OnLine First 2013

[Michael Scally MD]

I do not believe that the levels in men require this LoQ, but the note of cross reactivity should be of consideration.

Santen RJ, Demers L, Ohorodnik S, et al. Superiority of gas chromatography/tandem mass spectrometry assay (GC/MS/MS) for estradiol for monitoring of aromatase inhibitor therapy. Steroids 2007;72(8):666-71. Superiority of gas chromatography/tandem mass spectrometry assay (GC/MS/MS) for estradiol for monitoring of aromatase inhibitor therapy

Currently available radioimmunoassay methods for estradiol in serum lack sufficient sensitivity and precision to monitor estradiol levels in patients placed on third generation aromatase inhibitors.

We recently validated a gas chromatography/tandem mass spectrometry assay (GC/MS/MS) for estradiol and determined estrogen levels in normal post-menopausal women and in women with breast cancer before and during administration of aromatase inhibitors.

Validation of the GC/MS/MS assay in human plasma and human serum included determination of assay sensitivity (<0.63 pg/ml), precision (all CVs less than 17.8%), recovery (98-103%), and linearity of recovery (R=0.998). Levels of estradiol were lower when assayed by GC/MS/MS compared to RIA under all conditions (7.26+/-4.82 pg/ml versus 11.9+12.0 pg/ml in normal post-menopausal women; 5.88+/-3.43 pg/ml versus 13.8+/-7.5 pg/ml in breast cancer patients prior to treatment; and<0.63 pg/ml versus 5.8+/-4.1 pg/ml during aromatase inhibitor therapy). Fifty-five women treated either with atamestane/toremiphene or letrozole/placebo were monitored for estradiol levels at 4, 8 and 12 weeks of therapy.

The mean levels of estradiol during aromatase inhibitor therapy was 5.8+/-4.1 pg/ml as measured by RIA and <0.63 pg/ml by GC/MS/MS. The degree of suppression with the aromatase inhibitors as detected by RIA was 58% versus >89% by GC/MS.

These results suggest that most RIA methods detect cross-reacting estrogen metabolites and yield higher measured levels than GC/MS/MS. Several pharmacological and clinical considerations suggest that GC/MS/MS should become the preferred method for monitoring aromatase inhibitor therapy.

 

[Michael Scally MD]

Macdonald AA, Stewart AW, Farquhar CM. Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics. Hum Reprod. http://humrep.oxfordjournals.org/content/early/2013/10/14/humrep.det379.abstract

STUDY QUESTION: Is there an association between body mass index (BMI) and routine semen analysis parameters in adult men?

SUMMARY ANSWER: No significant correlation was found between BMI and semen parameters measured with the exception of normal sperm morphology.

WHAT IS KNOWN ALREADY: Multiple cross-sectional studies have found inconsistent results, with two meta-analyses finding no correlation between BMI and semen parameters. A relationship between BMI and male reproductive hormones, particularly total testosterone, has been established in several studies and a systematic review.

STUDY DESIGN, SIZE, DURATION: Cross-sectional study of 511 men recruited at the time of semen analysis over 4 years (2008-2012).

PARTICIPANTS/MATERIALS, SETTING, METHODS: Men presenting for semen analysis for any reason at participating fertility clinics in Auckland, New Zealand were recruited, with BMI measured or self-reported at this time. Exclusion criteria included azoospermia and pathological conditions of male genital tract. Conventional BMI categories were used (underweight <18.5 kg/m2, normal 18.5-24.99 kg/m2, overweight 25.00-29.99 kg/m2, obese >/=30 kg/m2). The routine semen analysis results for sperm concentration, total sperm count, sperm motility (total motility), sperm morphology, semen volume and total motile sperm (primary outcome) from one semen sample were recorded. Consent from 175 men was obtained to measure LH, FSH, estradiol, total testosterone, free testosterone and sex hormone-binding globulin (SHBG) in a blood sample (secondary outcome). Associations between BMI and these outcomes were assessed using Spearman correlation and analysis of variance, and a multiple linear regression analysis was performed. In addition, the relative risks for men having abnormal semen analysis results according to reference ranges of the World Health Organization, such as oligozoospermia, were calculated. This study has sufficient power to detect a doubling in abnormally low sperm concentration and total sperm count in overweight or obese men compared with men with normal BMI. Participation rate was not recorded.

