OnLine First 2013

[Michael Scally MD]

Leisegang K, Udodong A, Bouic PJD, Henkel RR. Effect of the metabolic syndrome on male reproductive function: a case-controlled pilot study. Andrologia. Effect of the metabolic syndrome on male reproductive function: a case-controlled pilot study - Leisegang - 2012 - Andrologia - Wiley Online Library

The metabolic syndrome (MetS) is a constellation of various risk factors. This study aimed to investigate the effect of MetS on testosterone and progesterone, and semen parameters, in a case-controlled pilot study. Male patients (n = 54) had body mass index, waist-to-hip ratio (WHR) and blood pressure recorded. Blood was analysed for HDL cholesterol, triglycerides and glucose. Saliva was assayed for free testosterone and free progesterone. Ejaculates were analysed for volume, sperm concentration, total sperm count, motility, vitality, mitochondrial membrane potential (MMP), DNA fragmentation and leucocyte concentration. Participants were divided into the control group (n = 28) and the MetS group (n = 26). Differences were found between the groups for body mass index, WHR, blood pressure, high-density lipoprotein (HDL), triglycerides and glucose. The MetS group showed significant reductions in sperm concentration (P = 0.0026), total sperm count (P = 0.0034), total motility (P = 0.0291), sperm vitality (P = 0.002), MMP (P = 0.0039), free testosterone (P = 0.0093) and free progesterone (P = 0.0130), while values for DNA fragmentation increased (P = 0.0287). Results indicate that patients with MetS have compromised sperm parameters in the absence of leucocytospermia. A reduction in free progesterone suggests that steroidogenesis cascades may be compromised. It is hypothesised that a systemic pro-inflammatory state with oxidative stress associated with MetS may provide a novel explanation.

 

[Michael Scally MD]

Flegal KM, Kit BK, Orpana H, Graubard BI. Association of All-Cause Mortality With Overweight and Obesity Using Standard Body Mass Index Categories: A Systematic Review and Meta-analysis. JAMA.2013;309(1):71-82. JAMA Network | JAMA | Association of All-Cause Mortality With Overweight and Obesity Using Standard Body Mass Index CategoriesA Systematic Review and Meta-analysisAll-Cause Mortality Using BMI Categories

Importance - Estimates of the relative mortality risks associated with normal weight, overweight, and obesity may help to inform decision making in the clinical setting.

Objective - To perform a systematic review of reported hazard ratios (HRs) of all-cause mortality for overweight and obesity relative to normal weight in the general population.

Data Sources - PubMed and EMBASE electronic databases were searched through September 30, 2012, without language restrictions.

Study Selection - Articles that reported HRs for all-cause mortality using standard body mass index (BMI) categories from prospective studies of general populations of adults were selected by consensus among multiple reviewers. Studies were excluded that used nonstandard categories or that were limited to adolescents or to those with specific medical conditions or to those undergoing specific procedures. PubMed searches yielded 7034 articles, of which 141 (2.0%) were eligible. An EMBASE search yielded 2 additional articles. After eliminating overlap, 97 studies were retained for analysis, providing a combined sample size of more than 2.88 million individuals and more than 270 000 deaths.

Data Extraction - Data were extracted by 1 reviewer and then reviewed by 3 independent reviewers. We selected the most complex model available for the full sample and used a variety of sensitivity analyses to address issues of possible overadjustment (adjusted for factors in causal pathway) or underadjustment (not adjusted for at least age, sex, and smoking).

Results - Random-effects summary all-cause mortality HRs for overweight (BMI of 25-<30), obesity (BMI of ?30), grade 1 obesity (BMI of 30-<35), and grades 2 and 3 obesity (BMI of ?35) were calculated relative to normal weight (BMI of 18.5-<25). The summary HRs were 0.94 (95% CI, 0.91-0.96) for overweight, 1.18 (95% CI, 1.12-1.25) for obesity (all grades combined), 0.95 (95% CI, 0.88-1.01) for grade 1 obesity, and 1.29 (95% CI, 1.18-1.41) for grades 2 and 3 obesity. These findings persisted when limited to studies with measured weight and height that were considered to be adequately adjusted. The HRs tended to be higher when weight and height were self-reported rather than measured.

