OnLine First 2013

[Michael Scally MD]

Yamada T, Hara K, Umematsu H, Kadowaki T. Male pattern baldness and its association with coronary heart disease: a meta-analysis. BMJ Open 2013;3(4). Male pattern baldness and its association with coronary heart disease: a meta-analysis -- Yamada et al. 3 (4) -- BMJ Open

Objective To confirm the association between male pattern baldness and coronary heart disease (CHD).

Design Meta-analysis of observational studies.

Data sources Medline and the Cochrane Library were searched for articles published up to November 2012 using keywords that included both ‘baldness’ and ‘coronary heart disease’ and the reference lists of those studies identified were also searched.

Study selection Observational studies were identified that reported risk estimates for CHD related to baldness. Two observers independently assessed eligibility, extracted data and assessed the possibility of bias.

Data synthesis The adjusted relative risk (RR) and 95% CI were estimated using the DerSimonian-Laird random-effect model.

Results 850 possible studies, 3 cohort studies and 3 case–control studies were selected (36 990 participants). In the cohort studies, the adjusted RR of men with severe baldness for CHD was 1.32 (95% CI 1.08 to 1.63, p=0.008, I2=25%) compared to those without baldness. Analysis of younger men (<55 or ?60 years) showed a similar association of CHD with severe baldness (RR 1.44, 95% CI 1.11 to 1.86, p=0.006, I2=0%). In three studies employing the modified Hamilton scale, vertex baldness was associated with CHD and the relation depended on the severity of baldness (severe vertex: RR 1.48 (1.04 to 2.11, p=0.03); moderate vertex: RR 1.36 (1.16 to 1.58, p<0.001); mild vertex: RR 1.18 (1.04 to 1.35, p<0.001)). However, frontal baldness was not associated with CHD (RR 1.11 (0.92 to 1.32, p=0.28)).

Conclusions Vertex baldness, but not frontal baldness, is associated with an increased risk of CHD. The association with CHD depends on the severity of vertex baldness and also exists among younger men. Thus, vertex baldness might be more closely related to atherosclerosis than frontal baldness, but the association between male pattern baldness and CHD deserves further investigation.

 

[Michael Scally MD]

Vlkova B, Mucska I, Hodosy J, Celec P. Short-term effects of continuous positive airway pressure on sex hormones in men and women with sleep apnoea syndrome. Andrologia. Short-term effects of continuous positive airway pressure on sex hormones in men and women with sleep apnoea syndrome - Vlkov[] - 2013 - Andrologia - Wiley Online Library

Patients with sleep apnoea syndrome (SAS) suffer from symptoms of hypogonadism. Besides surgical interventions, in some cases, the standard care of SAS for most patients is continuous positive airway pressure (CPAP). Studies focusing on the long-term effects of CPAP on testosterone levels revealed conflicting results. None of the studies included female patients with SAS. The aim of our study was to analyse and compare sex hormone levels in saliva before and after a night without and with CPAP in women and men with SAS. The results were negative. One night with CPAP did not affect the dynamics of sex hormones, neither in men nor in women. Future studies should focus on long-term effects of CPAP in both genders.

 

[Michael Scally MD]

Soljancic A, Lopez Ruiz AF, Chandrashekar K, et al. Protective Role of Testosterone in Ischemia-Reperfusion-induced Acute Kidney Injury. Am J Physiol Regul Integr Comp Physiol. Protective Role of Testosterone in Ischemia-Reperfusion-induced Acute Kidney Injury

Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease in general. In the present study we tested the hypothesis that I/R of the kidney reduces serum testosterone and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 hrs post reperfusion that remained at 24 hr. Infusion of testosterone 3 hrs after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 hrs, prevented the reduction in outer medullary blood flow, attenuated the increase in intrarenal TNF-alpha, and the decrease in intrarenal vascular endothelial growth factor at 48 hrs. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 hrs than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol.