MAIN RESULTS AND THE ROLE OF CHANCE: The body mass indices from measured and self-reported samples had an equivalent range of values which did not differ statistically. Median BMI was 27.1 kg/m2 [10th-90th percentile: 22.8-32.9]. Overall, 72.8% of the study population were overweight or obese (BMI >25 kg/m2), while 19 men (3.72%) had a BMI of 35-40 kg/m2 and 7 men (1%) had a BMI of >40 kg/m2. No significant correlation was found between BMI and the semen parameters measured with the exception of normal sperm morphology (r = 0.12, P = 0.024), although this finding is derived from only 330 samples. Overweight and obese men showed no significantly increased relative risk of abnormal semen parameters. Of the reproductive hormones, significant negative relationships with BMI were found for total testosterone (r = -0.35, P = <0.0001), free testosterone (r = -0.25, P = <0.0012) and SHBG (r = -0.44, P = <0.0001). Multiple linear regression analysis also showed that BMI had a marginally significant effect on normal sperm morphology (effect estimate =0.47, P = 0.038). In addition, <2 days of abstinence was negatively associated with semen volume (effect estimate =-0.80, P = 0.0074) and summer season was negatively associated with sperm concentration (effect estimate =-14.9, P = 0.020).

LIMITATIONS, REASONS FOR CAUTION: The power of this study is limited by the relatively small overall sample size, although it does have one of the largest proportions of obese men (23.3%) in published cross-sectional studies. The study involved samples from men attending a fertility clinic, who are likely to have a lower semen quality and higher rate of pathology compared with the general population, therefore limiting the possible generalization of this study to all adult men.

WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with those of other cross-sectional studies as well as two meta-analyses but do disagree in part with the most recent meta-analysis (which found significant odds ratios for oligozoospermia and azoospermia with increased BMI) and with studies measuring DNA fragmentation index. Therefore a definitive conclusion on the effect of BMI on semen quality remains uncertain while our data reinforce previous findings that BMI is negatively associated with male reproductive hormones.

STUDY FUNDING/COMPETING INTEREST(S): All funding for this study was from New Zealand academic and charitable sources including: Faculty of Medical and Health Sciences, University of Auckland (New Zealand), the Mercia Barnes Trust of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists and the Nurture Foundation for Reproductive Research. The authors have no conflicts of interest to declare.

 

[Michael Scally MD]

Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study - Traish - 2013 - International Journal of Clinical Practice - Wiley Online Library

AIM: The goal of this study was to determine if long-term testosterone (T) therapy in men with hypogonadism, henceforth referred to as testosterone deficiency (TD), ameliorates or improves metabolic syndrome (MetS) components.

METHODS: We performed a cumulative registry study of 255 men, aged between 33 and 69 years (mean 58.02 +/- 6.30) with subnormal plasma total T levels (mean: 9.93 +/- 1.38; range: 5.89-12.13 nmol/l) as well as at least mild symptoms of TD assessed by the Aging Males' symptoms scale. All men received treatment with parenteral T undecanoate 1000 mg (Nebido(R) , Bayer Pharma, Berlin, Germany), administered at baseline and 6 weeks and thereafter every 12 weeks for up to 60 months. Lipids, glucose, liver enzymes and haemoglobin A1c analyses were carried out in a commercial laboratory. Anthropometric measurements were also made throughout the study period.

RESULTS: Testosterone therapy restored physiological T levels and resulted in reductions in total cholesterol (TC) [7.29 +/- 1.03 to 4.87 +/- 0.29 mmol/l (281.58 +/- 39.8 to 188.12 +/- 11.31 mg/dl)], low-density lipoprotein cholesterol [4.24 +/- 1.07 to 2.84 +/- 0.92 mmol/l (163.79 +/- 41.44 to 109.84 +/- 35.41 mg/dl)], triglycerides [3.14 +/- 0.58 to 2.16 +/- 0.13 mmol/l (276.16 +/- 51.32 to 189.78 +/- 11.33 mg/dl)] and increased high-density lipoprotein levels [1.45 +/- 0.46 to 1.52 +/- 0.45 mmol/l (56.17 +/- 17.79 to 58.85 +/- 17.51 mg/dl)] (p < 0.0001 for all). There were marked reductions in systolic and diastolic blood pressure, blood glucose, haemoglobin A1c , C-reactive protein (6.29 +/- 7.96 to 1.03 +/- 1.87 U/l), alanine aminotransferase and aspartate aminotransferase (p < 0.0001 for all).

CONCLUSIONS: Long-term T therapy, at physiological levels, ameliorates MetS components. These findings strongly suggest that T therapy in hypogonadal men may prove useful in reducing the risk of cardiometabolic diseases.