Conclusions and Relevance - Relative to normal weight, both obesity (all grades) and grades 2 and 3 obesity were associated with significantly higher all-cause mortality. Grade 1 obesity overall was not associated with higher mortality, and overweight was associated with significantly lower all-cause mortality. The use of predefined standard BMI groupings can facilitate between-study comparisons.

 

[Michael Scally MD]

Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes Metab Res Rev 2012;28 Suppl 2:52-9. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? - Saad - 2012 - Diabetes/Metabolism Research and Reviews - Wiley Online Library

Obesity, hypertension, insulin resistance (IR), dyslipidaemia, impaired coagulation profile and chronic inflammation characterize cardiovascular risk factors in men. Adipose tissue is an active endocrine organ producing substances that suppress testosterone (T) production and visceral fat plays a key role in this process. Low T leads to further accumulation of fat mass, thus perpetuating a vicious circle.

In this review, we discuss reduced levels of T and increased cardiovascular disease (CVD) risk factors by focusing on evidence derived from three different approaches.

(i) epidemiological/ observational studies (without intervention);
(ii) androgen deprivation therapy (ADT) studies (standard treatment in advanced prostate cancer); and
(iii) T replacement therapy (TRT) in men with T deficiency (TD).

In epidemiological studies, low T is associated with obesity, inflammation, atherosclerosis and the progression of atherosclerosis. Longitudinal epidemiological studies showed that low T is associated with an increased cardiovascular mortality. ADT brings about unfavourable changes in body composition, IR and dyslipidaemia. Increases in fibrinogen, plasminogen activator inhibitor 1 and C-reactive protein have also been observed.

TRT in men with TD has consistently shown a decrease in fat mass and simultaneous increase in lean mass. T is a vasodilator and in long-term studies, it was shown to reduce blood pressure. There is increasing evidence that T treatment improves insulin sensitivity and lipid profiles. T may possess anti-inflammatory and anti-coagulatory properties and therefore TRT contributes to reduction of carotid intima media thickness.

We suggest that T may have the potential to decrease CVD risk in men with androgen deficiency.

 

[Michael Scally MD]

Lundberg TR, Fernandez-Gonzalo R, Gustafsson T, Tesch PA. Aerobic exercise does not compromise muscle hypertrophy response to short-term resistance training. Journal of Applied Physiology 2013;114(1):81-9. Aerobic exercise does not compromise muscle hypertrophy response to short-term resistance training

This study tested the hypothesis that chronic aerobic and resistance exercise (AE+RE) would elicit greater muscle hypertrophy than resistance exercise only (RE). Ten men (25 ± 4 yr) performed 5 wk unilateral knee extensor AE+RE. The opposing limb was subjected to RE. AE completed 6 hr prior to RE consisted of ?45 min one-legged cycle ergometry. RE comprised 4 × 7 maximal concentric-eccentric knee extensions. Various indexes of in vivo knee extensor function were measured before and after training. Magnetic resonance imaging (MRI) assessed m. quadricep femoris (QF) cross-sectional area (CSA), volume, and signal intensity (SI). Biopsies obtained from m. vastus lateralis determined fiber CSA, enzyme levels, and gene expression of myostatin, atrogin-1, MuRF-1, PGC-1?, and VEGF. Increases (P < 0.05) in isometric strength and peak power, respectively, were comparable in AE+RE (9 and 29%) and RE (11 and 24%). AE+RE showed greater increase (14%; P < 0.05) in QF volume than RE (8%). Muscle fiber CSA increased 17% after AE+RE (P < 0.05) and 9% after RE (P > 0.05). QF SI increased (12%; P < 0.05) after AE+RE, but not RE. Neither AE+RE nor RE showed altered mRNA levels. Citrate synthase activity increased (P < 0.05) after AE+RE. The results suggest that the increased aerobic capacity shown with AE+RE was accompanied by a more robust increase in muscle size compared with RE. Although this response was not carried over to greater improvement in muscle function, it remains that intense AE can be executed prior to RE without compromising performance outcome.

 

[Michael Scally MD]

Science, New Media, and the Public

Nine in 10 internet users in the United States turn to search engines to find information and 60% of the U.S. public seeking information about specific scientific issues lists the Internet as their primary source of information. This has created a new urgency for scientists to pay attention to these trends and to the emerging scholarly literature about communicating science in this brave new “online” world.