 

[Michael Scally MD]

Oxidative Stress And The Ageing Endocrine System

Key points
• Reactive oxygen species (ROS) are an inescapable by-product of oxidative metabolism and are believed to be involved in ageing, but they are also essential for several physiological functions
• Data indicate that the endocrine system is involved in the modulation of oxidative stress through the production of several hormones
• Oxidative stress also seems to have a role in the ageing of the endocrine system and in the pathogenesis of several endocrine diseases
• How oxidative stress causes ageing in endocrine tissues is unclear; in some tissues, inflammation is probably the link between the two processes
• ROS can induce inflammation directly by acting on transcription factors such as nuclear factor ?B and indirectly by modulating other processes such as cellular senescence, mitochondrial dysfunction and microRNA production


Vitale G, Salvioli S, Franceschi C. Oxidative stress and the ageing endocrine system. Nat Rev Endocrinol 2013;9(4):228-40. Oxidative stress and the ageing endocrine system : Article : Nature Reviews Endocrinology

Ageing is a process characterized by a progressive decline in cellular function, organismal fitness and increased risk of age-related diseases and death. Several hundred theories have attempted to explain this phenomenon. One of the most popular is the 'oxidative stress theory', originally termed the 'free radical theory'. The endocrine system seems to have a role in the modulation of oxidative stress; however, much less is known about the role that oxidative stress might have in the ageing of the endocrine system and the induction of age-related endocrine diseases. This Review outlines the interactions between hormones and oxidative metabolism and the potential effects of oxidative stress on ageing of endocrine organs. Many different mechanisms that link oxidative stress and ageing are discussed, all of which converge on the induction or regulation of inflammation. All these mechanisms, including cell senescence, mitochondrial dysfunction and microRNA dysregulation, as well as inflammation itself, could be targets of future studies aimed at clarifying the effects of oxidative stress on ageing of endocrine glands.

 

[Michael Scally MD]

Liu T-C, Lin C-H, Huang C-Y, Ivy J, Kuo C-H. Effect of acute DHEA administration on free testosterone in middle-aged and young men following high-intensity interval training. European Journal of Applied Physiology:1-10. Effect of acute DHEA administration on free testosterone in middle-aged and young men following high-intensity interval training - Online First - Springer

With advancing age, plasma testosterone levels decline, with free testosterone levels declining more significantly than total testosterone. This fall is thought to underlie the development of physical and mental weakness that occurs with advancing age. In addition, vigorous exercise can also lower total and free testosterone levels with the decline greatest in physically untrained men. The purpose of the study was to evaluate the effect of oral DHEA supplementation, a testosterone precursor, on free testosterone in sedentary middle-aged men during recovery from a high-intensity interval training (HIIT) bout of exercise. A randomized, double-blind, placebo-controlled crossover study was conducted for 8 middle-aged participants (aged 49.3 ± 2.4 years) and an additional 8 young control participants (aged 21.4 ± 0.3 years). Each participant received DHEA (50 mg) and placebo on separate occasions one night (12 h) before a 5-session, 2-min cycling exercise (100 % V?O2max ). While no significant age difference in total testosterone was found, middle-aged participants exhibited significantly lower free testosterone and greater luteinizing hormone (LH) levels than the young control group. Oral DHEA supplementation increased circulating DHEA-S and free testosterone levels well above baseline in the middle-aged group, with no significant effect on total testosterone levels. Total testosterone and DHEA-S dropped significantly until 24 h after HIIT for both age groups, while free testosterone of DHEA-supplemented middle-aged men remained unaffected. These results demonstrate acute oral DHEA supplementation can elevate free testosterone levels in middle-aged men and prevent it from declining during HIIT. Therefore, DHEA supplementation may have significant benefits related to HIIT adaptation.

 

[Michael Scally MD]

Hsiao W, Rosoff JS, Pale JR, Powell JL, Goldstein M. Varicocelectomy Is Associated With Increases in Serum Testosterone Independent of Clinical Grade. Urology. ScienceDirect.com - Urology - Varicocelectomy Is Associated With Increases in Serum Testosterone Independent of Clinical Grade

OBJECTIVE: To determine whether the varicocele grade is related to the degree of improvement in serum testosterone levels after varicocelectomy.

MATERIALS AND METHODS: We performed a retrospective review of men with a total serum testosterone level <400 ng/dL who had undergone microsurgical subinguinal varicocelectomy for infertility and/or hypogonadism. All men had clinically palpable left varicoceles and preoperative and postoperative total serum testosterone levels available. For patients with bilateral varicoceles, the greatest grade on either side was used to stratify the patients. The men with an isolated, left-side, grade I varicocele were not offered varicocelectomy. The changes in the testosterone levels were evaluated, with the results expressed as the mean +/- standard error. P </=.05 was considered statistically significant.

