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In Update on Sperm, Data Show No Decline
http://www.nytimes.com/2011/06/07/health/research/07sperm.html?_r=1

By GINA KOLATA
Published: June 6, 2011

It is one of the most fraught topics in environmental health. Are men becoming less fertile, with declining sperm counts and diminishing sperm quality? If they are, then sperm might be an early warning sign of environmental dangers. And the prime suspects have been substances like plastics and pesticides that can have weak estrogenlike effects on cells.

But now 15 years of data from 18-year-old Danish men taking their military physicals show no decline in sperm counts, after all. The idea that sperm counts were plummeting began with an alarming paper published in 1992 by a group of Danish researchers. Sperm counts, they reported, declined by 50 percent worldwide from 1938 to 1991, and the trend would continue, they said.

Many other researchers criticized the data’s quality, citing flaws like a lack of standardized methods of collecting semen, methodological issues in semen analysis, biases in the ways men were selected, and variations in the length of time men abstained from ejaculating before their semen was collected.

The study, said Dolores Lamb, a fertility expert at Baylor College of Medicine and president-elect of the American Society of Reproductive Medicine, “was problematic and raised alarms in society without critical thinking about the caveats and weaknesses inherent in the data and its analysis.”

Nonetheless, the paper was highly influential. It was cited by 1,000 subsequent scientific papers.

Other researchers soon published their own studies, but methodological problems persisted. And the later studies came to contradictory conclusions, with some saying sperm counts were declining and others saying they were not. The result was a body of evidence so poor that a panel of experts assembled by the National Academy of Sciences in 1999 said its members could not come to a consensus on whether counts were declining, mostly because of seriously flawed studies.

Meanwhile, the same Danish group that got the debate started began a study that analyzed annual semen samples collected from 18-year-old men who were being examined for their fitness for the military — a requirement in Denmark. Over the past 15 years, a total of 5,000 men provided semen for analysis.

That design was an improvement over older studies, Dr. Lamb said. The data are from men of the same age and from one geographic area (sperm numbers and quality can vary from one region to another). Analysis of sperm is better now than it was in years past. And with 15 years of data, she said, any decline in sperm numbers or quality should have been evident.

The problem was that the group did not publish its data, even though, said Dr. Jens Peter Bonde, a fertility researcher at Copenhagen University Hospital, “we have asked for these findings — they are of great public interest.” Dr. Niels Erik Skakkebaek of the University of Copenhagen, who initiated the study, said he wouldn’t comment on the data before the research appears in a scientific journal. And he would not say when that might be.

But the data have been published anyway, in an unusual manner.

In a telephone interview, Dr. Skakkebaek said the research group’s current leader, Niels Jorgensen, sent the data to the Danish Ministry of Health, which helped pay for the study, and the ministry then posted the data on its Web site. Dr. Skakkebaek was angry, saying in an e-mail: “The trend data has not been appropriately scientifically scrutinized. Also, I cannot guarantee that the civil servant in the ministry put our data into the figure without mistakes.”

Now, an American journal, Epidemiology, has published the data in a commentary and discussed them in an editorial.

The commentary, by Dr. Bonde, includes a graph of the data and says they constitute “the best longitudinal semen data yet available.”

The journal’s editor, Dr. Allen Wilcox, said he decided to reproduce the figure from the ministry Web site because the data are so important. Yet, he wrote in the editorial, “the presentation of a few raw data on a Web site — or in a commentary — is hardly the preferred way to advance science.” But, he added, “neither is it acceptable for valuable data to be held in storage.”


Wilcox AJ. On Sperm Counts and Data Responsibility. Epidemiology.

Are sperm counts declining over time? This question has been fiendishly difficult to address. Measurements of semen parameters are fraught with problems at every level: wide variations within a given man, incomplete and selective participation among groups of men, difficult-to-control confounding factors (such as abstinence time), and vagaries of laboratory methods. Without consistent collection and assay over time, we are left with confusion and conflict. Some researchers remain highly skeptical of the evidence for changes over time, whereas others argue that environmental pollutants (in particular, chemicals that act as endocrine disruptors) are causing serious damage to the male reproductive tract.

With this as background, the commentary by Jens Peter Bonde and his colleagues in this issue of EPIDEMIOLOGY is instructive. The authors present a graph posted online by the Danish National Board of Health last March. The graph provides what this field has lacked for so long: sperm data from samples collected consistently and regularly over time, from an unselected population of young men (in this case, Danish military draftees), and analyzed with standardized laboratory methods. On the face of it, the results are striking; there is no evidence of a decline in sperm counts in Denmark over the last 15 years.


Bonde JP, Ramlau-Hansen CH, Olsen J. Trends in Sperm Counts: The Saga Continues. Epidemiology.

Almost 20 years ago, a longstanding debate over possible declines in sperm counts was reignited by a paper in BMJ, claiming that sperm counts had declined worldwide by 50%.1 Despite its rather weak documentation, this paper by Carlsen et al had a strong impact in the public media, and has been cited in more than 1000 scientific papers— perhaps in part because the authors were bold enough to include a linear regression line pointing forward toward continuing declines and a doomed society. Since the publication of that paper, numerous studies have reported secular trends and geographical shifts in sperm counts, with conflicting findings and no emerging consensus. However, recent developments may be changing this picture.
 

Attachments

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

High Prevalence of Micropenis and Cryptorchidism in Brazilian Patients with Congenital Hypogonadotropic Hypogonadism: Impact of Testosterone Replacement Therapy Started in Adolescence or Adulthood on Final Penile Length

once again the treatment of choice is injections.
 
Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

I would've like to see it compared with androgel.
 
Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[OR27-4] Long-Term Growth Hormone (GH) Administration Increases Hepatic Insulin Resistance, but Not Muscle Insulin Resistance, in Healthy Older Men and Women http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_OR27-4

H-W Lee, R Muniyappa, SM Harman, MR Blackman. National Institutes of Health, Bethesda, MD; National Institutes of Health, Bethesda, MD; National Institutes of Health, Baltimore, MD; Kronos Longevity Research Institute, Phoenix, AZ; Johns Hopkins University School of Medicine, Baltimore, MD; Veterans Affairs Medical Center, Washington, DC, Washington, DC.

Background: Normal aging is associated with reduced GH and IGF-I production, increased total body and visceral adiposity, decreased lean body mass, and worsened insulin resistance. Several studies suggest that acute and chronic GH replacement in younger patients with adult GH deficiency worsen hepatic insulin resistance. However, the effects of chronic GH supplementation on hepatic and muscle insulin resistance in healthy older individuals are unknown.

Objective: We examined baseline relationships among serum IGF-I concentrations, measures of adiposity, age, and hepatic and muscle insulin resistance (HIR and MIR, respectively) in 101 older (age 65-88 yr) men (n = 61) and women (n = 40) with age-related declines in IGF-I (? 230 ng/ml). We then assessed the effects of GH administration (20 µg/kg, given subcutaneously 3x/week) for 26 weeks on surrogate indices of HIR and MIR derived from oral glucose tolerance testing (OGTT) in a subset of 46 of these subjects (age range: 65-83 yrs), using a double-masked, placebo-controlled randomized study design (Men: GH group, n = 14 vs. Placebo group, n = 12; Women: GH group, n = 10 vs. Placebo group, n = 10).

Methods: Measures of body composition were assessed by body mass index (BMI), DEXA [absolute and % total body fat (TBF), lean body mass (LBM)], and abdominal MRI [total (TAF), subcutaneous (SC fat) and visceral fat (VF)]. Surrogate indices of HIR and MIR were derived from circulating insulin and glucose concentrations during a 75g standard OGTT.

Results: Linear regression analysis of baseline measures revealed that IGF-I concentrations were directly related to VF (r = 0.32, P = 0.01) and HIR (r = 0.33, P = 0.02) in men. In contrast, IGF-I was not significantly related to any measures of adiposity, HIR, MIR or age in women. GH supplementation for 26 weeks increased LBM and decreased TBF (P < 0.05) in men and women, but did not affect VF (P > 0.05) in either sex. Despite these overall body composition changes, GH supplementation increased HIR, compared to placebo, in men and women (change from baseline: Men, 56.4% vs. -4.8%, P = 0.02; Women, 142% vs. 17.4%, P = 0.01, adjusted for baseline HIR values and changes in VF from baseline), but did not significantly affect MIR in either sex.

