OnLine First 2013

[Michael Scally MD]

Tkaczyszyn M, Nega K, Majda J, et al. Andropausal syndrome in men with systolic heart failure. Pol Arch Med Wewn. Andropausal syndrome in men with systolic heart failure | POLSKIE ARCHIWUM MEDYCYNY WEWN?TRZNEJ

INTRODUCTION Andropausal syndrome (AS) is an element of male aging, being associated with the age-related decline in circulating androgens.

OBJECTIVES We investigated the prevalence of AS, the severity of andropausal symptoms, and their clinical and hormonal determinants in men with heart failure (HF) and healthy peers.

PATIENTS AND METHODS We examined 232 men with systolic HF aged 40-80 years (New York Heart Association [NYHA] class I/II/III-IV: 17/54/29 %, left ventricular ejection fraction: 30+/-8%) and 362 healthy peers. 17 andropausal symptoms were assessed using the Aging Male Symptoms' Rating Scale.

RESULTS In men with HF aged 40-59 years, the prevalence of AS and the severity of andropausal symptoms were greater than in healthy peers (28 vs. 7%, 40+/-14 vs. 35+/-10 points, both P<0.001), whereas in the age group of 60-80 years, there were no differences in either the prevalence of AS or the severity of andropausal symptoms between men with HF vs. healthy peers (31 vs. 40%, 44+/-12 vs. 46+/-10 points, both P>0.1). In men with HF aged 40-59 years, advanced NYHA class, low haemoglobin, increased platelet number, and low serum dehydroepiandrosterone sulphate were independently associated with the greater prevalence of AS (all P<0.05), whereas in those aged 60-80 years only reduced haemoglobin was borderline related to the higher prevalence of AS (P=0.07).

CONCLUSIONS AS affects almost one third of men with HF, regardless of the age group. Clinical and hormonal associates differ between younger and older male patients. Endocrinological and sexual counseling is advisable in men with HF.

 

[Michael Scally MD]

Statins & Testosterone

Sniderman AD, Thanassoulis G. Do statins lower testosterone and does it matter? BMC Med 2013;11(1):58. BMC Medicine | Abstract | Do statins lower testosterone and does it matter?

Drugs are two-sided swords and statins are no exception. Schooling et al. demonstrate that, on average, statins produce small, but statistically significant, decreases in testosterone. They appropriately emphasize that the clinical significance of their observations is unclear but suggest that changes in testosterone might be related to the benefits of therapy as well as the risks, such as the increased chance of diabetes mellitus. Their findings and hypotheses are noteworthy. However, we believe this represents another example of the limitations in the published summaries of drug effects. How do we know all changes induced by drugs are normally distributed? Some may be affected much more than others. Moreover, the confidence intervals of a meta-analysis describe the variance of the mean effect, not the range of effects, and while the mean change characterizes the impact of a drug on a group of patients, the range more fully characterizes its effects on individuals. We treat individuals not groups. Averages do not disclose enough about the risks and benefits of drugs.


Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med 2013;11(1):57. BMC Medicine | Abstract | The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins' pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone.

METHODS: A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using '(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)' restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.

RESULTS: Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13).

CONCLUSIONS: Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases.

 

[Michael Scally MD]

Branch Retinal Vein Occlusion Associated With [Long-Term] Tamoxifen Use

Onder HI, Kilic AC, Kose SA, et al. Branch retinal vein occlusion associated with tamoxifen use. Semin Ophthalmol 2013;28(2):88-90. An Error Occurred Setting Your User Cookie

Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of hormone-responsive breast cancer. Tamoxifen-induced ocular complications are very rare. A post-menopausal woman with carcinoma of the left breast had presented with sudden loss of vision. The patient had been on tamoxifen therapy 20 mg daily for the last three years. Fundus examination showed left branch retinal vein occlusion. Fluorescein angiography and optical coherence tomography confirmed the diagnosis. Tamoxifen therapy was discontinued. Although branch retinal vein occlusion is rare, careful evaluation of patients on tamoxifen therapy with visual symptoms is required.

 

[Michael Scally MD]

Mauvais-Jarvis F, Clegg DJ, Hevener AL. The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis. Endocrine Reviews. http://edrv.endojournals.org/content/early/2013/03/04/er.2012-1055.abstract

Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet ?-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders.