A recent conference presented an examination of the effects of these unintended influences of Web 2.0 environments empirically by manipulating only the tone of the comments (civil or uncivil) that followed an online science news story in a national survey experiment. All participants were exposed to the same, balanced news item (covering nanotechnology as an emerging technology) and to a set of comments following the story that were consistent in terms of content but differed in tone.

Disturbingly, readers’ interpretations of potential risks associated with the technology described in the news article differed significantly depending only on the tone of the manipulated reader comments posted with the story. Exposure to uncivil comments (which included name-calling and other non–content-specific expressions of incivility) polarized the views among proponents and opponents of the technology with respect to its potential risks. In other words, just the tone of the comments following balanced science stories in Web 2.0 environments can significantly alter how audiences think about the technology itself.

Online environments are providing audiences with great opportunities to connect with science, but social scientists are only beginning to understand the nature of these connections and their potential outcomes on how audiences all make sense of complex scientific issues. Moreover, new tools of data collection and analysis (often captured under the “big data” label) have created opportunities for interdisciplinary collaborations among computer science, computational linguistics, and other social sciences. These collaborations will hopefully help in the analysis of audience-media interactions in Web 2.0 environments in more generalizable real world settings.

A world in which one in seven people actively use Facebook and more than 340 million tweets are being posted everyday is not the future of science communication any more. It is today’s reality. Scientists and social scientists must explore outcomes of online interactions about science in much greater detail. This work will have to be based on rigorous empirical social science rather than guesswork and anecdotal evidence about how to communicate complex and sometimes controversial science in these new information environments. Without applied research on how to best communicate science online, we risk creating a future where the dynamics of online communication systems have a stronger impact on public views about science than the specific research that we as scientists are trying to communicate.

Brossard D, Scheufele DA. Science, New Media, and the Public. Science 2013;339(6115):40-1. Science, New Media, and the Public

 

[Michael Scally MD]

Voluntary Exercise Does Not Ameliorate Spatial Learning And Memory Deficits Induced By Chronic Administration Of Nandrolone Decanoate

Highlights
? Chronic use of nandrolone decanoate (ND) is associated with changes in cognitive functions.
? Voluntary exercise enhances cognitive functions via a BDNF-dependent mechanism.
? Voluntary exercise was unable to improve the disruption of cognitive functions by chronic ND.
? Voluntary exercise-induced increase in hippocampal BDNF levels was potentiated by ND.
? Increased levels of BDNF may play a role in ND-induced impairments in learning and memory.


Tanehkar F, Rashidy-Pour A, Vafaei AA, et al. Voluntary exercise does not ameliorate spatial learning and memory deficits induced by chronic administration of nandrolone decanoate in rats. Hormones and Behavior. ScienceDirect.com - Hormones and Behavior - Voluntary exercise does not ameliorate spatial learning and memory deficits induced by chronic administration of nandrolone decanoate in rats

Chronic exposure to the anabolic androgenic steroids (AAS) nandrolone decanoate (ND) in supra-physiological doses is associated with learning and memory impairments. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we examined whether voluntary exercise would improve the cognitive deficits induced by chronic administration of ND. We also investigated the effects of ND and voluntary exercise on hippocampal BDNF levels.

The rats were randomly distributed into 4 experimental groups: the vehicle-sedentary group, the ND-sedentary group, the vehicle-exercise group, and the ND-exercise group. The vehicle-exercise and the ND-exercise groups were allowed to freely exercise in a running wheel for 15 days. The vehicle-sedentary and the ND-sedentary groups were kept sedentary for the same period. Vehicle or ND injections were started 14 days prior to the voluntary exercise and continued throughout the 15 days of voluntary exercise. After the 15-day period, the rats were trained and tested on a water maze spatial task using four trials per day for 5 consecutive days followed by a probe trial two days later.

Exercise significantly improved performance during both the training and retention of the water maze task, and enhanced hippocampal BDNF. ND impaired spatial learning and memory, and this effect was not rescued by exercise. ND also potentiated the exercise-induced increase in hippocampal BDNF levels.