Conclusions: In healthy older men and women, as in younger patients with adult GH deficiency, long-term GH administration increases hepatic insulin resistance with little or no effect on skeletal muscle insulin resistance.
 
Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-470] Weekly Administration of Sustained-Release Growth Hormone Reduces Abdominal Visceral Fat and Waist Circumference in Adults with Abdominal Obesity http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-470

JW Hong, WK Lee, YD Song, EJ Lee. Yonsei University College of Medicine, Seoul, Republic of Korea; National Health Insurance Cooperation Ilsan Hospital, Ilsan, Republic of Korea.

Objectives: Administration of recombinant human growth hormone (rhGH) in obesity has been known to lead to a decrease in visceral adiposity and an increase in lean body mass. Most studies have used supraphysiologic doses of rhGH which were administered daily or every other day. We aimed to evaluate whether weekly administered low dose of sustained-release rhGH (SR-rhGH) could play a therapeutic role in the treatment of abdominal obesity.

Methods: Prospective, single-arm, open-label, multicenter pilot study was carried out. Participants were 26 adults, 40-65 years old with abdominal obesity (male: waist circumference >90cm, female: waist circumference>85cm). The subjects were given 3 mg of SR-rhGH, administered subcutaneously, weekly for 26 weeks. The main outcome was measured using fat distribution, body composition, and waist circumference.

Results: After 26 weeks, SR-rhGH treatment reduced abdominal visceral adipose tissue (VAT) (140.35 ± 75.97 to 128.43 ± 73.85 cm2, p= 0.0038) and subcutaneous adipose tissue (SAT) (198.32 ± 55.57 to 185.77 ± 56.25 cm2, p=0.05). In the subgroup analysis for abdominal VAT according to sex and age, VAT significantly decreased after GH treatment in women only (p=0.0146), and not men (p=0.1681). When classified by age, only subjects in their 60s showed significant change in VAT after GH treatment (p= 0.0013). Average waist circumference decreased from 96.25 ± 6.41 to 91.93 ± 6.13 cm (p<0.0001) after treatment. However, body weight or lean body mass did not show any significant change. There were no severe adverse events or drop-outs during the study.

Conclusions: SR-rhGH treatment for 26 weeks reduced abdominal visceral/subcutaneous fat and waist circumference. Further studies may be considered on the role of weekly administered SR-rhGH as a treatment for abdominal obesity, especially in older women subjects.


[P2-418] Sustained-Release Recombinant Human Growth Hormone Improved Body Composition and Quality of Life in Adults over 50 Years Old with Somatopause http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-418

H Seok, JW Hong, YS Chung, SW Kim, EJ Lee, D Kim. Yonsei University College of Medicine, Seoul, Korea; Ajou University School of Medicine, Gyeonggi, Korea; Kyung Hee University School of Medicine, Seoul, Korea.

Background: Treatment with recombinant human GH (rhGH) can help the elderly experiencing somatopause and the resultant metabolic impairment obtain partial recovery. However, aged adults suffer inconvenience from daily injection of existing rhGH.

Objectives: To evaluate the effects, safety, and compliance of weekly administered low dose of sustained-release rhGH (SR-rhGH) in aged adults with somatopause.

Design: This is a 26-week prospective, single-arm, multicenter pilot study.

Intervention/Participants: A total of 38 subjects, aged ? 50 years were enrolled and each received 2 mg of SR-rhGH for 26 weeks.

Results: The mean baseline IGF-1 level of 123.4 ± 41.6 ng/ml increased to 174.8 ± 59.6 ng/ml at week 4, and the level was maintained for the remainder of the study period. At week 26, an average lean body mass increased by 0.45 kg, waist circumference reduced by 1.06 cm, and the quality of life (QoL) was significantly improved (P < 0.01 in each index). Serum levels of biochemical markers of bone resorption and formation simultaneously increased. An estrogen substitute in women attenuated the beneficial effects of SR-rhGH on body composition and metabolic indices. There was no significant change in the body fat distribution or fat mass. Adverse events included pruritus (10.5%), arthralgia (5.3%), and edema (5.3%), but their symptoms were well tolerable.

Conclusions: Body composition and quality of life can be restored in part by the replacement of low dose SR-rhGH for 26 weeks in patients with somatopause without significant adverse effects.
 
Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-472] Formoterol, a Highly ?2-Selective Adrenergic Agonist, Increases Energy Expenditure, Fat Utilization and Protein Anabolism in Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-472

P Lee, RO Day, V Birzniece, S Sutanto, JR Greenfield, KKY Ho. Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Hospital, Sydney, Australia; St Vincent's Hospital, Sydney, Australia.

The sympathetic nervous system regulates energy expenditure (EE) and substrate metabolism. Sympathetic stimulation of ?2-adrenoceptors in adipose tissue and skeletal muscle enhances fat utilisation and protein anabolism (1). However, therapeutic exploitation of ?2-adrenegic agonism for these metabolic benefits had been hindered by limited specificity of available ?2-adrenergic agonists, which cross-stimulate cardiac ?1-adrenoceptors and induce tachycardia. Formoterol is a new generation, highly ?2-selective adrenergic agonist. The metabolic effects of formoterol in humans have not been studied.

The aim is to investigate the effects of formoterol on energy and protein metabolism. We undertook a) a dose-finding study in 4 subjects, administered 80, 160 and 320 ?g daily of oral formoterol for 1 week each and b) a detailed metabolic evaluation in 8 men before and at the end of 1 week treatment. EE and fat oxidation (Fox) were quantified by indirect calorimetry with diet-induced thermogenesis measured over 120 minutes after a standardised meal. Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance (LRa) and leucine oxidation (Lox) were estimated. Statistical analysis was performed after log-transformation where appropriate.

In the dose finding study, 160 ?g achieved a maximal increase in resting EE and Fox without inducing tachycardia. In the metabolic study, this dose increased resting EE by 13±2% (p<0.001), Fox by 23±4% (p<0.01) but not heart rate (p=0.2). Basal plasma non-esterified free fatty acid concentration rose by 16±2% (p<0.05). Post-prandial EE was enhanced by 10±3% (p=0.03). Formoterol significantly reduced LRa (p<0.001) and Lox (p<0.01) by 9±2% and 14±3%, respectively. Lox as a proportion LRa was significantly lower after formoterol treatment by 6±1% (p=0.03).

In summary, formoterol 160 ?g/day increases resting energy expenditure, fat utilisation and protein anabolism, without inducing tachycardia. From this first metabolic evaluation of formoterol in humans, we conclude that formoterol imparts beneficial metabolic changes and may be a potential therapy for obesity and sarcopaenia.

(1) Lynch GS et al., Physiol Rev. 2008; 88: 729-67

[Lynch GS, Ryall JG. Role of Beta-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease. Physiological Reviews 2008;88(2):729-67. http://physrev.physiology.org/content/88/2/729.full (Role of ?-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease)

The importance of ?-adrenergic signaling in the heart has been well documented, but it is only more recently that we have begun to understand the importance of this signaling pathway in skeletal muscle. There is considerable evidence regarding the stimulation of the ?-adrenergic system with ?-adrenoceptor agonists (?-agonists). Although traditionally used for treating bronchospasm, it became apparent that some ?-agonists could increase skeletal muscle mass and decrease body fat. These so-called "repartitioning effects" proved desirable for the livestock industry trying to improve feed efficiency and meat quality. Studying ?-agonist effects on skeletal muscle has identified potential therapeutic applications for muscle wasting conditions such as sarcopenia, cancer cachexia, denervation, and neuromuscular diseases, aiming to attenuate (or potentially reverse) the muscle wasting and associated muscle weakness, and to enhance muscle growth and repair after injury. Some undesirable cardiovascular side effects of ?-agonists have so far limited their therapeutic potential. This review describes the physiological significance of ?-adrenergic signaling in skeletal muscle and examines the effects of ?-agonists on skeletal muscle structure and function. In addition, we examine the proposed beneficial effects of ?-agonist administration on skeletal muscle along with some of the less desirable cardiovascular effects. Understanding ?-adrenergic signaling in skeletal muscle is important for identifying new therapeutic targets and identifying novel approaches to attenuate the muscle wasting concomitant with many diseases.]
 