Contents

I. Contribution of Sex Hormones to Metabolic Diseases

II. Origin of Circulating and Tissue Estrogens in Males and Females

III. Mechanisms of Estrogen Receptor (ER) Action

IV. Evolutionary Importance of ER in Energy Metabolism

V. ER and Control of Energy Intake and Expenditure
A. Estrogen action in the hypothalamus in relation to energy balance
B. ERalpha in the ARC and control of food intake
C. ERalpha in the ventromedial hypothalamus and control of energy expenditure
D. ERalpha in the brainstem and control of food intake
E. Estrogen interaction with leptin
F. Estrogen interaction with neuropeptide-1

VI. ER and Regulation of Adipose Tissue Distribution
A. Intra-abdominal adipose tissue and the metabolic syndrome
B. Subcutaneous adipose tissue and lipid storage
C. ERalpha and adipose tissue distribution
D. ER and adipose tissue lipid metabolism

VII. ER and Insulin Sensitivity
A. Estrogens and insulin sensitivity
B. ERalpha in relation to skeletal muscle glucose transporter GLUT4
C. ERalpha in relation to skeletal muscle fatty acid metabolism and inflammation
D. ERs and insulin sensitivity in the liver

VIII. ERalpha and Functioning of Macrophages and Immune Cells

IX. ER in Relation to Pancreatic Beta-Cell Function

X. Estrogen Sulfotransferase and Metabolism

XI. Estrogen Therapy and Metabolism
A. Relation of route of estrogen administration and metabolism
B. Effect of selective estrogen receptor modulators and aromatase inhibitors on metabolism

XII. Conclusions and Perspectives

 

[Michael Scally MD]

Nine Months of Combined Training [Aerobic Training (AT) & Resistance Training (RT)] Improves Ex Vivo Skeletal Muscle Metabolism in Individuals With Type 2 Diabetes

Sparks LM, Johannsen NM, Church TS, et al. Nine Months of Combined Training Improves Ex Vivo Skeletal Muscle Metabolism in Individuals With Type 2 Diabetes. Journal of Clinical Endocrinology & Metabolism. Nine Months of Combined Training Improves Ex Vivo Skeletal Muscle Metabolism in Individuals With Type 2 Diabetes

Context: Type 2 diabetes (T2D) has features of disordered lipid and glucose metabolism, due in part to reduced mitochondrial content.

Objective: Our objective was to investigate effects of different types of exercise on mitochondrial content and substrate oxidation in individuals with T2D (ancillary study of the randomized controlled trial Health Benefits of Aerobic and Resistance Training in Individuals with Type 2 Diabetes, HART-D).

Intervention: T2D individuals were randomized to aerobic training (AT, n = 12), resistance training (RT, n = 18), combination training (ATRT, n = 12), or nonexercise control (n = 10). Blood draws, peak oxygen consumption tests, dual-energy x-ray absorptiometry scans and muscle biopsies of vastus lateralis were performed before and after 9 months. Ex vivo substrate oxidations (14CO2), mitochondrial content, and enzyme activities were measured. Glycated hemoglobin A1c and free fatty acids were also determined.

Results: Mitochondrial content increased after RT and ATRT. Octanoate oxidation increased after AT and ATRT, whereas palmitate, pyruvate, and acetate oxidations increased in all exercise groups. Exercise-induced responses in mitochondrial DNA were associated with improvements in peak oxygen consumption, ?-hydroxyacyl-coenzyme A dehydrogenase activity, and palmitate oxidation.

Conclusions: Nine months of AT and RT significantly improved most aspects of skeletal muscle mitochondrial content and substrate oxidation, whereas the combination improved all aspects. These exercise responses were associated with clinical improvements, indicating that long-term training, especially combination, is an effective lifestyle therapy for individuals with T2D by way of improving muscle substrate metabolism.

 

[Michael Scally MD]

Zhang J, Huang X, Liao M, et al. Both total testosterone and sex hormone-binding globulin are independent risk factors of metabolic syndrome: results from Fangchenggang Area Male Health and Examination Survey in China. Diabetes Metab Res Rev. Both total testosterone and sex hormone-binding globulin are independent risk factors of metabolic syndrome: results from Fangchenggang Area Male Health and Examination Survey in China - Zhang - Diabetes/Metabolism Research and Reviews - Wiley Online

BACKGROUND: Metabolic syndrome (MetS) is often beneficial from testosterone replacement therapy. Although testosterone and sex hormone-binding globulin (SHBG) are inversely associated with the risk of MetS, it is controversial whether the association between testosterone and MetS is independent of SHBG.