RESULTS: A total of 59 patients had undergone bilateral varicocelectomy and 19 unilateral varicocelectomy. Overall, an increase in testosterone was seen in 65 of the 78 men (83%) in the present study. The mean follow-up was 7 months. The mean serum testosterone level increased from 308.4 to 417.5 ng/dL, with a mean increase of 109.1 +/- 12.8 ng/dL (n = 78). The improvements in the serum testosterone levels were seen regardless of the clinical grade.

CONCLUSION: Microsurgical varicocelectomy resulted in significant increases in the serum testosterone level, independent of the varicocele grade.

 

[Michael Scally MD]

Gasco V, Prodam F, Grottoli S, et al. GH therapy in adult GH deficiency: a review of treatment schedules and the evidence for low starting doses. Eur J Endocrinol 2013;168(3):R55-66. THERAPY OF ENDOCRINE DISEASE: GH therapy in adult GH deficiency: A review of treatment schedules and the evidence for low starting doses

Recombinant human GH has been licensed for use in adult patients with GH deficiency (GHD) for over 15 years. Early weight- and surface area-based dosing regimens were effective but resulted in supraphysiological levels of IGF1 and increased incidence of side effects. Current practice has moved towards individualised regimens, starting with low GH doses and gradually titrating the dose according to the level of serum IGF1 to achieve an optimal dose. Here we present the evidence supporting the dosing recommendations of current guidelines and consider factors affecting dose responsiveness and parameters of treatment response. The published data discussed here lend support for the use of low GH dosing regimens in adult GHD. The range of doses defined as 'low dose' in the studies discussed here ( approximately 1-4 mg/week) is in accordance with those recommended in current guidelines and encompasses the dose range recommended by product labels.

 

[Michael Scally MD]

Appelman N, Claessen KMja, Roelfsema F, Pereira AM, Biermasz NR. Long-term effects of recombinant human Growth Hormone (rhGH) replacement in adults with Growth Hormone Deficiency (GHD): a systematic review. European Journal of Endocrinology. Long-term effects of recombinant human Growth Hormone (rhGH) replacement in adults with Growth Hormone Deficiency (GHD): a systematic review

Background - The beneficial effects of recombinant human growth hormone (rhGH) therapy in growth hormone deficient (GHD) adults are well-established in the short-term. However, data documenting the effects during prolonged follow-up are relatively scarce.

Objective - To evaluate the reported effects of rhGH replacement (?5 years) in GHD adults on biochemical and anthropometric parameters, quality of life (QoL), bone metabolism, muscle strength, serious adverse events (SAEs), and mortality.

Methods - We conducted a systematic literature search. Quality assessment of retrieved papers was performed using a quality assessment based on the modified STROBE statement.

Results - We included 23 prospective studies with a rhGH treatment duration ranging from 5 to 15 years. Overall, beneficial effects were reported on QoL, body composition, lipid profile, carotid IMT and BMD. In contrast, the prevalence of the metabolic syndrome, glucose levels, BMI and muscle strength were not, or negatively influenced. Most of the studies were uncontrolled, lacked the presence of a control group (of non-treated GHD patients), and reported no data on lipid-lowering and anti-diabetic medication. Overall mortality was not increased.

Conclusion - RhGH treatment in adult GHD patients is well-tolerated and positively affects QoL in the long-term. However, the metabolic and cardiovascular effects during long-term treatment are variable. The low numbers of long-term studies and studied patients and lack of control data hamper definite statements on the efficacy of prolonged treatment. Therefore, continuous monitoring of the effects of rhGH replacement to enable an adequate risk-benefit analysis that may justify prolonged, potentially life-long, treatment is advisable.

 

[Michael Scally MD]

Berryman DE, Glad CAM, List EO, Johannsson G. The GH/IGF-1 axis in obesity: pathophysiology and therapeutic considerations. Nat Rev Endocrinol;advance online publication. http://www.nature.com/nrendo/journal/vaop/ncurrent/full/nrendo.2013.64.html

Obesity has become one of the most common medical problems in developed countries, and this disorder is associated with high incidences of hypertension, dyslipidaemia, cardiovascular disease, type 2 diabetes mellitus and specific cancers. Growth hormone (GH) stimulates the production of insulin-like growth factor 1 in most tissues, and together GH and insulin-like growth factor 1 exert powerful collective actions on fat, protein and glucose metabolism.