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[P2-359] The Accuracy of Diagnostic Tests for Growth Hormone Deficiency in Adults: A Systematic Review and Meta-Analysis http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-359

A Hazem, M Elamin, G Malaga, I Bancos, CL Zeballos-Palacios, Y Prevost, ER Velasquez, P Erwin, MH Murad, V Montori. Mayo Clinic, Rochester, MN; Universidad Peruana Cayetano Heredia, Lima, Peru.

Context: The diagnostic accuracy of tests used to diagnose growth hormone (GH) deficiency in adults is unclear.

Objective: To conduct a diagnostic systematic review and meta-analysis of studies that provided data on diagnostic tests of choice.

Data Sources: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Sciences and Scopus) through September 2009. Review of reference lists and contact with experts further identified candidate studies.

Study Selection: Reviewers, working independently and in duplicate, determined study eligibility.

Data Extraction: Reviewers, working independently and in duplicate, determined the methodological quality of studies and collected descriptive, quality and outcome data.

Data Synthesis: Twenty-one studies provided diagnostic accuracy data. Studies were all nonrandomized and had fair methodological quality (assessed using the QUADAS checklist) and included 977 patients. Several tests had good diagnostic accuracy (diagnostic odds ratio >50) such as GH-RP6, Acipimox+GHRH test, GHRH+GHRP6, GHRH+GHRP2, hexarelin stimulation test, arginine and ITT (insulin tolerance test).Other tests such serum level of IGF-1 and growth hormone had lower accuracy. The gold standard varied widely between studies. Heterogeneity was significant in most analyses. No studies examined the effect of diagnostic strategies on patient-important outcomes.

Results: Out of 14 tests of interest covered by included studies, 5 tests proved to be significantly more accurate than the rest. Those tests are; ITT, GHRP6, GHRH+GHRP6, GHRH+GHRP2, Hexarelin stimulation, GHRH+Acipimox and arginine stimulation test (AST). This is evidenced by the high calculated diagnostic odds ratio scores achieved by these tests.

Conclusion: Several tests with fairly good diagnostic accuracy are available for the diagnosis of growth hormone deficiency in adults. The supporting evidence however, is indirect and at high risk of bias.
 
[P2-359] The Accuracy of Diagnostic Tests for Growth Hormone Deficiency in Adults: A Systematic Review and Meta-Analysis http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-359

A Hazem, M Elamin, G Malaga, I Bancos, CL Zeballos-Palacios, Y Prevost, ER Velasquez, P Erwin, MH Murad, V Montori. Mayo Clinic, Rochester, MN; Universidad Peruana Cayetano Heredia, Lima, Peru.

Context: The diagnostic accuracy of tests used to diagnose growth hormone (GH) deficiency in adults is unclear.

Objective: To conduct a diagnostic systematic review and meta-analysis of studies that provided data on diagnostic tests of choice.

Data Sources: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Sciences and Scopus) through September 2009. Review of reference lists and contact with experts further identified candidate studies.

Study Selection: Reviewers, working independently and in duplicate, determined study eligibility.

Data Extraction: Reviewers, working independently and in duplicate, determined the methodological quality of studies and collected descriptive, quality and outcome data.

Data Synthesis: Twenty-one studies provided diagnostic accuracy data. Studies were all nonrandomized and had fair methodological quality (assessed using the QUADAS checklist) and included 977 patients. Several tests had good diagnostic accuracy (diagnostic odds ratio >50) such as GH-RP6, Acipimox+GHRH test, GHRH+GHRP6, GHRH+GHRP2, hexarelin stimulation test, arginine and ITT (insulin tolerance test).Other tests such serum level of IGF-1 and growth hormone had lower accuracy. The gold standard varied widely between studies. Heterogeneity was significant in most analyses. No studies examined the effect of diagnostic strategies on patient-important outcomes.

Results: Out of 14 tests of interest covered by included studies, 5 tests proved to be significantly more accurate than the rest. Those tests are; ITT, GHRP6, GHRH+GHRP6, GHRH+GHRP2, Hexarelin stimulation, GHRH+Acipimox and arginine stimulation test (AST). This is evidenced by the high calculated diagnostic odds ratio scores achieved by these tests.

Conclusion: Several tests with fairly good diagnostic accuracy are available for the diagnosis of growth hormone deficiency in adults. The supporting evidence however, is indirect and at high risk of bias.
 
GHRT in Adults May Lead to Edema
Medical News: ENDO: GHRT in Adults May Lead to Edema - in Meeting Coverage, ENDO from MedPage Today

BOSTON -- Although growth hormone replacement therapy in adults can diminish body fat and help patients lose weight, it may increase the risk of edema that requires medical attention, researchers said here.

Patients on long-term therapy were six times more likely to have treatment-requiring medical edema compared with controls (RR 6.36, 95% CI 3.8 to 10.67), Ahmad Hazem, MD, of the Mayo Clinic in Rochester, Minn., and colleagues reported during a poster session at The Endocrine Society meeting.

"There's a significant effect [of growth hormone replacement therapy] on weight and fat content, but we may have to be aware of the risk of edema," Hazem told MedPage Today.

Hazem explained that the risks and benefits of growth hormone replacement therapy in adults remain unclear, so he and his colleagues conducted a review and meta-analysis of trials looking at the treatment's effects on weight, body mass index (BMI), bone mineral density (BMD), body composition, and quality of life (QOL).

They included 30 randomized, controlled trials with more than 1,400 patients.

Overall, treatment was associated with significant reductions in weight and body fat content, with patients dropping a mean of 2.39 kg (5.3 lbs) and reducing body fat by a mean of 1.91 kg (4.2 lbs) compared with results achieved by those on placebo.

Hazem said there was also a trend toward a reduction in BMI, but it wasn't significant.

Unlike several other studies reported at The Endocrine Society meeting, the researchers found no significant effects on BMD.

Nor was there an effect on the recurrence of pre-existing tumors associated with growth hormone replacement therapy, Hazem said.

However, they did observe a trend toward an increased risk of carpal tunnel syndrome and joint stiffness, although this trend was not significant.

But the increased risk of treatment-requiring edema was indeed significant (RR 6.36, 95% CI 3.8 to 10.67).

Hazem explained that fluid retention is an adverse effect of growth hormone replacement therapy in adults, which may explain the observations regarding edema and carpal tunnel syndrome, as well as other reports of muscle and joint pain.

The researchers also tried to assess QOL outcomes, but said that QOL data were infrequently reported. The available data were too heterogeneous in their measurements to use in a pooled analysis, they said.

Hazem noted that one trial reported a statistically significant improvement in at least one subsection of a QOL assessment tool among patients on treatment compared with those on placebo.

Overall, he added, the quality of evidence of the reviewed trials was very good in terms of weight and body fat outcomes, but was not as good for other outcomes.


[P2-360] Growth Hormone Replacement Therapy in Adults with Growth Hormone Deficiency: A Systematic Review and Meta-Analysis http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-360

A Hazem, M Elamin, G Malaga, CL Zeballos-Palacios, Y Prevost, ER Velasquez, N Abu Elnour, B Irina, J Almandoz, P Erwin, MH Murad, V Montori. Mayo Clinic, Rochester, MN; Universidad Peruana Cayetano Heredia, Lima, Peru.

Context: The benefits and harms of growth hormone (GH) treatment/replacement in adults with presumed deficiency are unclear.

Objective: To conduct a systematic review and meta-analysis of trials that provided data on outcomes of interest; changes in weight, BMI, BMD, fat content and quality of life.

Data Sources: We searched MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science and Scopus through September 2009. Review of reference lists and contact with experts further identified candidate studies.

Study Selection: Reviewers, working independently and in duplicate, determined study eligibility.

Data Extraction: Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality and outcome data.

Data Synthesis: From each study, we estimated the relative risk (or risk ratio, RR) and 95% confidence interval (CI) for dichotomous outcomes and weighted difference in means (WMD) and 95% CI for continuous outcome. Data were pooled using the random effects model and heterogeneity assessed using the I2 statistic. The GRADE methodology was used to evaluate the quality of evidence.