METHODS: Testosterone, sex hormone binding globulin (SHBG) and MetS were evaluated in 2361 men aged 20-73 years, who participated in the population-based Fangchenggang Area Male Health and Examination Survey (FAMHES). Total testosterone (TT), SHBG and other biochemical profiles were measured. Free testosterone (FT) and bio-available testosterone (BT) were calculated based on Vermeulen's formula. MetS was defined according to NCEP-ATP III criteria for Asian population. The independent associations with MetS were determined by multivariate logistic regression analysis.

RESULTS: Men with MetS had a lower level of TT, BT, FT or SHBG than those without MetS (all p < 0.001). Both TT and SHBG were inversely correlated with body mass index (BMI) or homeostasis model assessment of insulin resistance (HOMA-IR) (all age-adjusted p < 0.001). Men within the lowest quartile of TT (OR = 4.86, 95%CI = 2.72-8.68), BT (OR = 3.04, 95%CI = 1.81-5.10), FT (OR = 3.08, 95%CI = 1.81-5.27) or SHBG (OR = 4.28, 95%CI = 2.52-7.27) had a risk of MetS after adjusting for age, smoking, HOMA-IR and BMI. TT remained inversely associated with MetS after further adjusting for SHBG (OR = 0.95, 95%CI = 0.92-0.99), while SHBG remained inversely associated with MetS after further adjusting for TT (OR = 0.99, 95%CI = 0.97-1.00).

CONCLUSION: TT and SHBG are independent risk factors of MetS. Prospective studies are needed to explore whether the association between sex hormones and MetS was mediated by insulin resistance or obesity.

 

[Michael Scally MD]

Arrabal-Polo MA, Arias-Santiago S, Lopez-Carmona Pintado F, et al. Metabolic syndrome, hormone levels, and inflammation in patients with erectile dysfunction. Scientific World Journal. 2012:272769. Metabolic Syndrome, Hormone Levels, and Inflammation in Patients with Erectile Dysfunction

BACKGROUND: The end point of this study was to investigate the prevalence of MS in patients with ED in comparison with control subjects and to analyse the association with acute phase reactants (CRP, ESR) and hormone levels.

METHODS: This case-control study included 65 patients, 37 with erectile dysfunction, according to the International Index of Erectile Function (IIEF) from the Urology Department of San Cecilio University Hospital, Granada (Spain) and 28 healthy controls. The prevalence of metabolic syndrome was calculated according to ATP-III criteria. Hormone levels and acute phase parameters were studied in samples drawn.

RESULTS: The ATP-III criteria for MS were met by 64.9% of the patients with ED and only 9.5% of the controls (P < 0.0001, OR = 17.53, 95% CI: 3.52-87.37). Binary logistic regression analysis showed a strong association between patients with ED and MS, even after additional adjustment for confounding factors (OR = 20.05, 95% CI: 1.24-32.82, P < 0.034). Patients with hypogonadism presented a significantly higher prevalence of metabolic syndrome. Multiple linear regression analysis showed that systolic BP and CRP predicted 0.46 (model R(2)) of IIEF changes.

CONCLUSION: Chronic inflammation found in patients with ED might explain the association between ED and metabolic syndrome.

 

[Michael Scally MD]

De Sibio MT, Luvizotto RAM, Olimpio RMC, et al. A Comparative Genotoxicity Study of a Supraphysiological Dose of Triiodothyronine (T3) in Obese Rats Subjected to Either Calorie-Restricted Diet or Hyperthyroidism. PLoS ONE 2013;8(2):e56913. PLOS ONE: A Comparative Genotoxicity Study of a Supraphysiological Dose of Triiodothyronine (T3) in Obese Rats Subjected to Either Calorie-Restricted Diet or Hyperthyroidism

This study was designed to determine the genotoxicity of a supraphysiological dose of triiodothyronine (T3) in both obese and calorie-restricted obese animals.

Fifty male Wistar rats were randomly assigned to one of the two following groups: control (C; n = 10) and obese (OB; n = 40). The C group received standard food, whereas the OB group was fed a hypercaloric diet for 20 weeks. After this period, half of the OB animals (n = 20) were subjected to a 25%-calorie restriction of standard diet for 8 weeks forming thus a new group (OR), whereas the remaining OB animals were kept on the initial hypercaloric diet. During the following two weeks, 10 OR animals continued on the calorie restriction diet, whereas the remaining 10 rats of this group formed a new group (ORS) given a supraphysiological dose of T3 (25 µg/100 g body weight) along with the calorie restriction diet. Similarly, the remaining OB animals were divided into two groups, one that continued on the hypercaloric diet (OB, n = 10), and one that received the supraphysiological dose of T3 (25 µg/100 g body weight) along with the hypercaloric diet (OS, n = 10) for two weeks.