These results seem to indicate that voluntary exercise is unable to improve the disruption of cognitive functions by chronic ND. Moreover, increased levels of BDNF may play a role in ND-induced impairments in learning and memory. The harmful effects of ND and other AAS on learning and memory should be taken into account when athletes decide to use AAS for performance or body image improvement.

 

[Michael Scally MD]

Smith RP, Coward RM, Kovac JR, Lipshultz LI. The evidence for seasonal variations of testosterone in men. Maturitas. Elsevier

Ample evidence exists to support the concept of diurnal variations in testosterone levels; however, substantiation for seasonal fluctuations is sparse and inconsistent. Since circadian disparities exist, laboratory screening for hypogonadism has traditionally been conducted using serum testosterone levels obtained in the early morning. Should circannual variability of testosterone be confirmed, it would make the monitoring of testosterone levels more difficult while forcing the development of seasonal reference standards to allow for comparison. Moreover, decisions to begin treatment and adjustment of practice patterns would likely follow. This review thoroughly explores all of the available evidence concerning seasonal variations in testosterone levels. The impacts of melatonin, vitamin D, sleep-wake cycles, light exposure, physical activity, BMI, and waist circumference are also discussed. Current research suggests that while some evidence exists to support the notion of seasonal testosterone variations, the discussed inconsistencies preclude the incorporation of this concept into current clinical standards.

 

[Michael Scally MD]

Song B, Qian W-p. Effectiveness of Combined Testosterone Undecanoate with Tamoxifen Citrate Treatment in Men with Idiopathic Azoospermia or Serious Oligozoospermia. Journal of Reproduction and Contraception 2012;23(4):254-8. ScienceDirect.com - Journal of Reproduction and Contraception - Effectiveness of Combined Testosterone Undecanoate with Tamoxifen Citrate Treatment in Men with Idiopathic Azoospermia or Serious Oligozoospermia

Objective To assess the effect of treatment with a combination of the tamoxifen citrate and testosterone undecanoate on sperm variables in men with idiopathic azoospermia or oligozoospermia.

Methods Four men with idiopathic azoospermia and 8 men with idiopathic oligozoospermia were collected in this retrospective and self control trial. All patients were treated with testosterone undecanoate of 80 mg/d and tamoxifen citrate of 20 mg/d. Sperm characteristics and pregnancy incidence were measured every month during 4 months medication.

Results Tamoxifen citrate plus testosterone undecanoate treatment produced a satisfactory improvement of total sperm number, motility after 2 and 3 months whereas serum FSH, LH levels increased after 2 or 3 months.

Conclusion The combination of tamoxifen citrate with testosterone undecanoate could improve significantly sperm count. The combination could be used in men with idiopathic azoospermia or serious oligozoospermia.

 

[Michael Scally MD]

Liew CW, Boucher J, Cheong JK, et al. Ablation of TRIP-Br2, a regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance. Nat Med;advance online publication. http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3056.html

Obesity develops as a result of altered energy homeostasis favoring fat storage. Here we describe a new transcription co-regulator for adiposity and energy metabolism, SERTA domain containing 2 (TRIP-Br2, also called SERTAD2). TRIP-Br2–null mice are resistant to obesity and obesity-related insulin resistance. Adipocytes of these knockout mice showed greater stimulated lipolysis secondary to enhanced expression of hormone sensitive lipase (HSL) and ?3-adrenergic (Adrb3) receptors. The knockout mice also have higher energy expenditure because of increased adipocyte thermogenesis and oxidative metabolism caused by upregulating key enzymes in their respective processes.

Our data show that a cell-cycle transcriptional co-regulator, TRIP-Br2, modulates fat storage through simultaneous regulation of lipolysis, thermogenesis and oxidative metabolism. These data, together with the observation that TRIP-Br2 expression is selectively elevated in visceral fat in obese humans, suggests that this transcriptional co-regulator is a new therapeutic target for counteracting the development of obesity, insulin resistance and hyperlipidemia.