Results: Twenty-six randomized controlled trials reported data sufficient for inclusion in meta-analysis. The trials included over 1400 patients. GH treatment was associated with statistically significant reduction in weight (WMD= -2.39 kg; 95% CI, -2.75, -2.03; I2=0%) and body fat content (WMD= -1.91 kg; 95% CI, -2.92, -0.9; I2=32%). There was a trend that did not reach statistical significance for reduction in BMI and increase in the occurrence of carpal tunnel syndrome. GH replacement therapy was found to significantly increase the risk of treatment requiring edema (RR: 6.36, 95% CI: 3.8-10.67). There was no statistically significant effect on bone density, recurrence of pre-existing tumors or joint complaints. Quality of life outcomes were infrequently reported and were insufficient for meta-analysis. The quality of evidence was deemed high for the outcomes of weight and body fat and low for the remaining outcomes due to imprecision.

Conclusion: Growth hormone treatment/replacement in adults with presumed deficiency leads to reduction in weight and body fat content and to increased risk of treatment requiring edema. The evidence regarding other potential adverse effects or benefits is inconclusive and definite answers require studies with longer follow up duration and larger sample size.
 
GHD Patients See Rise in Hepatic Lipids With Exercise
Medical News: ENDO: GHD Patients See Rise in Hepatic Lipids With Exercise - in Meeting Coverage, ENDO from MedPage Today

BOSTON -- Patients on growth hormone replacement therapy may not have issues with insulin resistance, at least not when they exercise, researchers said here.

In a small study comparing endurance athletes with adult growth disorder patients and sedentary controls, all three groups had similar decreases in intramyocellular lipids and increases in intrahepatocellular lipids, reported Peter Diem, MD, of the University Hospital of Bern in Switzerland, during a poster session at The Endocrine Society meeting.

"There's some evidence that growth hormone disorder patients have issues with insulin resistance, but we were suspicious that this isn't the case," Diem said.

Increased levels of intramyocellular and intrahepatocellular lipids are related to impaired insulin action, although endurance athletes have been shown to have a high utilization of intramyocellular lipids during exercise.

The effect of aerobic exercise on intrahepatocellular lipids, on the other hand, is unknown.

So Diem and colleagues assessed 10 patients with growth hormone disorder, 10 sedentary matched controls, and 10 endurance athletes while they participated in a two-hour, incremental aerobic exercise test at 50% to 60% of maximal oxygen uptake (VO2 max).

They determined insulin sensitivity via the hyperinsulinemic euglycemic clamp test, and measured muscular and hepatic lipids before and after exercise.

Overall, mean VO2 max was highest in endurance athletes, and this group had significantly lower total fat and subcutaneous and visceral adipose tissue than controls and growth disorder patients (P<0.001).

Diem and colleagues found that pre-exercise levels of muscle lipids were similar in all three groups, and they fell significantly in all three groups after exercise, although endurance athletes did have a significantly greater drop than the other two groups (P<0.04).

Decreases in intramyocellular lipids correlated with increases in VO2 max, Diem added (P<0.05).

With regard to hepatic lipids, pre-exercise levels were lower in both endurance athletes and growth disorder patients than in controls (P=0.05)

Although levels increased significantly in all three groups after exercise, the greatest increases were seen in athletes and growth disorder patients, compared with controls.

"We were really surprised to see that," Diem said, adding that in general, it is unclear "why intrahepatocellular lipids would go up when you exercise."

Increases in intrahepatocellular lipids were associated with increases in fatty free acid availability during exercise, and the researchers speculated that these fats may play a role in upping levels of hepatic lipids.

Diem said the findings suggested that patients with growth disorders "do not have problems with insulin resistance as has been suspected" because their metabolic parameters often paralleled those of the endurance athletes.

He also said that since growth hormone replacement therapy doesn't appear to have a tremendous impact on exercise, "clinicians can use it without having to worry about doing harm." However, he cautioned that the findings need to be validated in larger trials.


[P2-363] The Effect of Aerobic Exercise on Intramyocellular (IMCL) and Intrahepatocellular Lipids (IHCL) in Hypopituitary Patients with Growth Hormone Deficiency (GHD), Sedentary Control Subjects (CS) and Endurance-Trained Athletes (EA) http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-363

ER Christ, C Stettler, A Egger, S Alleman, P Diem, T Buehler, C Boesch. University Hospital of Bern, Inselspital, Bern, Switzerland; University of Bern, Bern, Switzerland; University of Bern, Bern, Switzerland.

Introduction: Increased levels of IMCL and IHCL are related to impaired insulin action at the skeletal muscle and hepatic level.Conversely, IMCL utilization during exercise is high in EA.The effect of aerobic exercise on IHCL is unknown.

Methods: Ten GHD patients,10 sedentary CS matched for age, gender, BMI,waist and 10 EA (Vo2max>50 ml/kg body weight) were recruited.VO2max was assessed using a incremental exercise test.Insulin sensitivity was determined with a hyerinsulinaemic euglycaemic clamp.Using MR-imaging total fat mass (FM), visceral (VAT) and subcutaneous fat compartments (SCAT) were determined.IHCL and IMCL were measured before and after a 2-h aerobic exercise at 50-60% of individual VO2max using MR-spectroscopy.Plasma free fatty acid concentrations (FFA) were determined every 30 minutes during exercise and area under the curve (AUC) was calculated.

Results: Mean±SD VO2max was highest in EA followed by CS and GHD (62.4±7.2 vs 41.5±5.5 vs 35.5±7.3 ml/kg body weight; ANOVA p<0.001).The M-value was significantly higher in EA compared to GHD and CS (10.8±2.8 vs 7.4±2.8 vs 7.7±1.4, mg/kg body weight/min; p<0.007).FM, SCAT and VAT were similar in CS and GHD.EA had significantly lower total FM, SCAT and VAT compared to GHD and CS.Pre-exercise levels of IMCL were similar in all three groups.IMCL decreased significantly in all three groups following exercise.The highest decrease in IMCL (delta IMCL) was in EA (-26.3±12.6% from baseline) followed by CS (-17.8±12.5%) and GHD (-8.4±16.1%; p<0.04).Delta IMCL was negatively correlated with VO2max (r=-0.38; p<0.05).Pre-exercise levels of IHCL were lower in GHD and EA compared to CS (4.2±5 vs 1.8±0.9 vs 12.4±15, %, p=0.05). IHCL significantly increased in all three groups following exercise. The highest increase was observed in CS (+1.3±1.5%) with a similar increase in GHD and EA (+0.6±0.4 and +0.5±0.4, %). Delta IHCL values were positively correlated with FFA availability as assessed by AUC of FFA during exercise (r =0.35; p<0.05).

Conclusions: 1) GHD patients do not exhibit features of the classical insulin resistance syndrome (increase in VAT, M-value and IHCL) when compared to sedentary CS matched for age, gender, BMI and waist cirumference. 2) Aerobic physical exercise induces a decrease in IMCL and an increase in IHCL.3). Exercise capacity (VO2max) may be related to IMCL-utilization during exercise whereas FFA availability may be involved in increasing IHCL during exercise.
 
GHRT Will Not Up Cancer Risk in Adults
Medical News: ENDO: GHRT Won&apos;t Up Cancer Risk in Adults - in Meeting Coverage, ENDO from MedPage Today

BOSTON -- Growth hormone therapy does not appear to raise the risk of cancer in adult patients, researchers said here.

Analysis of data from a large post-marketing surveillance database found no increased risk of any cancer over an average of about 3.5 years of follow-up compared with expected rates in the general population, researchers reported at an oral session during the Endocrine Society meeting here.

"Recognizing the relatively limited length of follow-up in this report, the incidence of cancer in adult patients treated with growth hormone appears similar to that of the general population," Les Robison, PhD, of St. Jude Children's Research Hospital in Memphis, Tenn., and senior author of the study, told MedPage Today.

"However, extended follow-up of this patient population is essential to document the long-term safety relative to cancer risk."

Several researchers surveyed after the presentation said they're concerned that follow-up of just 3.5 years isn't a long enough time to determine whether such treatment-related cancers might occur.

Henry Anhalt, MD, chair of advocacy for The Endocrine Society and an endocrinologist in private practice in Hackensack, N.J., said there are a number of caveats to be addressed if the researchers were looking at a follow-up of that length of time.

