality in Aging Men

Context: Late-onset hypogonadism (LOH) has recently been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of low T. The natural history of LOH, especially its relationship to mortality, is currently unknown.

Objective: The aim of this study was to clarify the associations between LOH, low T, and sexual symptoms with mortality in men.

Design, Setting, and Participants: Prospective data from the European Male Aging Study (EMAS) on 2599 community-dwelling men aged 40’79 years in eight European countries was used for this study.

Main Outcome Measure(s): All-cause, cardiovascular, and cancer-related mortality was measured.

Results: One hundred forty-seven men died during a median follow-up of 4.3 years. Fifty-five men (2.1%) were identified as having LOH (31 moderate and 24 severe). After adjusting for age, center, body mass index (BMI), current smoking, and poor general health, compared with men without LOH, those with severe LOH had a 5-fold [hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.7, 11.4] higher risk of all-cause mortality. Compared with eugonadal men, the multivariable-adjusted risk of mortality was 2-fold higher in those with T less than 8 nmol/L (irrespective of symptoms; HR 2.3; 95% CI 1.2, 4.2) and 3-fold higher in those with three sexual symptoms (irrespective of serum T; compared with asymptomatic men; HR 3.2; 95% CI 1.8, 5.8). Similar risks were observed for cardiovascular mortality.

Conclusions: Severe LOH is associated with substantially higher risks of all-cause and cardiovascular mortality, to which both the level of T and the presence of sexual symptoms contribute independently. Detecting low T in men presenting with sexual symptoms offers an opportunity to identify a small subgroup of aging men at particularly high risk of dying.

 

[Michael Scally MD]

Borst SE, Yarrow JF, Conover CF, et al. Musculoskeletal and Prostate Effects of Combined Testosterone and Finasteride Administration in Older Hypogonadal Men: A Randomized, Controlled Trial. Am J Physiol Endocrinol Metab. Musculoskeletal and Prostate Effects of Combined Testosterone and Finasteride Administration in Older Hypogonadal Men: A Randomized, Controlled Trial | Endocrinology and Metabolism

Testosterone acts directly at androgen receptors and also exerts potent actions following 5alpha-reduction to dihydrotestosterone (DHT). Finasteride (type II 5alpha-reductase inhibitor) lowers DHT and is used to treat benign prostatic hyperplasia. However, it is unknown whether elevated DHT mediates either beneficial musculoskeletal effects or prostate enlargement resulting from higher-than-replacement doses of testosterone. Our purpose was to determine whether administration of testosterone plus finasteride to older hypogonadal men can produce musculoskeletal benefits without prostate enlargement.

60 men aged >/=60 years with a serum testosterone concentration of </= 300 ng/dL or bioavailable testosterone </=70 ng/dL received 52 weeks of treatment with testosterone-enanthate (125mg/week) vs. vehicle, paired with finasteride (5mg/day) vs. placebo using a 2x2 factorial design.

Over the course of 12 months, testosterone-enanthate increased upper and lower body muscle strength by 8-14% (p=0.015 to <0.001), fat-free mass 4.04 kg (p=0.032), lumbar spine bone mineral density (BMD) 4.19% (p<0.001), and total hip BMD 1.96% (p=0.024), while reducing total body fat -3.87kg (p<0.001) and trunk fat -1.88 kg (p =0.0051). In the first 3 months, testosterone increased hematocrit 4.13% (p<0.001). Co-administration of finasteride did not alter any of these effects.

Over 12 months, testosterone also increased prostate volume 11.4 cm3 (p=0.0051), an effect that was completely prevented by finasteride (p=0.0027).

We conclude that a higher-than-replacement testosterone-enanthate, combined with finasteride, significantly increases muscle strength and BMD, and reduces body fat, without causing prostate enlargement. These results demonstrate that elevated DHT mediates testosterone-induced prostate enlargement, but is not required for benefits in musculoskeletal or adipose tissue.

 

[Michael Scally MD]

Handelsman DJ, Newman JD, Jimenez M, McLachlan R, Sartorius G, Jones GR. Performance of Direct Estradiol Immunoassays with Human Male Serum Samples. Clin Chem. Performance of Direct Estradiol Immunoassays with Human Male Serum Samples

BACKGROUND: Steroid immunoassays originally required solvent extraction, chromatography, and structurally authentic tracers to avoid interference from steroid cross-reactivity and matrix effects. The demand for steroid assays has driven assay simplification, bypassing this triplet of validity criteria to allow use of unextracted serum, which has introduced bias and nonspecificity at low steroid concentrations. We aimed to evaluate the performance of commercial direct estradiol (E2) immunoassays relative to the reference method of LC-MS and compared serum E2 measurements from each assay with biomarkers of estrogen action.

METHODS: We measured serum E2 in duplicate using 5 commercial direct immunoassays and LC-MS in a nested cohort of 101 healthy, asymptomatic men >40 years old from the Healthy Man Study. For each immunoassay, we evaluated the detectability and distribution of serum E2 measurements, CV, and bias (relative to LC-MS) by Passing-Bablok regression and deviance plots.

RESULTS: Three assays detected E2 in all samples, whereas E2 was detected in only 53% and 72% of samples by 2 other assays. All 5 assays had positive biases, ranging from 6% to 74%, throughout their ranges. CVs were lower with 4 immunoassays than with LC-MS. LC-MS, but none of the direct immunoassays, correlated with serum testosterone and sex steroid-binding globulin.

CONCLUSIONS: The positive bias of direct E2 immunoassays throughout their working range reflects the nonspecific effects of steroid cross-reactivity and/or matrix interference arising from the violation of the triplet validity criteria for steroid immunoassay.