The OB group showed weight gain, increased adiposity, insulin resistance, increased leptin levels and genotoxicity; T3 administration in OS animals led to an increase in genotoxicity and oxidative stress when compared with the OB group. The OR group showed weight loss and normalized levels of adiposity, insulin resistance, serum leptin and genotoxicity, thus having features similar to those of the C group. On the other hand, the ORS group, compared to OR animals, showed higher genotoxicity.

Our results indicate that regardless of diet, a supraphysiological dose of T3 causes genotoxicity and potentiates oxidative stress.

 

[Michael Scally MD]

Basualto-Alarcon C, Jorquera G, Altamirano F, Jaimovich E, Estrada M. Testosterone Signals through mTOR and Androgen Receptor to Induce Muscle Hypertrophy. Med Sci Sports Exerc. Testosterone Signals through mTOR and Androgen Receptor to I... : Medicine & Science in Sports & Exercise

Purpose: The anabolic hormone testosterone induces muscle hypertrophy, but the intracellular mechanisms involved are poorly known. We addressed the question whether signal transduction pathways other than the androgen receptor are necessary to elicit hypertrophy in skeletal muscle myotubes.

Methods: Cultured rat skeletal muscle myotubes were pre-incubated with inhibitors for ERK1/2 (PD98059), PI3K/Akt (LY294002 and Akt-inhibitor-VIII) or mTOR/S6K1 (rapamycin), and then stimulated with 100 nM testosterone. The expression of alpha-actin and the phosphorylation levels of ERK1/2, Akt and S6K1 (a downstream target for mTOR), were measured by Western Blot. mRNA levels were evaluated by qRT-PCR. Myotube size and sarcomerization were determined by confocal microscopy. Inhibition of androgen receptor was assessed by bicalutamide.

Results: Testosterone induced myotube hypertrophy was assessed as: increased myotube cross sectional area, increased alpha-actin mRNA and alpha-actin protein levels, with no changes in mRNA expression of atrogenes (MAFbx and MuRF-1). Morphological development of myotube sarcomeres was evident in testosterone stimulated myotubes. Known hypertrophy signalling pathways were studied at short times: ERK1/2 and Akt showed an increase in phosphorylation status after testosterone stimulus at 5 and 15 minutes, respectively. S6K1 was phosphorylated at 60 minutes. This response was abolished by PI3K/Akt and mTOR inhibition but not by ERK1/2 inhibition. Similarly, the cross sectional area increase at 12 hours was abolished by inhibitors of the PI3K/Akt pathway as well as by androgen receptor inhibition.

Conclusions: These results suggest a cross talk between pathways involving fast intracellular signalling and the androgen receptor to explain testosterone-induced skeletal muscle hypertrophy.

 

[Michael Scally MD]

Derouiche A, Jafri A, Driouch I, et al. Effect of argan and olive oil consumption on the hormonal profile of androgens among healthy adult Moroccan men. Nat Prod Commun 2013;8(1):51-3. Effect of argan and olive oil consumption on... [Nat Prod Commun. 2013] - PubMed - NCBI

This study aimed to assess the effect of virgin argan oil (VAO) and extra virgin olive oil (EVO) on the hormonal profile of androgens and anthropometric parameters among healthy adult Moroccan men during a controlled nutritional intervention. The study was carried out on 60 young and healthy male volunteers aged between 23 and 40 years old. During a stabilization period of 2 weeks they consumed butter.

The group was then randomized into two categories, the first one consuming VAO and the second EVO for 3 weeks. Testosterone (T), luteinizing hormone (LH) and dehydroepiandrosterone (DHEAS) serum concentrations were measured at the beginning of the study and at the end of each period. The Mann-Whitney test was used to compare the two groups (VAO and EVO) during each step of the study. Differences in androgens and anthropometric parameters between the baseline and after 3 weeks of the diet in the VAO and EVO groups were analyzed using the Wilcoxon test.

T and LH serum concentrations significantly increased after the intervention period. T levels increased by 19.9% and 17.4% (p < 0.0001), and LH levels by 18.5% (p < 0.007) and 42.6% (p < 0.0001), respectively, for VAO and EVO (p < 0.0001). However, DHEAS serum concentrations, body weight, body mass index, arterial pressure and daily energetic intake did not show any significant variation after the intervention with either argan or olive oils. The results suggest that consumption of AVO and EVO might be the origin of a positive action on the androgen hormonal profile of men.