"You have to see whether they were treated as children, or whether the cause of their deficiency was idiopathic, so there are a lot of factors," Anhalt told MedPage Today. "But overall, that's probably not long enough, given a lot of the cancers that have been areas of concern tend to be slow growing."

He noted that in children, on the other hand, it's "pretty well accepted by the endocrine community that growth hormone treatment won't increase the risk of cancer."

Some reports have suggested that growth hormone treatment may promote cancer among adult patients who were started on treatment as children and in those with a history of previous tumors.

But there are few data on the impact of long-term growth hormone therapy on cancer incidence in adults with the disorder.

Robison and colleagues analyzed data from the multinational Hypopituitary Control and Complications Study (HypoCCS) and compared observed primary cancer cases with expected cases using the SEER database in the U.S. and GLOBOCAN for all other countries.

He said theirs is the first prospective, large-scale evaluation of primary cancer risk in adults on growth hormone replacement therapy.

Overall, they screened 6,840 treated and 940 nontreated patients and found 142 and 33 primary cancer cases, respectively.

The mean follow-up per patient was 3.7 years for treated patients and 2.9 years for nontreated patients.

All of the potential cancer cases were confirmed by three independent reviewers.

Overall, the researchers found no increased risk of primary cancers in treated patients in all countries compared with general population data, the researchers said.

Nor were there any significant increases in cancer in any individual country, they reported, including the U.S., where neither treated or nontreated patients had an increased risk of cancer.

The most frequent cancer types in treated patients were prostate (in 24 patients), breast (in 16 patients), malignant melanoma (in 15 patients), lung (in 11 patients), and colorectal (in 11 patients).

Because an earlier study published in The Lancet in 2002 had raised concerns about an increased risk of colorectal cancer in patients on the therapy, the researchers looked specifically at cases of this cancer in their database.

Robison and colleagues found no increased risk of colorectal cancer compared with nontreated patients or with the general population.

The study was limited because the mean follow-up time was relatively short, Robison said, and cancer induction time wasn't taken into account, adding that the findings would be strengthened by longer follow-up time and ongoing surveillance, especially for those with a history of neoplastic disease.

Robison and colleagues concluded that the study also demonstrated the benefit of post-marketing surveillance databases for evaluation of adverse effects in large cohorts.


[OR27-1] Assessment of Primary Cancers in Growth Hormone-Treated Adult Hypopituitary Patients Compared to Population Databases: An Analysis of the Hypopituitary Control and Complications Study (HypoCCS) http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_OR27-1

CJ Child, AG Zimmermann, WW Woodmansee, DM Green, JJ Li, H Jung, EM Erfurth, LL Robison. Eli Lilly and Company, Windlesham, UK; Eli Lilly and Company, Indianapolis, IN; Brigham and Women's Hospital/Harvard Medical School, Boston, MA; St Jude Children's Research Hospital, Memphis, TN; Eli Lilly and Company, Bad Homburg, Germany; Skånes University Hospital, Lund, Sweden.

GH treatment has been suggested to influence the occurrence and/or progression of neoplastic disease following the identification of 2 cases of colorectal cancer in adults previously treated with human pituitary GH during childhood (1), and the report of increased risk for second neoplasms in GH-treated childhood cancer survivors (2). However, the impact of long-term GH therapy on the incidence of cancer in adult patients (pts) with GH deficiency (GHD) remains unknown.

We assessed the reported primary cancer occurrence in the multinational HypoCCS observational study and compared the observed cases to expected cases using SEER for the USA (3) and GLOBOCAN (4) for all other countries. To our knowledge, this is the first reported prospective large-scale evaluation of primary cancer risk in adult pts with GHD receiving GH therapy during adulthood.

Study data and serious adverse event reports from pts enrolled in HypoCCS with ?1 follow-up visit available (GH-treated pts, N=6840; non-treated pts, N=940 [mainly from the USA]) were examined for potential primary cancer cases. The mean (±SD) follow-up per patient was 3.7 (±2.9) y for GH-treated and 2.9 (±2.4) y for non-treated pts. After initial assessment to eliminate obvious non-cancer events and recurrences, potential cancer cases were reviewed by 3 independent reviewers to identify cases for analysis.

The standardized incidence ratio (SIR) and 95% confidence interval (CI) for primary cancers in GH-treated pts was 0.88 (0.74-1.04) for all countries. SIRs for the US cohort were 0.94 (0.73-1.18) for GH-treated pts and 1.16 (0.76-1.69) for non-treated pts. The most frequent cancer types observed in GH-treated pts were prostate (N=24), breast (N=16), malignant melanoma (N=15), lung (N=11) and colorectal (N=11). Due to the previous concern regarding the latter (1), colorectal cancers were analyzed specifically; 11 cases were identified in GH-treated pts from all countries, with an overall SIR of 0.54 (0.27-0.98) and for US pts only, 6 cases with a SIR of 0.84 (0.31-1.83).

In summary, we did not find an increased risk for all-sites or colorectal primary cancers in the HypoCCS cohort when compared to general population cancer registries and a similar SIR was found in the GH-treated and non-treated groups in the USA. Nevertheless, as these findings would be strengthened by longer follow-up time, ongoing surveillance of GH-treated adult pts, especially those with history of previous neoplastic disease, remains critical.

(1) Swerdlow AJ et al., Lancet 360:273

(2) Ergun-Longmire B et al., JCEM 91:3494

(3) Ries LAG et al. (SEER Cancer Statistics Review 1975-2004 - Previous Version - SEER Cancer Statistics)

(4) Globocan 2002. IARC. (CANCERMondial)
 
GHRT Has Bone Benefits
Medical News: ENDO: GHRT Has Bone Benefits - in Meeting Coverage, ENDO from MedPage Today

BOSTON -- At least two years of growth hormone replacement therapy improves bone mineral density, especially in men, researchers said here.

In a Slovakian study, both men and women had significant increases in bone density at the lumbar spine and femoral neck after taking the hormone for that length of time, Juraj Payer, MD, of Comenius University in Bratislava, reported during a poster session at The Endocrine Society meeting here.

Yet men put on significantly more bone mass than did women (P<0.001), they reported.

"Long-term growth hormone therapy in adults [with the disease] has a positive effect on bone status," the researchers said.

Diminished bone density is an established problem associated with growth hormone deficiency, particularly in adults. In fact, studies have shown that women with childhood-onset growth hormone disorder are at twice the risk of osteoporosis as women in the general population.

Growth hormone itself affects bone growth and influences peak bone mass and bone remodeling, Payer said, and it induces chondrocyte proliferation and enchondral bone formation. It also influences the osteoprotegerin system.

Thus, growth hormone replacement therapy has been associated with improvements in bone mineral density and other biomarkers of bone health, and may decrease the risk of osteoporotic fractures.

For their study, Payer and colleagues assessed 40 patients (22 women and 18 men) ages 19 to 57 who were treated for growth hormone disorders of various etiologies -- 18 had hypopituitarism after surgery, 7 had congenital deficiency, and 15 had idiopathic disease.

The researchers assessed bone mineral density at the femoral neck and lumbar spine one and two years after treatment initiation.

Overall, they found a significant increase in bone density during all phases of treatment, although improvements were greater in the spine compared with the femur at two years (10.7% versus 8.06%).

Judith Turgeon, PhD, of the University of California Davis, who was not involved in the study, said this is an expected finding because different bones have different mineral densities, which are related to the amount of trabecular bone versus cortical bone.

"It's thought that bones that normally are composed of more trabecular bone, like vertebrae, have a greater response to many of the treatments," she told MedPage Today in an email. "So it was not unusual in this work that the lumbar spine had a higher bone mineral density increase."

Also, bone density changes were greater in men than in women (17.66% versus 5%,P<0.001).

Payer said it's likely that estrogens play a role in the difference in bone density changes between men and women.

He and colleagues also saw significant changes in bone markers at all time points, with increases in carboxyterminal cross-linking telopeptide of bone collagen (CTX) -- a marker of bone resorption -- and higher levels of osteocalcin, a marker of bone formation.

Payer said there were no gender differences based on bone markers -- nor were there any fractures over the course of the study.