 

[Michael Scally MD]

Also, see: YK11 Is a Partial Agonist of the Androgen Receptor https://thinksteroids.com/community/posts/750865

Kanno Y, Ota R, Someya K, Kusakabe T, Kato K, Inouye Y. Selective Androgen Receptor Modulator, YK11, Regulates Myogenic Differentiation of C2C12 Myoblasts by Follistatin Expression. Biol Pharm Bull 2013;36(9):1460-5. https://www.jstage.jst.go.jp/article/bpb/36/9/36_b13-00231/_html

The myogenic differentiation of C2C12 myoblast cells is induced by the novel androgen receptor (AR) partial agonist, (17alpha,20E)-17,20-[(1-methoxyethylidene)bis-(oxy)]-3-oxo-19-norpregna-4,20-dien e-21-carboxylic acid methyl ester (YK11), as well as by dihydrotestosterone (DHT). YK11 is a selective androgen receptor modulator (SARM), which activates AR without the N/C interaction. In this study, we further investigated the mechanism by which YK11 induces myogenic differentiation of C2C12 cells. The induction of key myogenic regulatory factors (MRFs), such as myogenic differentiation factor (MyoD), myogenic factor 5 (Myf5) and myogenin, was more significant in the presence of YK11 than in the presence of DHT. YK11 treatment of C2C12 cells, but not DHT, induced the expression of follistatin (Fst), and the YK11-mediated myogenic differentiation was reversed by anti-Fst antibody. These results suggest that the induction of Fst is important for the anabolic effect of YK11.

 

[Michael Scally MD]

Schroeder ET, Villanueva M, West DD, Phillips SM. Are Acute Post-Resistance Exercise Increases in Testosterone, Growth Hormone, and IGF-1 Necessary to Stimulate Skeletal Muscle Anabolism and Hypertrophy? Med Sci Sports Exerc 2013;45(11):2044-51. Are Acute Post–Resistance Exercise Increases in Testosterone... : Medicine & Science in Sports & Exercise

Acute post–resistance exercise (RE) increases in anabolic hormones may not be “necessary” to stimulate skeletal muscle anabolism and hypertrophy; however, as we will support in the following discussion, post-RE increases in these hormones are “optimal” for maximizing skeletal muscle anabolism and hypertrophy.

For purposes of this presentation, increases in testosterone (T) and growth hormone (GH) will also imply increases in insulinlike growth factor 1 (IGF-1).

Studies examining the influence of acute RE-induced T and GH responses on skeletal muscle anabolism have included both trained and untrained young (18–30 yr) and older (60–80 yr) men.

There is strong evidence that RE can result in substantial postexercise elevations in anabolic hormones.

So the question posed is, “Do these acute RE-induced elevations in T and GH translate into skeletal muscle anabolism and hypertrophy?”

It is time to write the requiem for studies that measure only postexercise hormonal responses and infer a potential effect on hypertrophy.

We find that the evidence for such an assertion lacking and causal interpretation unwarranted given the lack of evidence that exercise-induced hormones are important in regulating hypertrophy after resistance exercise.

Moreover, pharmacologic ablation and exogenous androgen administration are not appropriate models from which to draw conclusions about the effect of exercised-induced changes in hormonal concentrations on hypertrophy.

 

[Michael Scally MD]

Pollock RF, Qian Y, Wisniewski T, Seitz L, Kappelgaard AM. Product wastage from modern human growth hormone administration devices: a laboratory and computer simulation analysis. Med Devices (Auckl) 2013;6:107-14. Product wastage from modern human growth hormone administration devices: a laboratory and computer simulation analysis

BACKGROUND: Treatment of growth hormone disorders typically involves daily injections of human growth hormone (GH) over many years, incurring substantial costs. We assessed the extent of undesired GH loss due to leakage in the course of pen preparation prior to injection, and differences between the prescribed dose, based on patient weight, and the actual delivered dose based on pen dosing increments in five GH administration devices.

METHODS: Norditropin(R) prefilled FlexPro(R), NordiFlex(R), NordiLet(R), and durable NordiPen(R)/SimpleXx(R) 5 mg pens (Novo Nordisk A/S, Bagsvaerd, Denmark) and durable Omnitrope(R) Pen-5 devices (Sandoz, Holzkirchen, Germany) were tested (n = 40 for each device type). Product wastage was measured in accordance with validated protocols in an ISO (International Organization for Standardization) 11608-1 and Good Manufacturing Practice compliant laboratory. The average mass of wasted GH from each device type was measured in simulations of dripping with the needle attached prior to injection and while setting a dose. Statistical significance (P < 0.05) was confirmed by Student's t-test, and a model was constructed to estimate mean annual GH wastage per patient in cohorts of pediatric patients with GH disorders.

RESULTS: Mean GH mass wasted with the needle on prior to injection was 0.0 mug with Norditropin pens, relative to 98 mug with Omnitrope Pen-5. During dose dialing, 0.0-2.3 mug of GH was lost with Norditropin pens versus 0.8 mug with Omnitrope Pen-5. All Norditropin and Omnitrope device comparisons were statistically significant. Modeling GH wastage in a US cohort showed 5.5 mg of annual GH wastage per patient with FlexPro versus 43.6 mg with Omnitrope, corresponding to 7-8 additional pens per patient annually.