 

[Michael Scally MD]

Zhang S-J, Qian H-N, Zhao Y, et al. Relationship between age and prostate size. Asian J Androl 2013;15(1):116-20. http://www.nature.com/aja/journal/v15/n1/full/aja2012127a.html

In a community-based study, the relationship between age and human prostate size was investigated in a population of men between the ages of 40 and 70 years to determine the normal prostate increase curve equation. One thousand male volunteers were randomly recruited from the Shanghai community, and the length, width, height, volume of the transition zone (TZ) and the whole prostates were measured by transrectal ultrasound (TRUS). Each volunteer was evaluated by the International Prostate Symptom Score (IPSS). Among those who completed the examination, the mean prostate parameters were all positively associated with increased age. There were statistically significant differences between each age group (P<0.05). The mean transition zone volume (TZV) had a higher increase rate with age than the mean total prostate volume (TPV), indicating that the enlargement of the TZ contributed the most to the increase in TPV. While all prostate parameters were positively correlated with the IPSS, the strongest correlation was associated with the TZ length (TZL) and TZV. The growth curve equations for prostate width, height and length were also positively associated with increasing age.

 

[Michael Scally MD]

Jensen TK, Heitmann BL, Jensen MB, et al. High dietary intake of saturated fat is associated with reduced semen quality among 701 young Danish men from the general population. The American Journal of Clinical Nutrition. http://ajcn.nutrition.org/content/early/2012/12/23/ajcn.112.042432.abstract

Background: Saturated fat intake has been associated with both cardiovascular disease and cancer risk, and a newly published study found an association between saturated fat intake and a lower sperm concentration in infertile men.

Objective: The objective was to examine the association between dietary fat intake and semen quality among 701 young Danish men from the general population.

Design: In this cross-sectional study, men were recruited when they were examined to determine their fitness for military service from 2008 to 2010. They delivered a semen sample, underwent a physical examination, and answered a questionnaire comprising a quantitative food-frequency questionnaire to assess food and nutrient intakes. Multiple linear regression analyses were performed with semen variables as outcomes and dietary fat intakes as exposure variables, adjusted for confounders.

Results: A lower sperm concentration and total sperm count in men with a high intake of saturated fat was found. A significant dose-response association was found, and men in the highest quartile of saturated fat intake had a 38% (95% CI: 0.1%, 61%) lower sperm concentration and a 41% (95% CI: 4%, 64%) lower total sperm count than did men in the lowest quartile. No association between semen quality and intake of other types of fat was found.

Conclusions: Our findings are of potentially great public interest, because changes in diet over the past decades may be part of the explanation for the recently reported high frequency of subnormal human sperm counts. A reduction in saturated fat intake may be beneficial for both general and reproductive health.

 

[Michael Scally MD]

Raynaud J-P, Gardette J, Rollet J, Legros J-J. Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment. BJU International. Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment - Raynaud - 2013 - BJU International - Wiley Online Library

What's known on the subject? and What does the study add?
* Hypogonadism affects an estimated 2–4 million men in the USA, but only 5% receive treatment. Testosterone replacement therapy reduces the effects of testosterone deficiency on sexual function, mood and energy in hypogonadal patients. Long-term hypogonadism management requires testosterone treatment to restore serum concentrations of testosterone and its active metabolites, within physiological ranges; a testosterone preparation that achieves physiological plasma concentrations without supra-physiological escape is a preferred option. A previous 1-year study European clinical study showed the efficacy and safety of a transdermal testosterone patch (Testopatch®).
* The present study shows the long-term (6-year) safety and efficacy of Testopatch in patients with primary or secondary hypogonadism. We show that, over the long-term, Testopatch was associated with no relevant changes in PSA concentration and PSA velocity, or any significant prostate risks (there were no cases of prostate cancer).

Objective
* To assess the change in prostate-specific antigen (PSA) concentrations in patients with primary or secondary hypogonadism, receiving transdermal testosterone.

Patients and Methods
* This was an interventional, 6-year study, conducted in Urology and Endocrinology centres in Belgium, France, Germany, the Netherlands and Spain.
* Participants were primary (48%) or secondary (52%) hypogonadal patients who received two 60?cm2 testosterone patches (Testopatch®), delivering 4.8?mg of testosterone per day, applied every 2 days.
* During treatment, total testosterone (TT), dihydrotestosterone, oestradiol and, PSA concentrations were measured in a centralised laboratory every 3 months during the first year, and every 6 months thereafter.