They concluded that growth hormone works through insulin-like growth factor-1 (IGF-1) to improve bone growth, via increased peak bone mass and bone remodeling -- noting that peak bone mass is a predictor of osteoporotic fracture risk.


[P2-365] The Effect of 24-Month Therapy with Recombinant Growth Hormone on Bone Metabolism in GHD Adults http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-365

J Payer, M Kuzma, Z Homerova, T Koller, P Jackuliak, P Vanuga, Z Killinger. University Hospital and Medical Faculty of Comenius University, Bratislava, Slovakia (Slovak Republic); National Institute of Endocrinology and Diabetology, Lubochna, Slovakia (Slovak Republic).

Introduction: Growth hormone (GH) through IGF-I effects on linear bone growth, it influences also peak bone mass (PBM) and bone remodelation. GH induces also chondrocyte proliferation, enchondral bone formation and influences RANK-RANK-L/osteoprotegerin system. More than 2x higher risk of osteoporotic has been proven in women with childhood onset growth hormone deficiency (CO-GHD). Positive influence of therapy with recombinant GH on bone mineral density (BMD) and bone markers was repeatedly shown in GHD patients. The therapy has also influence on risk of osteoporotic fractures.

Aim: Monitoring of bone changes in patients with GHD after 24 months recombinant growth hormone treatment.

Methods: 40 patients (22 women, 18 men) in age from 19 to 57 (average 35,9). 18 patients from this group were treated hypopituitarism after surgery, 7 patients with congenital deficiency and 15 patients with idiopathic GHD. Other hormonal deficiencies (if present) were adequately treated. We were observing BMD (DXA – Hologic Discovery) of femoral neck and L-spine before the start of the treatment, after 1st year of treatment and after 2nd year of treatment with recombinant growth hormone. In those intervals we have also observed the change in bone resorption marker CTX and bone formation marker osteocalcin. Each patient was adequately treated for at least one pituitary hormone deficiency, average dose were 0.35 mg/day. Levels of IGF-I were in therapeutic range (12.month 142.85 ng/ml, in 24. month 171,86 ng/ml).

Results: Significant increase in BMD has been found out during the GH treatment, higher increase in comparison with femoral neck has been recorded in L-spine (10,7% after 2 years). Significant changes have been observed in increasing BMD in men in comparison with women (p<0.001). Significant higher increase has been found out in bone markers (at beginning 28,85 ug/l; 12.mth 44,95 ug/l, 24.mth. 49,53 ug/l) and CTX levels (beginning 187,26 ng/l; 12.mth. 222,09 ng/l; 24. mth. 250,87 ng/l) after 2 years GH treatment. Sexual differences have not been shown in bone markers. No clinical fractures have been proven.

Conclusion: A significantly higher BMD of femoral neck and L-spine has been proven in every patient (more in men). Higher increase was recorded in L-spine. During the given period, increase in levels of bone markers has been found out. Longterm GH therapy in GHD adults has a positive effect on bone status.
 
[Also, see: https://thinksteroids.com/community/threads/134308016 ]

Life Expectancy Has Fallen In Hundreds Of US Counties.

"A new study shows that in hundreds of US counties -- mostly in the South -- life expectancy has fallen," possibly due to smoking and obesity, researchers conjecture. Specifically, the study found that "in 158 counties, it dropped for both men and women," despite the fact that "overall, life expectancy in the US is at an all-time high." Lifespan fell for women in 702 of some 3,100 US counties, while it declined for men in 251 counties. But, "the US estimate actually dropped from 2004 to 2005, noted Bob Anderson of the CDC's National Center for Health Statistics. Given that downward blip -- and the fact that statistics fluctuate more when you're dealing with smaller populations -- it's not unexpected to see some declines at the local level, he said."

Large disparities in health outcomes have been documented in the US in relation to race, community of residence, and individual and community socioeconomic factors. Their analysis shows that community-level disparities in 2007 cover a range of global health experiences – from counties with life expectancies better than the best-performing nations to those lagging behind these nations by 50 or more years. The extent of geographic inequality is substantially larger in the US than in the UK, Canada, or Japan. Equally concerning is that between 2000 and 2007, more than 85% of American counties have fallen further behind the international life expectancy frontier, of which 55% were statistically significant at the 90% confidence level. While the US and most of its communities fell further behind, the US maintained its position as the country that spent the most per capita on health care throughout this period.


Kulkarni SC, Levin-Rector A, Ezzati M, Murray CJL. Falling behind: life expectancy in US counties from 2000 to 2007 in an international context. Population Health Metrics. 2011;9:16. http://www.pophealthmetrics.com/content/pdf/1478-7954-9-16.pdf

Background - The United States health care debate has focused on the nation's uniquely high rates of lack of insurance and poor health outcomes relative to other high-income countries. Large disparities in health outcomes are well-documented in the US, but the most recent assessment of county disparities in mortality is from 1999. It is critical to tracking progress of health reform legislation to have an up-to-date assessment of disparities in life expectancy across counties. US disparities can be seen more clearly in the context of how progress in each county compares to international trends.

Methods - We use newly released mortality data by age, sex, and county for the US from 2000 to 2007 to compute life tables separately for each sex, for all races combined, for whites, and for blacks. We propose, validate, and apply novel methods to estimate recent life tables for small areas to generate up-to-date estimates. Life expectancy rates and changes in life expectancy for counties are compared to the life expectancies across nations in 2000 and 2007. We calculate the number of calendar years behind each county is in 2000 and 2007 compared to an international life expectancy time series.

Results - Across US counties, life expectancy in 2007 ranged from 65.9 to 81.1 years for men and 73.5 to 86.0 years for women. When compared against a time series of life expectancy in the 10 nations with the lowest mortality, US counties range from being 15 calendar years ahead to over 50 calendar years behind for men and 16 calendar years ahead to over 50 calendar years behind for women. County life expectancy for black men ranges from 59.4 to 77.2 years, with counties ranging from seven to over 50 calendar years behind the international frontier; for black women, the range is 69.6 to 82.6 years, with counties ranging from eight to over 50 calendar years behind. Between 2000 and 2007, 80% (men) and 91% (women) of American counties fell in standing against this international life expectancy standard.

Conclusions - The US has extremely large geographic and racial disparities, with some communities having life expectancies already well behind those of the best-performing nations. At the same time, relative performance for most communities continues to drop. Efforts to address these issues will need to tackle the leading preventable causes of death.
 
Male Late-Onset Hypogonadism: Pathogenesis, Diagnosis And Treatment

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Huhtaniemi I, Forti G. Male late-onset hypogonadism: pathogenesis, diagnosis and treatment. Nat Rev Urol 2011;8(6):335-44. Male late-onset hypogonadism: pathogenesis, diagnosis and treatment : Abstract : Nature Reviews Urology

Some aging men develop a condition of suppressed serum testosterone levels, which is associated with diffuse sexual, physical and psychological symptoms. Several terms are used for this syndrome, but late-onset hypogonadism (LOH) is preferred. The diagnosis of LOH is often uncertain because symptoms (occurring in 20–40% of men) and low circulating testosterone (found in 20% of men >70 years of age) seldom occur together. The strict diagnostic criteria for LOH include reproducibly low serum testosterone levels and sexual symptoms, including erectile dysfunction and reduced frequency of sexual thoughts and morning erections. Using these diagnostic criteria, only 2% of 40–80-year-old men have LOH. Obesity and impaired general health (including diabetes mellitus, cardiovascular and chronic obstructive pulmonary disease, and frailty) are more common reasons for low testosterone than advanced age per se. It seems logical, therefore, to begin by treating these conditions before testosterone replacement therapy is initiated. Even then, testosterone should only be used if there are no contraindications, such as unstable cardiac disease, serious prostate symptoms and high hemoglobin level. The long-term benefit of testosterone replacement therapy is uncertain, and the experimental nature of the treatment, and its associated risks, must be fully explained to the patient before treatment begins.
 

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Association Between Sarcopenia And Mortality In Healthy Older People

Sarcopenia is defined as the inexorable loss of muscle mass that occurs with ageing. It is associated with loss of muscle strength and functionality but it could also be a potential predictor of mortality. The available prospective studies show an association between functional measures or frailty and mortality rather than muscle mass per se. Recently, the importance of fat mass on the functional impact of sarcopenia has been underscored, showing that obesity has a greater impact on functional performance of older people, than the loss of muscle mass. The predictive value of fat mass on mortality among older people, especially visceral fat mass, is well known.