CONCLUSION: Overall, Norditropin pens resulted in significantly less wastage than the Omnitrope Pen-5. The study suggests that GH devices of the same nominal volume exhibit differences that may affect the frequency of GH prescription refills required to remain adherent to therapy.

 

[Michael Scally MD]

Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A. Effects of 5-Year Treatment With Testosterone Undecanoate on Lower Urinary Tract Symptoms in Obese Men With Hypogonadism and Metabolic Syndrome. Urology. Effects of 5-Year Treatment With Testosterone Undecanoate on Lower Urinary Tract Symptoms in Obese Men With Hypogonadism and Metabolic Syndrome

OBJECTIVE: To investigate the possible effects of testosterone undecanoate (TU) injections in a population of obese (mean age 57) hypogonadal men with lower urinary tract symptoms (LUTS) in a long-term observational study.

METHODS: Twenty obese hypogonadal men with metabolic syndrome were treated with TU injections every 12 weeks for 60 months; also 20 matched subjects in whom TU was unaccepted or contraindicated were used as controls. LUTS severity and the impact of TU injections were assessed by differences in International Prostate Symptom Score (IPSS), maximum urinary flow (Qmax) rate in milliliters, post-void residual (PVR) volume, and prostate size every 12 months in a 5-year controlled study.

RESULTS: TU injections did not produce differences in IPSS, Qmax, PVR, and prostate size in both groups. No modification in prostate-specific antigen (PSA) and hematocrit levels was also found between the 2 groups. Interestingly, controls showed increased incidence of prostatitis than TU-treated men (10% vs 30%, P <.01).

CONCLUSION: We showed that 5 years of TU treatment did not change IPSS, PVR, Qmax, or prostate size in obese hypogonadal men with metabolic syndrome and moderate LUTS at baseline. Therefore, long-term TU replacement therapy is a safe and effective treatment for reverting hypogonadal features related to metabolic syndrome and does not impact negatively on LUTS and prostate volume.

 

[Michael Scally MD]

Mazur A, Westerman R, Mueller U. Is Rising Obesity Causing a Secular (Age-Independent) Decline in Testosterone among American Men? PLoS One 2013;8(10):e76178. PLOS ONE: Is Rising Obesity Causing a Secular (Age-Independent) Decline in Testosterone among American Men?

The testosterone of men in industrial societies peaks in their twenties and tends to decline with increasing age. Apart from this individual-level decline, there have been reports of a secular (age-independent population-level) decline in testosterone among American and Scandinavian men during the past few decades, possibly an indication of declining male reproductive health. It has been suggested that both declines in testosterone (individual-level and population-level) are due to increasing male obesity because men in industrial society tend to add body fat as they age, and overall rates of obesity are increasing. Using an unusually large and lengthy longitudinal dataset (991 US Air Force veterans examined in six cycles over 20 years), we investigate the relationship of obesity to individual and population-level declines in testosterone. Over twenty years of study, longitudinal decline in mean testosterone was at least twice what would be expected from cross-sectional estimates of the aging decline. Men who put on weight intensified their testosterone decline, some greatly so, but even among those who held their weight constant or lost weight during the study, mean testosterone declined 117 ng/dl (19%) over 20 years. We have not identified the reason for secular decline in testosterone, but we exclude increasing obesity as a sufficient or primary explanation, and we deny the supposition that men who avoid excessive weight will maintain their youthful levels of testosterone.

 

[Michael Scally MD]

Liu Z, Ye F, Zhang H, et al. The Association between the Levels of Serum Ferritin and Sex Hormones in a Large Scale of Chinese Male Population. PLoS One 2013;8(10):e75908. PLOS ONE: The Association between the Levels of Serum Ferritin and Sex Hormones in a Large Scale of Chinese Male Population

BACKGROUND: The ferritin is an important participant of iron-storage but its regulation and related factors were not well defined. The present objective was to explore the potential association between serum ferritin levels and sex hormones.

METHODS: 1999 Chinese men in the Fangchenggang Area Male Health and Examination Survey (FAMHES) were recruited in this cross-sectional study. Levels of serum ferritin, total testosterone (free testosterone was calculated from the total one), estradiol and sex hormone-binding protein were detected in venous blood samples. The effects of age, BMI, smoking as well as alcohol consumption were analyzed on ferritin levels, respectively, and then the Pearson's correlation analysis was used to evaluate the association between ferritin levels and sex hormones adjusting for the above factors.

RESULTS: The age, BMI and alcohol consumption significantly affected serum ferritin levels, but there was no significant difference between smokers and nonsmokers. Ferritin levels were significantly and negatively associated with total testosterone (R = -0.205, P< 0.001), sex hormone-binding protein (R = -0.161, P<0.001) and free testosterone (R = -0.097, P<0.001). After age and alcohol consumption were adjusted, the above associations were still significant (R = -0.200, -0.181 and -0.083, respectively, all P<0.001). However, there was only borderline negative association between ferritin levels and estradiol (adjusted R = -0.039, P = 0.083).