Results
* In all, 200 patients [mean (sd) age 41.0?(12.5) years, body weight 82.5?(13.7)?kg, height 177.2?(9.3)?cm, body mass index 26.2?(3.4)?kg/m2] were treated with transdermal testosterone patches.
* In all, 161 patients completed the 1-year study and 115 entered into a 5-year study extension; 51 patients completed the sixth year of the study.
* The mean baseline concentrations of TT and PSA were 1.4?ng/mL and 0.47?ng/mL, respectively; TT serum concentrations >3?ng/mL were achieved in 85% of patients and fluctuated between 4.4 and 6.0?ng/mL.
* At each successive 6-month time point, mean the PSA values were 0.60, 0.67, 0.76, 0.70, 0.61, 0.68, 0.64, 0.71, 0.75, 0.74, 1.01, 0.78, 0.80?ng/mL, respectively. The mean PSA velocity was negligible (0.00–0.03?ng/mL/year) from 30 months to the end of the trial, except for a value of 0.08 at 60 months. Seven patients had a PSA concentration of >4?ng/mL due to a sharp PSA increase. Six of these patients had prostatitis and PSA concentrations returned to previous levels with appropriate treatment. No prostate cancer was reported during the trial.

Conclusion
* These data support a strong safety profile for Testopatch, even at the highest registered dosage.

 

[Michael Scally MD]

Kievit P, Halem H, Marks DL, et al. Chronic Treatment With a Melanocortin 4 Receptor Agonist Causes Weight Loss, Reduces Insulin Resistance, and Improves Cardiovascular Function in Diet-Induced Obese Rhesus Macaques. Diabetes. Chronic Treatment With a Melanocortin 4 Receptor Agonist Causes Weight Loss, Reduces Insulin Resistance, and Improves Cardiovascular Function in Diet-Induced Obese Rhesus Macaques

The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects.

 

[Michael Scally MD]

Singh MS, Charbel Issa P, Butler R, et al. Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation. Proceedings of the National Academy of Sciences. Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation

One strategy to restore vision in retinitis pigmentosa and age-related macular degeneration is cell replacement. Typically, patients lose vision when the outer retinal photoreceptor layer is lost, and so the therapeutic goal would be to restore vision at this stage of disease. It is not currently known if a degenerate retina lacking the outer nuclear layer of photoreceptor cells would allow the survival, maturation, and reconnection of replacement photoreceptors, as prior studies used hosts with a preexisting outer nuclear layer at the time of treatment. Here, using a murine model of severe human retinitis pigmentosa at a stage when no host rod cells remain, we show that transplanted rod precursors can reform an anatomically distinct and appropriately polarized outer nuclear layer. A trilaminar organization was returned to rd1 hosts that had only two retinal layers before treatment. The newly introduced precursors were able to resume their developmental program in the degenerate host niche to become mature rods with light-sensitive outer segments, reconnecting with host neurons downstream. Visual function, assayed in the same animals before and after transplantation, was restored in animals with zero rod function at baseline. These observations suggest that a cell therapy approach may reconstitute a light-sensitive cell layer de novo and hence repair a structurally damaged visual circuit. Rather than placing discrete photoreceptors among preexisting host outer retinal cells, total photoreceptor layer reconstruction may provide a clinically relevant model to investigate cell-based strategies for retinal repair.

 

[Michael Scally MD]

Varewijck AJ, Lamberts SWJ, Neggers SJCMM, Hofland LJ, Janssen JAMJL. IGF-I Bioactivity Might Reflect Different Aspects of Quality of Life Than Total IGF-I in GH-Deficient Patients During GH Treatment. Journal of Clinical Endocrinology & Metabolism. IGF-I Bioactivity Might Reflect Different Aspects of Quality of Life Than Total IGF-I in GH-Deficient Patients During GH Treatment

Context: No relationship has been found between improvement in quality of life (QOL) and total IGF-I during GH therapy.

Aim: Our aim was to investigate the relationship between IGF-I bioactivity and QOL in GH-deficient (GHD) patients receiving GH for 12 months.

Methods: Of 106 GHD patients, 84 on GH treatment discontinued therapy 4 weeks before establishing baseline values and 22 were GH-naive. IGF-I bioactivity was determined by IGF-I kinase receptor activation assay, total IGF-I by immunoassay (Immulite), and QOL by the disease-specific Question on Life Satisfaction Hypopituitarism (QLS-H) module and by the general SF-36 questionnaire (SF-36Q).