 

[Michael Scally MD]

Highlights

• Treatment of men with finasteride is used for primary prevention of prostate cancer.
• Finasteride suppresses serum DHT levels.
• Effect of finasteride on DHT precursors/metabolites in men was studied during 1 year.
• DHT sulfate (DHT S) and androstanediol glucuronide were suppressed, similar to DHT.
• DHT S, a novel metabolite, may serve as an important marker of 5?-reductase inhibition.


Stanczyk FZ, Azen CG, Pike MC. Effect of Finasteride on Serum Levels of Androstenedione, Testosterone and Their 5alpha-Reduced Metabolites in Men at Risk for Prostate Cancer. J Steroid Biochem Mol Biol. ScienceDirect.com - The Journal of Steroid Biochemistry and Molecular Biology - Effect of Finasteride on Serum Levels of Androstenedione, Testosterone and Their 5?-Reduced Metabolites in Men at Risk for Prostate Cancer

Studies show that treatment of men with 5alpha-reductase inhibitors such as finasteride is effective for the primary prevention of prostate cancer. Although it is known that finasteride treatment suppresses serum levels of dihydrotestosterone (DHT) and its distal metabolite, 5alpha-androstane-3alpha,17beta-diol glucuronide (3alpha-diol G), and increases serum testosterone (T) levels, little is known about its effect on other precursors and metabolites of DHT, as well as on the relationship of these androgens to prostate specific antigen (PSA), a marker of prostatic intraepithelial neoplasia. The present study provides new data on the effect of finasteride on precursors and metabolites of DHT.

Fifty-three men, ages 57-79 years, with elevated PSA levels (>4ng/ml), were randomized to treatment with finasteride (5mg/day) or observation (controls) for 12 months. Blood samples were obtained at baseline, 1, 3, 6 and 12 months for measurement of PSA, androstenedione (A), T, DHT, 3alpha-diol G, androsterone glucuronide (ADT G) and DHT sulfate (DHT S) in serum by validated, highly specific radioimmunoassays. Statistical analysis was carried out using mixed model ANOVA and t-tests.

In the control group, PSA and androgen levels were unchanged throughout the 12 months of treatment. In the finasteride group, PSA, DHT, DHT S, 3alpha-diol G and ADT G decreased from baseline to 1 month by 23.2%, 78.7%, 71.0%, 75.7% and 43.0%, respectively. The change in PSA decreased further to 46.1% and 55.1% at 3 and 12 months of treatment, respectively, whereas the decrease in androgens observed at 1 month did not change by more than 6.9% for DHT, DHT S and 3alpha-diol G in the subsequent months of sampling. However, the decline in ADT G was only 22.2% at month 3, and remained essentially at this level after that time. In contrast, T and A increased significantly from baseline, and the increase in A of approximately 34.5% was about 1.9 times the increase in T (approximately 18.3%).

The present data suggest that either 3alpha-diol G or DHT S may serve as a potential diagnostic marker of intraprostatic 5alpha-reductase activity during treatment of patients with 5alpha-reductase inhibitors.

 

[Michael Scally MD]

Tirabassi G, Gioia A, Giovannini L, et al. Testosterone and cardiovascular risk. Intern Emerg Med. Testosterone and cardiovascular risk - Online First - Springer

Cardiovascular (CV) disease is one of the most common causes of death in the western populations and, nowadays, its incidence is increasing even in the developing countries; although CV disease affects both sexes, it is more frequent in males in whom it shortens the average life expectancy. In this regard, this difference has been wrongly attributed for many years to the negative effects of testosterone (T); however, nowadays, a large amount of evidence suggests that this hormone may have protective effects on the CV system and that, indeed, the low levels of T could be associated with an increased CV risk and with an augmentation of morbidity and mortality in males. Such an aspect gains great relevance in light of the consideration that T decrease, besides occurring as a consequence of rare pathological conditions, can often take place with natural aging, causing a state of "male menopause", also called late-onset hypogonadism. In this review, we aimed to summarize the present state of the art concerning the association between T deficit and CV disease by analyzing the protective role of T on CV system and the relationship of this hormonal lack with metabolic syndrome, CV morbidity and mortality, and with the CV complications, such as ischemic heart disease, heart failure and stroke, that frequently occur in T deficiency.

 

[Michael Scally MD]

Seredynski AL, Balthazart J, Christophe VJ, Ball GF, Cornil CA. Neuroestrogens rapidly regulate sexual motivation but not performance. J Neurosci 2013;33(1):164-74. Neuroestrogens Rapidly Regulate Sexual Motivation But Not Performance

Estrogens exert pleiotropic effects on reproductive traits, which include differentiation and activation of reproductive behaviors and the control of the secretion of gonadotropins. Estrogens also profoundly affect non-reproductive traits, such as cognition and neuroprotection. These effects are usually attributed to nuclear receptor binding and subsequent regulation of target gene transcription. Estrogens also affect neuronal activity and cell-signaling pathways via faster, membrane-initiated events. How these two types of actions that operate in distinct timescales interact in the control of complex behavioral responses is poorly understood.