CONCLUSION: The large scale of epidemic results showed the significantly negative associations between serum ferritin levels and sex hormones, which may provide more clues to explore the potential regulation and biological mechanism of ferritin.

 

[Michael Scally MD]

Saleh BO, Majeed MJ. Andropause phenomenon by measurement of serum free testosterone concentration in Iraqi healthy men. Age related study. Saudi Med J 2013;34(10):1026-9. http://www.smj.org.sa/DetailArticle.asp?ArticleId=6125

OBJECTIVE: To investigate the andropause phenomenon in Iraqi healthy subjects by evaluating serum free testosterone (FT) concentrations in association with age.

METHODS: This study was carried out at the Biochemistry Department, College of Medicine, University of Baghdad, between February 2012 and October 2012. This cross sectional control subject's study included 251 healthy Iraqi men with an age range of 20-82 years. Subjects were divided into variant age groups, group 1 (20-40 years, n=16), group 2 (40-60 years, n=165) and group 3 (60-82 years, n=70), group A-I (<50 years, n=137) and group A-II (>/=50 years, n=114), and group B-I (<60 years, n=215) and group B-II (>/=60 years, n=36). Serum FT concentrations were measured by using enzyme-linked immunosorbent assay technique.

RESULTS: The results revealed significant negative correlation between serum FT concentrations and the age values of the studied subjects (r= -0.231, p=0.0001). The mean (+/-SEM) value of serum FT concentrations was significantly decreased in group 3 when compared with that of group 1 (p<0.009) and group 2 (p=0.031) as well as in group BII than in group BI (p=0.043).

CONCLUSION: This study found significant decline in serum FT level, the gold test for andropause phenomenon, in healthy male subjects in age-related changes and the cutoff at which such significant decrease occurred is at 60 years of age and above.

 

[Michael Scally MD]

Gao S, Geng YJ. LOX-1: a Male Hormone-regulated Scavenger Receptor for Atherosclerosis. Vascul Pharmacol. https://www.sciencedirect.com/science/article/pii/S1537189113001183

Lectin-like oxidized LDL receptor-1 (LOX-1) is a unique scavenger receptor that mediates the binding and uptake of oxidized LDL (ox-LDL) by vascular cells during the development of atherosclerosis. Exposure to ox-LDL induces LOX-1 expression and LOX-1-dependent biological activities, such as activation of NF-kappaB, a nuclear factor important for signal transduction in inflammation. Accumulating evidence indicates that male hormones may regulate expression of LOX-1 and NF-kappaB as well as atherogenesis.

Deficiency or low levels of the male hormone testosterone promotes LOX-1 expression and NF-kappaB activation, while testosterone replacement therapy reduces the expression of LOX-1 and the activation of NF-kappaB, thereby protecting the arterial wall against atherogenesis.

 

[Michael Scally MD]

Anawalt BD. Approach to Male Infertility and Induction of Spermatogenesis. Journal of Clinical Endocrinology & Metabolism 2013;98(9):3532-42. Approach to Male Infertility and Induction of Spermatogenesis

Male subfertility is common, and it causes significant duress to couples. Although the most common cause of male subfertility is idiopathic failure of spermatogenesis, a significant percentage of male subfertility is medically treatable. Compared to reproductive specialists, endocrinologists may see a population of men that have a higher prevalence of treatable causes of subfertility including sexual disorders, endocrinopathies, obesity, drugs, and ejaculatory dysfunction. Seminal fluid analysis is the most important diagnostic study, and at least 2 samples should be analyzed. All patients with sperm concentrations < 10 million/mL due to idiopathic spermatogenic defects should be referred for genetic counseling and karyotyping; most experts also recommend that these patients be tested for Y chromosomal microdeletions. For most men with low sperm concentrations due to gonadotropin deficiency, gonadotropin therapy effectively increases spermatogenesis. The endocrinologist must recognize when to use medical therapy to stimulate spermatogenesis and when to refer for consideration of assisted reproductive technology.

 

[Michael Scally MD]

Park MG, Koo HS, Lee B. Characteristics of testosterone deficiency syndrome in men with chronic kidney disease and male renal transplant recipients: a cross-sectional study. Transplant Proc 2013;45(8):2970-4. Characteristics of Testosterone Deficiency Syndrome in Men With Chronic Kidney Disease and Male Renal Transplant Recipients: A Cross-Sectional Study

OBJECTIVES: Testosterone deficiency syndrome (TDS) is common among male patients with chronic kidney disease (CKD). We compared the characteristics of TDS in men with CKD versus renal transplantation (RT) with those of age-matched normal controls.