Clinical trials assessing the effects of GH treatment in patients with obesity have shown consistent reductions in total adipose tissue mass, in particular abdominal and visceral adipose tissue depots. Moreover, studies in patients with abdominal obesity demonstrate a marked effect of GH therapy on body composition and on lipid and glucose homeostasis. Therefore, administration of recombinant human GH or activation of endogenous GH production has great potential to influence the onset and metabolic consequences of obesity.

However, the clinical use of GH is not without controversy, given conflicting results regarding its effects on glucose metabolism. This Review provides an introduction to the role of GH in obesity and summarizes clinical and preclinical data that describe how GH can influence the obese state.

 

[Michael Scally MD]

Quinta Gomes AL, Nobre PJ. Prevalence of Sexual Problems in Portugal: Results of a Population-Based Study Using a Stratified Sample of Men Aged 18 to 70 Years. J Sex Res. An Error Occurred Setting Your User Cookie

Despite the use of different methodologies, target populations, and clinical definitions of sexual problems, recent epidemiological studies have shown that the occurrence of sexual difficulties is a very common experience among men from the general population regardless of their age. The objective of this study was to present epidemiological data on the prevalence of sexual difficulties in a community sample of 650 sexually active Portuguese men, stratified by age, marital status, and educational level. Participants completed a self-reported questionnaire assessing sexual function in the previous four weeks (International Index of Erectile Function). Results showed that sexual difficulties were relatively common among this sample. Rapid ejaculation was the most frequently reported sexual difficulty (23.2%), followed by erectile difficulties (10.2%), orgasm problems (8.2%), and low desire (2.9%) in the previous four weeks. With the exception of rapid ejaculation, all categories showed age-specific prevalence rates, with sexual difficulties increasing gradually in men above age 45. Age was a significant predictor of all sexual difficulties except rapid ejaculation, and lower educational levels were related to orgasm difficulties. Findings are consistent with the majority of epidemiological studies indicating a high prevalence of sexual difficulties among men in the general population and highlight the importance and the need to implement sexual health promotion programs in the target population.

 

[Michael Scally MD]

Birketvedt GS, Geliebter A, Kristiansen I, Firgenschau Y, Goll R, Florholmen JR. Diurnal secretion of ghrelin, growth hormone, insulin binding proteins, and prolactin in normal weight and overweight subjects with and without the night eating syndrome. Appetite 2013;59(3):688-92. ScienceDirect.com - Appetite - Diurnal secretion of ghrelin, growth hormone, insulin binding proteins, and prolactin in normal weight and overweight subjects with and without the night eating syndrome

The regulatory peptide ghrelin has been proposed to help mediate both hunger and sleep. The neuroendocrine circadian patterns in the night eating syndrome (NES) have been distinguished by an attenuated nocturnal rise in the plasma concentrations of melatonin and leptin and a greater increase in the concentrations of cortisol. In this study we wanted to test the hypothesis that night eaters have disturbances in the circadian levels of ghrelin, growth hormone (GH) and associated regulatory peptides. In 12 female night eaters (6 normal weight and 6 overweight), and 25 healthy controls (12 normal weight and 13 overweight), blood was sampled over a 24-hour period. Four meals were served from 8 AM to 8 PM, and blood samples were drawn every second hour for determination of plasma ghrelin concentrations and GH by radioimmunoassay (RIA). Analysis of serum GH, IGF-1, IGFBP-3 and prolactin were performed by ELISA. In healthy normal weight subjects there was a slight but non significant nocturnal increase of ghrelin, whereas a more or less flat curve was observed for healthy overweight, NES normal weight and NES overweight patients. The RMANOVA analysis showed a significant independent lowering effect of overweight on the grand mean of ghrelin. No direct effects on NES normal weight and overweight subjects were found, but a near-significant interaction was found between healthy overweight and overweight NES subjects. There were independent significant lowering effects of overweight and NES on the serum GH levels. During the time course no changes in the serum levels of IGF-1 or IGFB-3 were observed. Independent significant lowering effects of overweight and NES on the levels of IGF-1 were detected, whereas a near significant reduction in the global levels of IGFBP-3 was observed in both NES groups. Finally, significant nocturnal changes were observed for serum levels of prolactin in all four subgroups. Grand mean levels tended to be higher in NES subjects whereas the opposite was observed in healthy overweight (ns). We conclude that in both NES groups and in healthy overweight subjects more or less attenuated ghrelin and GH secretions were observed, whereas divergent secretions were observed for prolactin.