Muscle mass can be easily measured in older people using dual energy X-ray absorptiometry (DEXA). However, the correlation between muscle mass and strength or functional measures is weak, although significant. Therefore, it is worth examining the association between mortality and muscle and fat mass in healthy older people. The aim of this work was to evaluate the association between muscle and fat mass, measured by DEXA and mortality in a cohort of healthy older people.


Bunout D, de la Maza MP, Barrera G, Leiva L, Hirsch S. Association between sarcopenia and mortality in healthy older people. Australasian Journal on Ageing 2011;30(2):89-92. Association between sarcopenia and mortality in healthy older people - Bunout - 2011 - Australasian Journal on Ageing - Wiley Online Library

Aim: To evaluate the association between loss of fat-free mass and mortality among older people.

Methods: Information of healthy Chilean older people evaluated by dual energy X-ray absorptiometry was used, identifying those who died in a period of 12 years. A Cox proportional hazards model was used to identify mortality predictors. Life tables were constructed calculating survival using predictive variables.

Results: Information from 1413 participants aged 74.3 ± 5.6 years (1001 women), was obtained. During the follow-up (median 1594 days), 221 participants died. The Cox model identified age and appendicular fat-free mass as predictors of death (hazard ratios 1.08 and 0.85, respectively). According to life tables, participants in the lower sex-specific quartile for appendicular fat-free mass/height had significantly higher mortality. This association was significant among participants aged over 73 years.

Conclusion: A low fat-free mass was predictive of mortality in older people.
 
What odds do you give for my endo RXing GHRT based upon a years Fosamax(70mg) use and no substantial change in BD form a year ago? Dx a year ago was osteopenia.
My guess would have to be near 0%. :(



GHRT Will Not Up Cancer Risk in Adults
Medical News: ENDO: GHRT Won&apos;t Up Cancer Risk in Adults - in Meeting Coverage, ENDO from MedPage Today

BOSTON -- Growth hormone therapy does not appear to raise the risk of cancer in adult patients, researchers said here.

Analysis of data from a large post-marketing surveillance database found no increased risk of any cancer over an average of about 3.5 years of follow-up compared with expected rates in the general population, researchers reported at an oral session during the Endocrine Society meeting here.

"Recognizing the relatively limited length of follow-up in this report, the incidence of cancer in adult patients treated with growth hormone appears similar to that of the general population," Les Robison, PhD, of St. Jude Children's Research Hospital in Memphis, Tenn., and senior author of the study, told MedPage Today.

"However, extended follow-up of this patient population is essential to document the long-term safety relative to cancer risk."

Several researchers surveyed after the presentation said they're concerned that follow-up of just 3.5 years isn't a long enough time to determine whether such treatment-related cancers might occur.

Henry Anhalt, MD, chair of advocacy for The Endocrine Society and an endocrinologist in private practice in Hackensack, N.J., said there are a number of caveats to be addressed if the researchers were looking at a follow-up of that length of time.

"You have to see whether they were treated as children, or whether the cause of their deficiency was idiopathic, so there are a lot of factors," Anhalt told MedPage Today. "But overall, that's probably not long enough, given a lot of the cancers that have been areas of concern tend to be slow growing."

He noted that in children, on the other hand, it's "pretty well accepted by the endocrine community that growth hormone treatment won't increase the risk of cancer."

Some reports have suggested that growth hormone treatment may promote cancer among adult patients who were started on treatment as children and in those with a history of previous tumors.

But there are few data on the impact of long-term growth hormone therapy on cancer incidence in adults with the disorder.

Robison and colleagues analyzed data from the multinational Hypopituitary Control and Complications Study (HypoCCS) and compared observed primary cancer cases with expected cases using the SEER database in the U.S. and GLOBOCAN for all other countries.

He said theirs is the first prospective, large-scale evaluation of primary cancer risk in adults on growth hormone replacement therapy.

Overall, they screened 6,840 treated and 940 nontreated patients and found 142 and 33 primary cancer cases, respectively.

The mean follow-up per patient was 3.7 years for treated patients and 2.9 years for nontreated patients.

All of the potential cancer cases were confirmed by three independent reviewers.

Overall, the researchers found no increased risk of primary cancers in treated patients in all countries compared with general population data, the researchers said.

Nor were there any significant increases in cancer in any individual country, they reported, including the U.S., where neither treated or nontreated patients had an increased risk of cancer.

The most frequent cancer types in treated patients were prostate (in 24 patients), breast (in 16 patients), malignant melanoma (in 15 patients), lung (in 11 patients), and colorectal (in 11 patients).

Because an earlier study published in The Lancet in 2002 had raised concerns about an increased risk of colorectal cancer in patients on the therapy, the researchers looked specifically at cases of this cancer in their database.

Robison and colleagues found no increased risk of colorectal cancer compared with nontreated patients or with the general population.

The study was limited because the mean follow-up time was relatively short, Robison said, and cancer induction time wasn't taken into account, adding that the findings would be strengthened by longer follow-up time and ongoing surveillance, especially for those with a history of neoplastic disease.

Robison and colleagues concluded that the study also demonstrated the benefit of post-marketing surveillance databases for evaluation of adverse effects in large cohorts.


[OR27-1] Assessment of Primary Cancers in Growth Hormone-Treated Adult Hypopituitary Patients Compared to Population Databases: An Analysis of the Hypopituitary Control and Complications Study (HypoCCS) http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_OR27-1

CJ Child, AG Zimmermann, WW Woodmansee, DM Green, JJ Li, H Jung, EM Erfurth, LL Robison. Eli Lilly and Company, Windlesham, UK; Eli Lilly and Company, Indianapolis, IN; Brigham and Women's Hospital/Harvard Medical School, Boston, MA; St Jude Children's Research Hospital, Memphis, TN; Eli Lilly and Company, Bad Homburg, Germany; Skånes University Hospital, Lund, Sweden.

GH treatment has been suggested to influence the occurrence and/or progression of neoplastic disease following the identification of 2 cases of colorectal cancer in adults previously treated with human pituitary GH during childhood (1), and the report of increased risk for second neoplasms in GH-treated childhood cancer survivors (2). However, the impact of long-term GH therapy on the incidence of cancer in adult patients (pts) with GH deficiency (GHD) remains unknown.

We assessed the reported primary cancer occurrence in the multinational HypoCCS observational study and compared the observed cases to expected cases using SEER for the USA (3) and GLOBOCAN (4) for all other countries. To our knowledge, this is the first reported prospective large-scale evaluation of primary cancer risk in adult pts with GHD receiving GH therapy during adulthood.

Study data and serious adverse event reports from pts enrolled in HypoCCS with ?1 follow-up visit available (GH-treated pts, N=6840; non-treated pts, N=940 [mainly from the USA]) were examined for potential primary cancer cases. The mean (±SD) follow-up per patient was 3.7 (±2.9) y for GH-treated and 2.9 (±2.4) y for non-treated pts. After initial assessment to eliminate obvious non-cancer events and recurrences, potential cancer cases were reviewed by 3 independent reviewers to identify cases for analysis.

The standardized incidence ratio (SIR) and 95% confidence interval (CI) for primary cancers in GH-treated pts was 0.88 (0.74-1.04) for all countries. SIRs for the US cohort were 0.94 (0.73-1.18) for GH-treated pts and 1.16 (0.76-1.69) for non-treated pts. The most frequent cancer types observed in GH-treated pts were prostate (N=24), breast (N=16), malignant melanoma (N=15), lung (N=11) and colorectal (N=11). Due to the previous concern regarding the latter (1), colorectal cancers were analyzed specifically; 11 cases were identified in GH-treated pts from all countries, with an overall SIR of 0.54 (0.27-0.98) and for US pts only, 6 cases with a SIR of 0.84 (0.31-1.83).

In summary, we did not find an increased risk for all-sites or colorectal primary cancers in the HypoCCS cohort when compared to general population cancer registries and a similar SIR was found in the GH-treated and non-treated groups in the USA. Nevertheless, as these findings would be strengthened by longer follow-up time, ongoing surveillance of GH-treated adult pts, especially those with history of previous neoplastic disease, remains critical.