MATERIALS AND METHODS: The 129 patients were: RT recipients (n = 25) group I, CKD patients (n = 37) group II, and controls (n = 67). We performed estimates of testosterone, hemoglobin (Hgb), hematocrit (Hct), glucose, creatinine, and lipid profile. Self-assessment questionnaires-International Index of Erectile Function (IIEF), Aging Males' Symptoms (AMS), Center for Epidemiologic Studies Depression Scale-were used to evaluate erectile function, testosterone deficiency, and depression, respectively. We also investigated morning erection as well as the presence and duration of erectile dysfunction (ED).

RESULTS: Group I (RT) showed significantly higher serum testosterone levels than group II (CKD), who displayed significantly worse erectile function, more severe testosterone deficiency symptoms, and a greater trend toward depression. Similarly, the prevalences of ED and TDS were significantly greater in group II than group I. Group I and controls differed significantly only in the results of serologic tests, such as serum creatinine, Hgb, and glucose and lipid profiles, but not in serum testosterone levels, scores of self-assessment questionnaires, or prevalence of ED or TDS. Serum testosterone levels correlated significantly with scores on the IIEF and AMS questionnaires in both group II and controls, but not group I.

CONCLUSIONS: RT recipients showed higher serum testosterone levels and a lower prevalence of TDS with milder symptom severity than CKD patients. RT recipients beyond the early acute posttransplant period, displayed serum testosterone levels and TDS prevalence similar to those of healthy controls. Unlike CKD patients and normal controls, serum testosterone did not significantly influence TDS symptoms in RT recipients.

 

[Michael Scally MD]

Stanworth RD, Akhtar S, Channer K, Jones TH. The role of the androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and tpye 2 diabetes - TIMES2 sub-study. European Journal of Endocrinology. The role of the androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and tpye 2 diabetes - TIMES2 sub-study

Context. The TIMES2 study reported beneficial effects of testosterone replacement therapy on insulin resistance and other variables in men with diabetes or metabolic syndrome. The androgen receptor CAG repeat polymorphism (AR CAG) is known to affect stimulated androgen receptor activity and has been linked to various clinically relevant variables.

Objective. Assess role of AR CAG in altering clinical response to testosterone replacement therapy in the TIMES2 study.

Design. Subgroup analysis from a multicentre, randomised, double-blind, placebo-controlled, parallel group study

Setting. Outpatient study recruiting from secondary and primary care

Patients. 139 men with hypogonadism and type 2 diabetes or metabolic syndrome. 73 of these men received testosterone during the TIMES2 study.

Intervention. Testosterone 2% transdermal gel versus placebo

Main outcome measure. Regression coefficient of AR CAG from linear regression models for each variable.

Results. AR CAG was independently positively associated with change in fasting insulin, triglycerides and diastolic blood pressure during testosterone replacement therapy with a trend to association with HOMA-IR- the primary outcome variable. There was a trend to negative association between AR CAG and change in PSA. There was no association of AR CAG with change in other glycaemic variables, other lipid variables or obesity.

Conclusion. AR CAG affected response of some variables to testosterone replacement therapy in the TIMES2 study although the association with HOMA-IR did not reach significance. Various factors may have limited the power of our study to detect significant associations between AR CAG, testosterone levels and change in variables with testosterone treatment. Analysis of similar data sets from other clinical trials is warranted.

 

[Michael Scally MD]

Khadilkar V, Radjuk KA, Bolshova E, et al. 24-Month Use of Once-Weekly GH, LB03002, in Prepubertal Children with GH Deficiency. Journal of Clinical Endocrinology & Metabolism. http://jcem.endojournals.org/content/early/2013/10/28/jc.2013-2502.abstract

Background: Sustained-release GH formulations may provide a strategy for improving treatment compliance and persistence in GH-deficient patients.
Objective: To examine efficacy and safety of LB03002, a sustained-release GH formulation for once-weekly administration.

Design: Phase III, 12-month, multinational, randomized, open-label, comparator-controlled trial, with a 12-month uncontrolled extension.
Patients: Prepubertal GH-treatment-naïve GH-deficient children (mean age 7.8 years)

Intervention: Once-weekly LB03002 (N=91) or daily GH (N=87) for 1 year, followed by once-weekly LB03002 for all patients for another year (LB03002 throughout N=87; switched to LB03002 N=80).

Outcome measures: Height, height velocity (HV), IGF-I, GH antibodies, and adverse events determined throughout. Primary analysis was non-inferiority of LB03002 versus daily GH at 1 year by ANCOVA.