 

[Michael Scally MD]

Integrative Role for the Circadian Clock in the Regulation of Physiological Function

Richards J, Gumz ML. Invited Review EB 2012: Mechanism of the Circadian Clock in Physiology. Am J Physiol Regul Integr Comp Physiol. Invited Review EB 2012: Mechanism of the Circadian Clock in Physiology

It has been well established that the circadian clock plays a crucial role in the regulation of almost every physiologic process. It also plays a critical role in pathophysiological states including those of obesity and diabetes. Recent evidence has highlighted the potential for targeting the circadian clock as a potential drug target. New studies have also demonstrated the existence of "clock-independent effects" of the circadian proteins, leading to exciting new avenues of research in the circadian clock field in physiology. The goal of this review is to provide an introduction to and overview of the circadian clock in physiology, including mechanisms, targets, and role in disease states. The role of the circadian clocks in the regulation of the cardiovascular system, renal function, metabolism, the endocrine system, immune, and reproductive systems will be discussed.


Circadian proteins listed in parentheses dictate which proteins have been implicated in regulating the process in question. If a protein is not listed, it does not imply that it is not involved, but that it has not yet been tested. Green arrows represent induction by the circadian protein; red arrows represent repression. The time shown on the clock is for illustrative purposes only.

 

[Michael Scally MD]

Yavuz S, Linderman JD, Smith S, Zhao X, Pucino F, Celi FS. The Dynamic Pituitary Response to Escalating-Dose TRH Stimulation Test in Hypothyroid Patients Treated With Liothyronine or Levothyroxine Replacement Therapy. Journal of Clinical Endocrinology & Metabolism. The Dynamic Pituitary Response to Escalating-Dose TRH Stimulation Test in Hypothyroid Patients Treated With Liothyronine or Levothyroxine Replacement Therapy

Context: A recent trial showed that 1:3 ?g:?g liothyronine (L-T3) substitution for levothyroxine (L-T4) achieving near-identical TSH levels resulted in a significant decrease in weight and cholesterol levels with no appreciable changes in cardiovascular parameters, suggesting a differential peripheral response to the therapy.

Objective: We characterized the pituitary-thyroid axis in hypothyroid patients receiving equivalent doses of L-T3 or L-T4 by escalating-dose TRH stimulation test.

Design: A secondary analysis of a L-T3 vs L-T4 therapy trial was performed.

Setting: The study was conducted at the National Institutes of Health.

Patients: Thirteen patients were studied.

Interventions: Escalating-dose (5, 15, and 200 ?g) TRH stimulation test on both treatment arms.

Main Outcome Measures: Study outcomes were peak serum TSH concentration (Cmax), time to peak TSH concentration (Tmax), area under the curve from 0 to 60 minutes (AUC0–60) after TRH injection.

Results: Thirteen patients aged 51.2 ± 8.29 years completed escalating-dose TRH stimulation test. No significant difference between L-T3 and L-T4 treatments was observed in TSH Cmax or area under the curve. L-T4 resulted in a small but significantly shorter Tmax compared to L-T3 (3.5 ± 0.73 min on 200 ?g TRH dose, P < .03). In addition, 5 ?g TRH dose compared to 200 ?g resulted in a shorter Tmax on both treatment arms (6.9 ± 0.59 min L-T3, 4 ± 0.3 min L-T4; P = .0002).

Conclusions: The assessment of the dynamic pituitary response to escalating doses of TRH confirms that substitution of L-T3 for L-T4 on a 1:3 ratio achieves a near-identical degree of pituitary euthyroidism. Furthermore, the data suggest that lower doses of TRH might provide clinically relevant information of thyrotroph function, particularly when investigating partial pituitary insufficiency states.

 

[Michael Scally MD]

Stalder T, Kirschbaum C, Alexander N, et al. Cortisol in hair and the metabolic syndrome. Journal of Clinical Endocrinology & Metabolism. Cortisol in hair and the metabolic syndrome

Context: While exposure to supraphysiological levels of glucocorticoids is known to contribute to the development of the metabolic syndrome (MetS), the importance of physiological variation in basalcortisol secretion is less clear. This issue can be addressed by utilizing hair cortisol analysis which for the first time allows the assessment of long-term integrated hormone levels.