Results: IGF-I bioactivity increased after 6 months (?2.5 vs ?1.9 SD, P <; .001) and did not further increase after 12 months (?1.8 SD, P = .23); total IGF-I increased from ?2.3 to ?0.9 SD (P <; .001) and to ?0.6 SD (P = .005), respectively. QLS-H did not change over 12 months (?0.66 ± 0.16 to ?0.56 ± 0.17 SD [P = .42] to ?0.68 ± 0.17 SD [P = .22]). The mental component summary of the SF-36Q increased from 47.4 (38.7–52.8) to 50.2 (43.1–55.3) (P = .001) and did not further improve (49.4 [42.1–54.1], P = .19); the physical component summary did not change (47.5 [42.0–54.2] vs 47.0 [41.9–55.3], P = .91, vs 48.3 [39.9–55.4], P = .66). After 12 months, IGF-I bioactivity was related to QLS-H (r = 0.28, P = .01); total IGF-I was not (r = 0.10, P = .37). IGF-I bioactivity and total IGF-I were related to PCS (r = 0.35, P = .001; and r = 0.31, P = .003).

Conclusion: IGF-I bioactivity remained subnormal after GH treatment and was positively related to QLS-H, whereas total IGF-I was not. This suggests that IGF-I bioactivity reflects different aspects of QOL than total IGF-I in GHD patients during GH treatment.

 

[Michael Scally MD]

Stein EM, Carrelli A, Young P, et al. Bariatric Surgery Results in Cortical Bone Loss. Journal of Clinical Endocrinology & Metabolism. Bariatric Surgery Results in Cortical Bone Loss

Background: Bariatric surgery results in bone loss at weight-bearing sites, the mechanism of which is unknown.

Methods: Twenty-two women (mean body mass index 44 kg/m2; aged 45 years) who underwent Roux-en-Y gastric bypass (n = 14) and restrictive procedures (n = 8) had measurements of areal bone mineral density by dual-energy x-ray absorptiometry at the lumbar spine, total hip (TH), femoral neck (FN), and one third radius and trabecular and cortical volumetric bone mineral density and microstructure at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 12 months postoperatively.

Results: Mean weight loss was 28 ± 3 kg (P < .0001). PTH rose 23% (P < .02) and 25-hydroxyvitamin D was stable. C-telopeptide increased by 144% (P < .001). Bone-specific alkaline phosphatase did not change. Areal bone mineral density declined at TH (?5.2%; P < .005) and FN (?4.5%; P < .005). By HR-pQCT, trabecular parameters were stable, whereas cortical bone deteriorated, particularly at the tibia: cortical area (?2.7%; P < .01); cortical thickness (?2.1%; P < .01); total density (?1.3%; P = .059); cortical density (?1.7%; P < .01). In multivariate regression, bone loss at the TH and FN were predicted by weight loss. In contrast, only PTH increase predicted cortical deterioration at the tibia. Roux-en-Y gastric bypass patients lost more weight, had more bone loss by dual-energy x-ray absorptiometry and HR-pQCT than those with restrictive procedures, and had declines in cortical load share estimated by finite element analysis.

Conclusions: After bariatric surgery, hip bone loss reflects skeletal unloading and cortical bone loss reflects secondary hyperparathyroidism. This study highlights deterioration of cortical bone loss as a novel mechanism for bone loss after bariatric surgery.

 

[Michael Scally MD]

Benso A, Gramaglia E, Olivetti I, et al. THE GH RELEASING EFFECT OF ACYLATED GHRELIN IN NORMAL SUBJECTS IS REFRACTORY TO GH ACUTE AUTO-FEEDBACK BUT IS INHIBITED AFTER SHORT-TERM GH ADMINISTRATION INDUCING IGF-I INCREASE. European Journal of Endocrinology. THE GH RELEASING EFFECT OF ACYLATED GHRELIN IN NORMAL SUBJECTS IS REFRACTORY TO GH ACUTE AUTO-FEEDBACK BUT IS INHIBITED AFTER SHORT-TERM GH ADMINISTRATION INDUCING IGF-I INCREASE

Objective: Growth hormone (GH) secretion is regulated by an interplay between GH-releasing hormone (GHRH), somatostatin (SST) and other central and peripheral signals. Acylated ghrelin (AG) amplifies GH pulsatility acting, at least partially, independently from GHRH and SST. The GH response to GHRH is inhibited by recombinant human GH (rhGH), likely due to a somatostatin-mediated negative GH auto-feedback. The effect of exogenous rhGH on the GH-releasing effect of AG has never been tested.