Results: Mean (±SD) HV during year 1 was 11.63 ± 2.60 cm/year with LB03002 and 11.97 ± 3.09 cm/year with daily GH, with respective increases from baseline of 8.94 ± 2.91 cm/year and 9.04 ± 3.19 cm/year. Least square mean HV difference for LB03002 – daily GH was -0.43 cm/year (99% CI -1.45 to 0.60 cm/year). Mean HV also remained above baseline in year 2 (8.33 ± 1.92 cm/year in the LB03002 throughout group and 7.28 ± 2.34 cm/year in the switched to LB03002 group). Injection site reactions occurred more frequently in LB03002-treated patients, but were considered mild to moderate in >90% of cases.

Conclusions: Growth response with once-weekly LB03002 in GH-deficient children is comparable to that with daily GH, achieving expected growth rates for 24 months. Once-weekly LB03002 is a strong candidate for long-term GH replacement in GH-deficient children.

 

[Michael Scally MD]

Akita K, Harada K, Ichihara J, Takata N, Takahashi Y, Saito K. A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain, without serious side effects on prostate. Eur J Pharmacol. A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate

Age-related androgen depletion is known to be a risk factor for various diseases, such as osteoporosis and sarcopenia. Furthermore, recent studies have demonstrated that age-related androgen depletion results in accumulation of beta-amyloid protein and thereby acts as a risk factor for the development of Alzheimer's disease. Supplemental androgen therapy has been shown to be efficacious in treating osteoporosis and sarcopenia. In addition, studies in animals have demonstrated that androgens can play a protective role against Alzheimer's disease.

However, androgen therapy is not used routinely for these indications, because of side effects. Selective androgen receptor modulators (SARMs) are a new class of compounds. SARMs maintain the beneficial effects of androgens on bone and muscle while reducing unwanted side effects. NEP28 is a new SARM exhibiting high selectivity for androgen receptor.

To investigate the pharmacological effects of NEP28, we compared the effects on muscle, prostate, and brain with mice that were androgen depleted by orchidectomy and then treated with either placebo, NEP28, dihydrotestosterone, or methyltestosterone. We demonstrated that NEP28 showed tissue-selective effect equivalent to or higher than existing SARMs. In addition, the administration of NEP28 increased the activity of neprilysin, a known Abeta-degrading enzyme.

These results indicate that SARM is efficacious for the treatment of not only osteoporosis and sarcopenia, but also Alzheimer's disease.

 

[Michael Scally MD]

Schulte DM, Hahn M, Oberhauser F, et al. Caloric Restriction Increases Serum Testosterone Concentrations in Obese Male Subjects by Two Distinct Mechanisms. Horm Metab Res. https://www.thieme-connect.de/ejournals/abstract/10.1055/s-0033-1358678

The concentration of serum testosterone is mainly regulated by the testicular function, which is under control of the central hypothalamic-pituitary-gonadal axis. A certain amount of testosterone is converted into beta-estradiol by adipose tissue. Obesity in men is often associated with decreased androgen levels.

The aim of the present study was to examine the effect of caloric restriction on serum testosterone levels in obese men. Dietary intervention study was performed with a very low calorie diet (800 kcal/d) for 12 weeks. Thirteen obese human male subjects (median body mass index: 42.7 kg/m2) were included. Body composition was assessed by impedance analysis. Insulin sensitivity was estimated by leptin-to-adiponectin ratio (LAR). Testosterone (T), beta-estradiol, albumin, sex hormone-binding globulin (SHBG), LH, and FSH serum concentrations were measured by enzyme immunoassays. Statistical analysis was performed on baseline and values after 3 months.

Caloric restriction significantly increased total testosterone (6.97 nmol/l to 13.21 nmol/l; p=0.001) and SHBG (22.11 nmol/l to 42.12 nmol/l; p=0.001) concentrations in serum. This is caused by a significant improvement of the testicular function (LH/T: 0.36-0.20; p=0.005) and a significant reduction of the T/beta-estradiol conversion rate (73.59-104.29; p=0.003). There was a significant negative correlation of improvement of testicular function and LAR (rs=-0.683 (p=0.042)).

In obese men caloric restriction significantly increases the serum testosterone concentration. This is achieved by 2 distinct mechanisms, that is, improvement of testicular function and reduced conversion of testosterone to beta-estradiol by aromatase activity of the adipose tissue.

 

[Michael Scally MD]

Rajan TV, Kerstetter J, Feinn R, Kenny A. Evidence for low androgenicity among Indian (South Asian) men. Aging Male. An Error Occurred Setting Your User Cookie

There are increasing data indicating profound ethnic differences in the levels of virilization of males [1-4]. It is well understood that the intensity of testosterone-mediated effects is modulated by sex hormone binding globulin (SHBG) [5] and the CAG repeat lengths in the androgen receptor (AR) gene [6]. We determined the serum testosterone, estradiol and SHBG levels and average CAG repeat lengths among a group of healthy older Indian men living in Connecticut, USA and compared these parameters with those of a reference group of white Caucasian men. We also compared various parameters that represent the end-manifestations of testosterone activity - serum prostate-specific antigen (PSA) levels, lean body mass, skeletal mineralization and visceral fat. Our data suggest that men from the Indian subcontinent are smaller, manifest lower levels of circulating free testosterone, lower mean PSA levels and lean body mass, but are comparable to white Caucasian men in terms of SHBG, estradiol, levels of visceral fat and CAG repeat length. These data suggest that Indian men manifest a lower level of virilization compared to white Caucasian males and that this might be due to lower mean circulating testosterone levels rather than higher AR CAG repeat length or SHBG.