Objective and Design: We used the analysis of cortisol in hair (hairF) to examine associations of long-term cortisol levels with prevalence of MetS and individual cardiometabolic parameters in a large occupational cohort. In additional exploratory analyses, we also studied cardiometabolic associations with hair cortisone (hairE) levels.

Participants: 1,258 employees of a large aerospace company (16–64 years; 84.8% males) who partook in a voluntary health assessment.

Main Outcome Measures: Scalp-near 3cm hair samples were analysed for glucocorticoid concentrations using liquid chromatography tandem mass spectrometry. Relevant cardiometabolic risk factors were assessed and MetS was diagnosed (according to 2009 international task force criteria).

Results: A higher prevalence of MetS was seen in individuals falling into the third [OR = 1.71, 95% CI = 1.08 – 2.69] or fourth hairF quartile [OR = 2.42, 95% CI = 1.55 – 3.75] compared to the first quartile, in fully adjusted analyses. HairF also showed positive associations with weight-related anthropometric measures (BMI, WHR, waist circumference) and glycated haemoglobin. The exploratory analysis of hairE also indicated relevant associations with cardiometabolic parameters.

Conclusion: Normal physiological differences in long-term cortisol secretion, as assessed in hair, show relevant relationships with MetS and individual cardiometabolic parameters.

 

[Michael Scally MD]

Yuen KCJ, Conway GS, Popovic V, et al. A long-acting human growth hormone with delayed clearance (VRS-317): Results of a double-blind, placebo-controlled, single ascending dose study in growth hormone deficient adults. Journal of Clinical Endocrinology & Metabolism. A long-acting human growth hormone with delayed clearance (VRS-317): Results of a double-blind, placebo-controlled, single ascending dose study in growth hormone deficient adults

Background: Administration of daily recombinant human growth hormone (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes.

Objectives: This study assessed the safety and tolerability, and the potential for achieving IGF-I levels within target range in adults with GH deficiency (GHD) after a single dose of the long-acting rhGH analogue, VRS-317.

Design: Randomized, double-blind, placebo-controlled, single ascending dose study.

Patients: 50 GHD adults (mean age 45 y) were studied in 5 treatment groups of 10 subjects each (8 active, 2 placebo).Setting: 17 adult Endocrinology centers in North America and Europe.

Main Outcome Measures: Adverse events, safety laboratories, VRS-317 pharmacokinetics and pharmacodynamics (IGF-I, IGFBP-3).

Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40 and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3 to 5.0 μ g/kg over 30 days) safely increased the amplitude and duration of IGF-I responses in a dose dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between -1.5 to 1.5 standard deviations (SD) for a mean of three weeks. No unexpected or serious adverse events were observed.

Conclusions: The elimination half-life for VRS-317 is 30-60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of over-exposure to high IGF-I levels. The pharmacokinetic and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.

 

[Michael Scally MD]

Fonseca TL, Correa-Medina M, Campos MPO, et al. Coordination of hypothalamic and pituitary T3 production regulates TSH expression. The Journal of Clinical Investigation 2013;123(4):1492-500. JCI - Coordination of hypothalamic and pituitary T3 production regulates TSH expression

Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3?-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.

 

[Michael Scally MD]

Bouloux PM, Legros JJ, Elbers JM, et al. Effects of oral testosterone undecanoate therapy on bone mineral density and body composition in 322 aging men with symptomatic testosterone deficiency: a 1-year, randomized, placebo-controlled, dose-ranging study. Aging Male. An Error Occurred Setting Your User Cookie

Objective: We investigated the effects of oral testosterone undecanoate (TU) on bone mineral density (BMD), lean body mass (LBM) and body fat mass (BFM) in aging men with symptomatic testosterone deficiency (TD).

Methods: Three hundred twenty-two men >/=50 years with TD symptoms and calculated free testosterone <0.26 nmol/L participated in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to placebo, oral TU 80 mg/d, oral TU 160 mg/d, or oral TU 240 mg/d, administered as divided doses with normal meals. BMD of the hip and lumbar spine were evaluated by dual energy X-ray absorptiometry (DEXA), and body composition (LBM and BFM) by whole body DEXA.

Results: Oral TU significantly increased BMD at Month 12 at the lumbar spine (240 mg/d), total hip (240 mg/d), and trochanter and intertrochanter (160 and 240 mg/d) compared with placebo. Oral TU significantly increased LBM at Months 6 and 12 for all oral TU groups compared with placebo. BFM significantly decreased at Month 6 (all oral TU groups) and Month 12 (160 mg/d) compared with placebo. The effects on BMD and body composition showed a clear dose response.