Design and Methods: In 6 healthy volunteers we studied the GH response to acute AG administration (1.0 µg/kg i.v.) during saline or rhGH infusion (4.0 µg/kg/h i.v.) or after 4-day rhGH (10.0 µg/kg s.c.) administration. Results: Compared to saline, rhGH infusion increased GH levels (p<0.01). During saline, acute i.v. AG induced a marked increase (p<0.01) of GH levels similar to that observed after AG administration during rhGH infusion. During s.c. rhGH, IGF1 levels rose from day 0 to day 5 (p<0.01). After 4-day s.c. rhGH, i.v. AG increased (p<0.01) GH levels, though significantly (p<0.05) less than on day 0.

Conclusions: The marked somatotroph-releasing effect of AG is refractory to a direct GH auto-feedback whereas is markedly inhibited after 4-day rhGH administration, suggesting the possibility of a selective IGF1-mediated inhibitory feedback.

 

[Michael Scally MD]

Alsemari A. Hypogonadism and neurological diseases. Neurol Sci. Hypogonadism and neurological diseases - Online First - Springer

Affected patients with hypogonadism have unnaturally low amounts of sex hormones that produce male and female sex characteristics. Males who suffer from this condition lack testosterone, while females fail to produce enough estrogen. Hypogonadism may be present at birth, or it may take effect years later following injury or illness to the sex glands. Hypogonadism has remarkable associations with variable medical disorders; however, it is characterized by a distinctive association with variable neurological disorders: such as epilepsy, ataxia, dysmyelination, nerve muscle disease, movement disorders, mental retardation and deafness. The remarkable neurological diseases with hypogonadism should not basically be regarded as coincidental findings, but possibly related to an intrinsic pathophysiological association.

 

[Michael Scally MD]

Huang G, Bhasin S, Tang ER, et al. Effect of Testosterone Administration on Liver Fat in Older Men With Mobility Limitation: Results From a Randomized Controlled Trial. J Gerontol A Biol Sci Med Sci. Effect of Testosterone Administration on Liver Fat in Older Men With Mobility Limitation: Results From a Randomized Controlled Trial

BACKGROUND: Androgen receptor (AR) knockout male mice display hepatic steatosis, suggesting that AR signaling may regulate hepatic fat. However, the effects of testosterone replacement on hepatic fat in men are unknown. The aim of this study was to determine the effects of testosterone administration on hepatic fat in older men with mobility limitation and low testosterone levels who were participating in a randomized trial (the Testosterone in Older Men trial).

METHODS: Two hundred and nine men with mobility limitation and low total or free testosterone were randomized in the parent trial to either placebo or 10-g testosterone gel daily for 6 months. Hepatic fat was determined by magnetic resonance imaging in 73 men (36 in placebo and 37 in testosterone group) using the volumetric method. Insulin sensitivity (homeostatic model assessment-insulin resistance) was derived from fasting glucose and insulin.

RESULTS: Baseline characteristics were similar between the two groups, including liver volumes (1583+/-363 in the testosterone group vs 1522+/-271mL in the placebo group, p = .42). Testosterone concentrations increased from 250+/-72 to 632+/-363ng/dL in testosterone group but did not change in placebo group. Changes in liver volume during intervention did not differ significantly between groups (p = .5) and were not related to on-treatment testosterone concentrations. The change in homeostatic model assessment-insulin resistance also did not differ significantly between groups and was not related to either baseline or change in liver fat.

CONCLUSION: Testosterone administration in older men with mobility limitation and low testosterone levels was not associated with a reduction in hepatic fat. Larger trials are needed to determine whether testosterone replacement improves liver fat in men with nonalcoholic hepatic steatosis.

 

[Michael Scally MD]

Thomas SS, Mitch WE. Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin. Clin Exp Nephrol. Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin - Online First - Springer

Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle, yielding fragments that are substrates that are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF-1, and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin, which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting, suggesting that therapies that block myostatin could prevent muscle wasting in catabolic conditions.