 

[Michael Scally MD]

Brusca MI, Verdugo F, Amighini C, Albaina O, Moragues MD. Anabolic steroids affect human periodontal health and microbiota. Clin Oral Investig. Anabolic steroids affect human periodontal health and microbiota - Online First - Springer

OBJECTIVES: This study aims to evaluate periodontal microbiological differences between systemically healthy nonsmoker males taking anabolic androgenic steroids (AASs) and non-AAS users and to find associations between disease severity and AAS use.

METHODS: Ninety-two men practicing bodybuilding were included in the study. They were divided into AAS users and a matched control nonuser group and subgrouped based on their most severe periodontal condition. Pooled subgingival samples from each individual were cultured to evaluate specific periodontopathogen infection.

RESULTS: AAS users had significantly higher prevalence of severe periodontitis. AAS users had greater gingival inflammation and clinical attachment loss of >/=3 mm than nonusers (odds ratio (OR) = 2.4; p = 0.09; 95 % confidence interval (CI) 0.8-6.4). AAS users were 4.9 times more likely to be infected with Prevotella intermedia than AAS nonusers (OR = 4.9; p = 0.003; 95 % CI 1.6-14.7). The OR of presenting subgingival Aggregatibacter actinomycetemcomitans was 8.2 times higher in AAS users (OR = 8.2; p = 0.03; 95 % CI 0.9-70.8). AAS users were 5.6 times more likely to present subgingival Candida spp. than nonusers (OR = 5.6; p = 0.02; 95 % CI 1.1-27.1). AAS users were 14.8 times more likely to present subgingival Candida parapsilosis than nonusers (OR = 14.8; p < 0.0001; 95 % CI 3.1-69.2). The likelihood of AAS users presenting subgingival Candida tropicalis was 4.3 times higher than nonusers (OR = 4.3; p = 0.03; 95 % CI 1.1-16.9). A. actinomycetemcomitans was mostly isolated in individuals with severe periodontitis and was associated with subgingival Porphyromonas gingivalis, P. intermedia, and Candida spp.

CONCLUSIONS: AAS use may increase the risk for severe periodontitis and may cause a subgingival selection of certain Candida species. Specific periodontopathogens, such as Candida dubliniensis and Candida albicans, seem to be negatively affected by AAS use. The higher risk for disease progression in AAS users may be explained by the significantly higher proportions of A. actinomycetemcomitans, P. gingivalis, P. intermedia, and Candida species as compared to controls.

CLINICAL SIGNIFICANCE: Data on the influence of AAS on subgingival periodontopathogens and disease progression are scarce. Higher proportions of specific periodontopathogens are plausible in AAS users. AAS users had a higher prevalence of severe periodontitis, gingival inflammation, and clinical attachment loss. Men taking AAS are at greater risk of periodontitis and specific periodontopathogen infection.

 

[Michael Scally MD]

Hassan A, Elhanbly S, El-Mogy MS, Mostafa T. Triorchidism: two case reports. Andrologia. http://onlinelibrary.wiley.com/doi/10.1111/and.12192/abstract

In this study, two cases of triorchidism are reported. The first case (29 years) had two right discrete ovoid nontender, firm, mobile lumps with testicular sensation. The second case (32 years) had two left discrete ovoid nontender, firm, mobile lumps with normal testicular sensation. They were subjected to the estimation of serum follicle-stimulating hormone, luteinising hormone, free and total testosterone, alpha-fetoprotein, prostate-specific antigen, karyotyping and semen analysis. Imaging included ultrasonography, transrectal ultrasound, magnetic resonance imaging and intravenous pyelography. The first case had two testes in the right side. Each one had an epididymis where one vas deferens was palpated. The second case had two left testes with normal testicular sensation. The lower left lump represented normal-sized testis attached to its epididymis and a single palpated vas deferens. Diagnosis of the first case was triorchidism associated with left varicocele (grade I) with oligoasthenoteratozoospermic semen profile. Intracytoplasmic sperm injection was carried out resulting in a twin. Diagnosis of the second case was triorchidism with accessory testis on the left side associated with left varicocele (grade I) and asthenozoospermic semen profile that was submitted to medical treatment. It is concluded that triorchidism is an uncommon congenital anomaly that should be not overlooked in diagnosing scrotal masses.