Here, we show that the central administration of estradiol rapidly increases the expression of sexual motivation, as assessed by several measures of sexual motivation produced in response to the visual presentation of a female but not sexual performance in male Japanese quail. This effect is mimicked by membrane-impermeable analogs of estradiol, indicating that it is initiated at the cell membrane. Conversely, blocking the action of estrogens or their synthesis by a single intracerebroventricular injection of estrogen receptor antagonists or aromatase inhibitors, respectively, decreases sexual motivation within minutes without affecting performance.

The same steroid has thus evolved complementary mechanisms to regulate different behavioral components (motivation vs performance) in distinct temporal domains (long- vs short-term) so that diverse reproductive activities can be properly coordinated to improve reproductive fitness. Given the pleiotropic effects exerted by estrogens, other responses controlled by these steroids might also depend on a slow genomic regulation of neuronal plasticity underlying behavioral activation and an acute control of motivation to engage in behavior.

 

[Michael Scally MD]

Corona G, Rastrelli G, Monami M, et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. European Journal of Endocrinology. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis

Objective. Few randomized clinical studies have evaluated the impact of diet and physical activity on testosterone (T) levels in obese men with conflicting results. Conversely, studies on bariatric surgery in men generally showed an increase in T levels. The aim of the present study is to perform a systematic review and meta-analysis of available trials on the effect of body weight loss on sex hormones levels.

Design. Meta-analysis Methods. An extensive Medline search was performed including the following words "testosterone", "diet", "weight loss" and "bariatric surgery" and "males". The search was restricted to data from January 1, 1969 up to August 31, 2012.

Results. Out of 266 retrieved articles, 24 were included in the study. Of the latter, 22 evaluated the effect of diet or of bariatric surgery, whereas 2 compared diet and bariatric surgery. Overall both low calorie diet and bariatric surgery are associated with a significant (p<0.0001) increase plasma sex hormone binding globulin bound and unbound T levels (TT), bariatric surgery being more effective in comparison with low calorie diet (TT increase = 8.73[6.51-10.95] vs 2.87[1.68-4.07] for bariatric surgery and low calorie diet, respectively; both p<0.0001 vs baseline). Androgen rise is greater in those patients that lose more weight as well as in younger, non-diabetic subjects with a greater degree of obesity. Body weight loss is also associated with and decrease in estradiol and increase in gonadotropins levels. Multiple regression analysis shows that the degree of body weight loss is the best determinant of TT rise (B=2.50±0.98; p=0.029).

Conclusions. Present data show that weight loss is associated with an increase of both bound and unbound T levels. The normalization of sex hormones induced by body weight loss is a possible mechanism contributing to the beneficial effects of surgery in morbid obesity.

 

[Michael Scally MD]

Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. The Lancet Oncology. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial : The Lancet Oncology

Background - Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer.

Methods - We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844.

Findings - Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1•5 kg, range ?2•1 to 12•6, p=0•0012; enodosarm 3 mg 1•0 kg, ?4•8 to 11•5, p=0•046). Change in total lean body mass within the placebo group (median 0•02 kg, range ?5•8 to 6•7) was not significant (p=0•88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6% vs one [2%] vs none). None of these events were deemed related to study drug.

Interpretation - Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents.

 

[Michael Scally MD]

Fontana K, Rocha T, da Cruz-Hofling MA. Regulation of neuronal and endothelial nitric oxide synthase by anabolic-androgenic steroid in skeletal muscles. Histol Histopathol 2013;27(11):1449-58. Histol Histopathol, Vol 27, Fontana et al.

Anabolic-androgenic steroids (AAS) and exercise share comparable effects on myogenic differentiation, force development, fiber growth and skeletal muscle plasticity. The participation of nitric oxide synthase (NOS) on these effects was only demonstrated in response to exercise.

Using immunohistochemistry and western blotting we examined the effect of AAS on the expression of NOS I and III isoforms in three muscles, distinct metabolically and physiologically: soleus (SOL), tibialis anterioris (TA) and gastrocnemius (GAS). Mice with a lipid profile akin to humans were used.