(1) Swerdlow AJ et al., Lancet 360:273

(2) Ergun-Longmire B et al., JCEM 91:3494

(3) Ries LAG et al. (SEER Cancer Statistics Review 1975-2004 - Previous Version - SEER Cancer Statistics)

(4) Globocan 2002. IARC. (CANCERMondial)

GHRT Has Bone Benefits
Medical News: ENDO: GHRT Has Bone Benefits - in Meeting Coverage, ENDO from MedPage Today

BOSTON -- At least two years of growth hormone replacement therapy improves bone mineral density, especially in men, researchers said here.

In a Slovakian study, both men and women had significant increases in bone density at the lumbar spine and femoral neck after taking the hormone for that length of time, Juraj Payer, MD, of Comenius University in Bratislava, reported during a poster session at The Endocrine Society meeting here.

Yet men put on significantly more bone mass than did women (P<0.001), they reported.

"Long-term growth hormone therapy in adults [with the disease] has a positive effect on bone status," the researchers said.

Diminished bone density is an established problem associated with growth hormone deficiency, particularly in adults. In fact, studies have shown that women with childhood-onset growth hormone disorder are at twice the risk of osteoporosis as women in the general population.

Growth hormone itself affects bone growth and influences peak bone mass and bone remodeling, Payer said, and it induces chondrocyte proliferation and enchondral bone formation. It also influences the osteoprotegerin system.

Thus, growth hormone replacement therapy has been associated with improvements in bone mineral density and other biomarkers of bone health, and may decrease the risk of osteoporotic fractures.

For their study, Payer and colleagues assessed 40 patients (22 women and 18 men) ages 19 to 57 who were treated for growth hormone disorders of various etiologies -- 18 had hypopituitarism after surgery, 7 had congenital deficiency, and 15 had idiopathic disease.

The researchers assessed bone mineral density at the femoral neck and lumbar spine one and two years after treatment initiation.

Overall, they found a significant increase in bone density during all phases of treatment, although improvements were greater in the spine compared with the femur at two years (10.7% versus 8.06%).

Judith Turgeon, PhD, of the University of California Davis, who was not involved in the study, said this is an expected finding because different bones have different mineral densities, which are related to the amount of trabecular bone versus cortical bone.

"It's thought that bones that normally are composed of more trabecular bone, like vertebrae, have a greater response to many of the treatments," she told MedPage Today in an email. "So it was not unusual in this work that the lumbar spine had a higher bone mineral density increase."

Also, bone density changes were greater in men than in women (17.66% versus 5%,P<0.001).

Payer said it's likely that estrogens play a role in the difference in bone density changes between men and women.

He and colleagues also saw significant changes in bone markers at all time points, with increases in carboxyterminal cross-linking telopeptide of bone collagen (CTX) -- a marker of bone resorption -- and higher levels of osteocalcin, a marker of bone formation.

Payer said there were no gender differences based on bone markers -- nor were there any fractures over the course of the study.

They concluded that growth hormone works through insulin-like growth factor-1 (IGF-1) to improve bone growth, via increased peak bone mass and bone remodeling -- noting that peak bone mass is a predictor of osteoporotic fracture risk.


[P2-365] The Effect of 24-Month Therapy with Recombinant Growth Hormone on Bone Metabolism in GHD Adults http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-365

J Payer, M Kuzma, Z Homerova, T Koller, P Jackuliak, P Vanuga, Z Killinger. University Hospital and Medical Faculty of Comenius University, Bratislava, Slovakia (Slovak Republic); National Institute of Endocrinology and Diabetology, Lubochna, Slovakia (Slovak Republic).

Introduction: Growth hormone (GH) through IGF-I effects on linear bone growth, it influences also peak bone mass (PBM) and bone remodelation. GH induces also chondrocyte proliferation, enchondral bone formation and influences RANK-RANK-L/osteoprotegerin system. More than 2x higher risk of osteoporotic has been proven in women with childhood onset growth hormone deficiency (CO-GHD). Positive influence of therapy with recombinant GH on bone mineral density (BMD) and bone markers was repeatedly shown in GHD patients. The therapy has also influence on risk of osteoporotic fractures.

Aim: Monitoring of bone changes in patients with GHD after 24 months recombinant growth hormone treatment.

Methods: 40 patients (22 women, 18 men) in age from 19 to 57 (average 35,9). 18 patients from this group were treated hypopituitarism after surgery, 7 patients with congenital deficiency and 15 patients with idiopathic GHD. Other hormonal deficiencies (if present) were adequately treated. We were observing BMD (DXA – Hologic Discovery) of femoral neck and L-spine before the start of the treatment, after 1st year of treatment and after 2nd year of treatment with recombinant growth hormone. In those intervals we have also observed the change in bone resorption marker CTX and bone formation marker osteocalcin. Each patient was adequately treated for at least one pituitary hormone deficiency, average dose were 0.35 mg/day. Levels of IGF-I were in therapeutic range (12.month 142.85 ng/ml, in 24. month 171,86 ng/ml).

Results: Significant increase in BMD has been found out during the GH treatment, higher increase in comparison with femoral neck has been recorded in L-spine (10,7% after 2 years). Significant changes have been observed in increasing BMD in men in comparison with women (p<0.001). Significant higher increase has been found out in bone markers (at beginning 28,85 ug/l; 12.mth 44,95 ug/l, 24.mth. 49,53 ug/l) and CTX levels (beginning 187,26 ng/l; 12.mth. 222,09 ng/l; 24. mth. 250,87 ng/l) after 2 years GH treatment. Sexual differences have not been shown in bone markers. No clinical fractures have been proven.

Conclusion: A significantly higher BMD of femoral neck and L-spine has been proven in every patient (more in men). Higher increase was recorded in L-spine. During the given period, increase in levels of bone markers has been found out. Longterm GH therapy in GHD adults has a positive effect on bone status.
 
Antibody Directed Myostatin Inhibition

The aim was to investigate the therapeutic potential of antibody-directed myostatin inhibition on the mass and functional properties of skeletal muscles from tumor-bearing cachectic mice. We tested the hypothesis that acute myostatin inhibition would attenuate muscle fiber atrophy and enhance muscle functional capacity in limb muscles and diaphragm muscle strips from tumor-bearing mice.

PF-354 antibody-directed myostatin inhibition attenuated the atrophy and loss of functional capacity of the TA muscles of tumor-bearing mice exhibiting mild cachexia. The findings are clinically relevant since prognosis is best when treatments are initiated at the early stages of cachexia. Furthermore, improvements in muscle structure and function could enhance the capacity of affected patients to perform the activities of daily living and improve their quality of life. The improvements in muscle structure and function are also likely to increase compliance with other anti-cancer therapies and so, antibody-directed myostatin inhibition could also provide synergistic benefits for patients with cancer cachexia.

This is the first study to investigate whether antibody-directed myostatin inhibition can improve the functional properties of limb muscles and diaphragm muscle strips from tumor-bearing mice. PF-354 antibody-directed myostatin inhibition prevented the loss of force producing capacity of TA muscles from LLC tumor-bearing mice but did not attenuate the loss of force producing capacity of diaphragm muscle strips from tumor-bearing mice. The findings indicate that antibody-directed myostatin inhibition has therapeutic potential for cancer cachexia and could preserve or improve the functional independence of affected patients.


Murphy KT, Chee A, Gleeson BG, et al. Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology. http://ajpregu.physiology.org/content/early/2011/06/10/ajpregu.00121.2011.abstract (Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice)

Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve week old C57BL/6 mice received a subcutaneous injection of saline (Control) or Lewis Lung Carcinoma (LLC) tumor cells. One week later, mice received either once-weekly injections of saline (Control, n=12; LLC, n=9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg/week, LLC+PF-354, n=11) for 5 weeks. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8-10% (P<0.05), but the muscle atrophy and weakness was prevented with PF-354 treatment (P>0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection (P<0.05), but was not improved with PF-354 treatment (P>0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively (P<0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross-sections from saline treated LLC tumor-bearing mice (P<0.05), but was not different in PF-354 treated tumor-bearing mice (P>0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia.
 
The original:




Q: Which artist sounds more and more like a bad Bob Dylan impersonator?
A: Bob Dylan.
 
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