Conclusions: Treatment with oral TU led to improvement in BMD, LBM and BFM in aging men with symptomatic TD.

 

[Michael Scally MD]

Kaplan SA, O’Neill E, Lowe R, Hanson M, Meehan AG. Prevalence of low testosterone in aging men with benign prostatic hyperplasia: data from the Proscar Long-term Efficacy and Safety Study (PLESS). The Aging Male 2013:1-4. An Error Occurred Setting Your User Cookie

Objectives: We examined the prevalence of low testosterone (LT) in the subset of men in the Proscar Long-term Efficacy and Safety Study (PLESS) who had serum total testosterone (TT) measured at baseline.

Methods: PLESS enrolled 3040 men with benign prostatic hyperplasia (BPH). Of these men, 299 had TT and body mass index (BMI) measurements at baseline. Patients were classified as having LT if their baseline TT was <300?ng/dl.

Results: Of the 299 PLESS patients with baseline TT and BMI measurements, 65 (21.7%) had LT. The prevalence of LT increased with increasing BMI, occurring in 8/78 (10.3%) normal weight patients (baseline BMI <25?kg/m2), 35/160 (21.9%) overweight patients (baseline BMI ?25–<30?kg/m2), and 22/61 (36.1%) obese patients (baseline BMI ?30?kg/m2).

Conclusions: LT was observed in more than one in five PLESS patients with baseline TT and BMI measurements. The prevalence of LT increased with increasing BMI – more than one in three obese PLESS patients with baseline TT measurements had LT.

 

[Michael Scally MD]

Tan WS, Low WY, Ng CJ, et al. Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. BJU International. Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study - Tan - 2013 - BJU International - Wiley Online Library

Objective * To evaluate the efficacy and safety of long-acting i.m. testosterone undecanoate (TU) in Malaysian men with testosterone deficiency (TD).

Patients and Methods * A total of 120 men, aged 40–70 years, with TD (serum total testosterone [TT] ? 12?nmol/L) were randomised to receive either i.m. TU (1000?mg) or placebo. * In all, 58 and 56 men in the placebo and treatment arm, respectively, completed the study. * Participants were seen six times in the 48-week period and the following data were collected: physical examination results, haemoglobin, haematocrit, TT, lipid profile, fasting blood glucose, sex hormone-binding globulin, liver function test, prostate- specific antigen (PSA) and adverse events.

Results * The mean (sd) age of the participants was 53.4 (7.6) years. * A significant increase in serum TT (P < 0.001), PSA (P = 0.010), haematocrit (P < 0.001), haemoglobin (P < 0.001) and total bilirubin (P = 0.001) were seen in the treatment arm over the 48-week period. * Two men in the placebo arm and one man in the treatment arm developed myocardial infarction. * Common adverse events observed in the treatment arm included itching/swelling/pain at the site of injection, flushing and acne. * Overall, TU injections were well tolerated.

Conclusions * TU significantly increases serum testosterone in men with TD. * PSA, haemoglobin and haematocrit were significantly elevated but were within clinically safe limits. * There was no significant adverse reaction that led to the cessation of treatment.

 

[Michael Scally MD]

Carre JM, Campbell JA, Lozoya E, Goetz SM, Welker KM. Changes in testosterone mediate the effect of winning on subsequent aggressive behaviour. Psychoneuroendocrinology. Elsevier

Testosterone concentrations rise rapidly in the context of competitive interactions and remain elevated in winners relative to losers. Theoretical models suggest that this divergent neuroendocrine response serves to mediate future dominance behaviours. Although research in animal models provides compelling support for this model, evidence for its applicability to human social behaviour is limited. In the current study, men and women were randomly assigned to experience a series of victories or defeats, after which aggressive behaviour was assessed using a well-validated behavioural measure. Winning produced elevated testosterone concentrations relative to losing in men, but not women. More importantly, testosterone reactivity to competition mediated the effect of winning on subsequent aggressive behaviour in men, but not women. We discuss limitations of the current study (e.g., the status manipulation may have affected other variables not measured in the study including competitiveness and physical activity expended), as well as discuss a potential neural mechanism underlying the effect of testosterone reactivity on aggressive behaviour.