Sedentary mice (Sed-C) or exercised, submitted to six-weeks of aerobic treadmill running (one hour/day, 5 days/week) were administered mesterolone (Sed-M and Ex-M, respectively) or gum arabic (vehicle, Ex-C) during the last three weeks, three alternate days per week.

Consistently, The TA showed the strongest labeling and the SOL the weakest with NOS III predominating over NOS I. Mesterolone administered to sedentary mice (Sed-C x Sed-M) significantly upregulated NOS I in TA and SOL and NOS III in all three muscles. Mesterolone administered to exercised mice (Ex-C x Ex-M) upregulated NOS I in all three muscles and NOS III in TA and SOL. The exercise to mesterolone-treated mice (Sed-M x Ex-M) produced a strong increase in NOS I expression in GAS; in contrast it antagonized the mesterolone-induced upregulation of NOS I in TA muscle and NOS III in SOL and GAS.

The data show nitric oxide (NO) as a potential signaling mediator of AAS effects in skeletal muscle and that NOS I and NOS III upregulations were muscle phenotype-specific. These may be regarded as an indication of the complex NOS/NO signaling mechanism related with AAS effects vs. metabolic/physiological muscle characteristics.

 

[Michael Scally MD]

Norman C, Miles JM, Bowers CY, Veldhuis JD. Differential Pulsatile Secretagogue Control of GH Secretion in Healthy Men. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology. Differential Pulsatile Secretagogue Control of GH Secretion in Healthy Men

Pulsatile GH secretion putatively reflects integrated regulation by GH-releasing hormone (GHRH), somatostatin (SST) and GH-releasing peptide (GHRP). GHRH and SST secretion are themselves pulsatile. However, how GHRH and SST pulses act along with GHRP to jointly determine pulsatile GH secretion is unclear. Moreover, how testosterone (T) modulates such interactions is unknown.

These queries were assessed in a prospectively randomized, placebo-controlled double-blind cohort comprising 26 healthy older men randomized to testosterone (T) vs placebo supplementation. Pulses of GHRH, SST or saline were infused i.v. at 90-min intervals for 13 hr along with either continuous saline or ghrelin analog (GHRP-2). The train of pulses was followed by a triple stimulus (combined L-arginine, GHRH and GHRP-2) to estimate near-maximal GH secretion over a final 3 hr.

Testosterone vs placebo supplementation doubled pulsatile GH secretion during GHRH pulses combined with continuous saline (GHRH/saline) [P<0.01]. Pulsatile GH secretion correlated positively with T concentrations (270-1170 ng/dL) in the 26 men during saline pulses/saline (P=0.015, R2=0.24), GHRH pulses/saline (P=0.020, R2=0.22), and combined GHRH pulses/GHRP-2 (P=0.016, R2=0.25) infusions. Basal nonpulsatile GH secretion correlated with T during saline pulses/GHRP-2 drive (P=0.020, R2=0.16). By regression analysis, pulsatile GH secretion varied negatively with BMI during saline/GHRP-2 infusion (P=0.001, R2=0.36), as well as after the triple stimulus preceded by GHRH/GHRP-2 (P=0.013, R2=0.23). Mean (10-h) GH concentrations under GHRP-2 were predicted jointly by estradiol [positively] and BMI [negatively] (P<0.001, R2=0.520).

These data indicate that estradiol, T and BMI control pulsatile secretagogue-specific GH-regulatory mechanisms in older men.

 

[Michael Scally MD]

Trajkovic-Arsic M, Kalideris E, Siveke JT. Role of Insulin and Igf signaling in pancreatic cancer. Journal of Molecular Endocrinology. http://jme.endocrinology-journals.org/content/early/2013/03/14/JME-12-0259.abstract

The importance of the insulin-like growth factor system in carcinogenesis has been established for many solid cancers. It is well known that individuals with higher circulating levels of the insulin-like growth factor 1(IGF1) ligand present an increased risk of cancer. However, therapies with monoclonal antibodies targeting the IGF1 receptor (IGF1R) have been largely unsuccessful. One of the potential reasons for this failure is the existence of the highly homologous insulin receptor (IR) which appears to be at least as equally efficient as the IGF1R in the transition of mitogenic signals to the nucleus and promotion of cell growth. Furthermore, IGF1 and insulin receptors can form hybrid receptors sensitive to stimulation of all three ligands of the system: insulin, insulin-like growth factor 1 and insulin-like growth factor 2. Although the connection between insulin, diabetes and cancer has been established for years now, clear evidence that demonstrate the redundancy of insulin and insulin receptors and insulin-like growth factors and their receptors in cancer are missing.

In this review, we focus on the contribution of insulin and IGFs to carcinogenesis in the insulin-producing organ, the pancreas. We give a short summary on the complexity of insulin and the IGF system in the pancreas and their potential roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC). Finally, we discuss drug targeting options of this system and the rationale of simultaneous targeting of both the insulin and IGF systems.

 

[Michael Scally MD]

Kosola J, Vaara JP, Ahotupa M, et al. Elevated concentration of oxidized LDL together with poor cardiorespiratory and abdominal muscle fitness predicts metabolic syndrome in young men. Metabolism. ScienceDirect.com - Metabolism - Elevated concentration of oxidized LDL together with poor cardiorespiratory and abdominal muscle fitness predicts metabolic syndrome in young men

Background - Metabolic syndrome (MetS) is associated with increased oxidized LDL (ox-LDL), systemic inflammation, and poor cardiorespiratory fitness. We examined affiliations of these factors and the effect of muscular fitness on MetS in young healthy men.

Methods - Physical fitness, ox-LDL, tumor necrosis factor ? (TNF?), interleukin-6 (IL-6) and serum lipids were measured in a nationally representative sample of Finnish young men with and without MetS. Participants (mean age 25.1 years) performed tests of maximal oxygen uptake (VO2max) and muscle fitness, and were divided into MetS (n = 54, IDF 2007 criteria) and non-MetS (n = 790). Age, smoking and leisure-time physical activity were used as covariates (ANCOVA).

Results - The MetS group had lower results in VO2max and all of the muscular fitness tests (excluding grip strength) (P < 0.0001, in all). Ox-LDL, ox-LDL/HDL-cholesterol, ox-LDL/LDL-cholesterol, TNF? and IL-6 were all higher in the MetS group than in the non-MetS group (P < 0.01, in all). In stepwise multivariate logistic regression analysis (adjusted to MetS criteria), higher ox-LDL (OR 1.118, 95% CI 1.078–1.160), lower VO2max (OR 0.938, 95% CI 0.901–0.977) and lower sit-ups (OR 0.898, 95% CI 0.844-0.956) predicted MetS (p < 0.05, in all).

Conclusions - Young men with MetS possess significantly poorer cardiorespiratory and muscle fitness, together with elevated systemic levels of ox-LDL, TNF? and IL-6 compared to non-MetS young men. Of these variables, ox-LDL, VO2max and sit-ups predicted MetS. Based on these findings, poor physical fitness and elevated concentration of ox-LDL are significant predisposing factors in the development of MetS.

 

[Michael Scally MD]

Bethea CL, Reddy AP, Robertson N, Coleman K. Effects of Aromatase Inhibition and Androgen Activity on Serotonin and Behavior in Male Macaques. Behav Neurosci. http://psycnet.apa.org/psycinfo/2013-08688-001/

Aggression in humans and animals has been linked to androgens and serotonin function. To further our understanding of the effect of androgens on serotonin and aggression in male macaques, we sought to manipulate circulating androgens and the activity of aromatase; and to then determine behavior and the endogenous availability of serotonin.

Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with (a) placebo; (b) testosterone (T); (c) T + Dutasteride (5a reductase inhibitor; AvodartTM); (d) T + Letrozole (nonsteroidal aromatase inhibitor; FemeraTM); (e) Flutamide + ATD (androgen antagonist plus steroidal aromatase inhibitor); or (f) dihydrotestosterone (DHT) + ATD (n = 5/group). Behavioral observations were made during treatments.

At the end of the treatment period, each animal was sedated with propofol and administered a bolus of fenfluramine (5 mg/kg). Fenfluramine causes the release of serotonin proportional to endogenous availability and in turn, serotonin stimulates the secretion of prolactin. Therefore, serum prolactin concentrations reflect endogenous serotonin.

Fenfluramine significantly increased serotonin/prolactin in all groups (p < .0001). Fenfluramine-induced serotonin/prolactin in the T-treated group was significantly higher than the other groups (p < .0001). Castration partially reduced the serotonin/prolactin response and Letrozole partially blocked the effect of T. Complete inhibition of aromatase with ATD, a noncompetitive inhibitor, significantly and similarly reduced the fenfluramine-induced serotonin/prolactin response in the presence or absence of DHT. Neither aggressive behavior nor yawning (indicators of androgen activity) correlated with serotonin/prolactin, but posited aromatase activity correlated significantly with prolactin (p < .0008; r2 = 0.95).

In summary, androgens induced aggressive behavior but they did not regulate serotonin. Altogether, the data suggest that aromatase activity supports serotonin production and that androgens increase aggression by another mechanism.