OnLine First

[Michael Scally MD]

Diabetes (DM) is a significant risk factor for total cancer incidence and mortality and for some site-specific cancers, notably breast and colorectal (CRC), and probably endometrial, prostate, and pancreas. Diabetes treatment might affect cancer incidence and mortality. Since the 1960s, metformin (one of the biguanides) has become the first line antihyperglycemic agent in type 2 diabetes (T2DM) treatment worldwide. It has been shown to be potentially cancer protective. No information is available about these possibilities with regard to non-Caucasian ethnicity, especially where both T2DM prevalence is increasing and cancer patterns changing towards those in advanced economies, as in the Asia Pacific region. In this study, Metformin was found to reduce the incidences of several gastroenterological cancers in an Oriental population.


Lee M-S, Hsu C-C, Wahlqvist M, Tsai H-N, Chang Y-H, Huang Y-C. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011;11(1):20. Abstract | Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals

BACKGROUND: Metformin protection against cancer risk in Orientals is uncertain. We examined the possible metformin effect on total, esophageal, gastric, colorectal (CRC), hepatocellular (HCC) and pancreatic cancers in a Taiwanese cohort.

METHODS: A representative sample of 800,000 was drawn from the Taiwanese National Health Insurance data of 2000. A cohort of 480,984 participants 20 years or older, diabetes-cancer-free on 1st January 2000 was formed and categorized as four groups by DM and metformin usage status. Eligible incident cancer events had to occur one year after the index date until the end of 2007. The Cox proportional-hazards model evaluated relative risk of cancer for treated DM patients with or without metformin. The covariates included age, gender, other oral anti-hyperglycemic medication, Charlson comorbidity index (CCI) score and metformin exposure dosage and duration.

RESULTS: With diabetes but no anti-hyperglycemic medication, cancer incidence density increased at least 2-fold for total, CRC and HCC. On metformin, total, CRC and HCC incidences decreased to near non-diabetic levels but to varying degrees depending on gender and cancer type (CRC in women, liver in men). Adjustment for other oral anti-hyperglycemic agents usage and CCI made the benefit of metformin more evident [hazard ratios (95% confidence intervals): total 0.12 (0.08-0.19), CRC 0.36 (0.13-0.98), liver 0.06 (0.02-0.16), pancreas 0.15 (0.03-0.79)]. There was a significant gender interaction with metformin in CRC which favored women. Metformin dosage for a significant decrease in cancer incidence was [less than or equal to] 500 mg/day.

CONCLUSIONS: Metformin can reduce the incidences of several gastroenterological cancers in treated diabetes.

 

[Michael Scally MD]

Statins: Benefits questionable in low-risk patients
Statins: Benefits questionable in low-risk patients

January 19, 2011

There is not enough evidence to recommend the widespread use of statins in people with no previous history of heart disease, according to a new Cochrane Systematic Review. Researchers say statins should be prescribed with caution in those at low risk of cardiovascular disease (CVD).

CVD is the most common cause of death, accounting for nearly a third of all deaths worldwide. Cholesterol-lowering statins are first line treatments for heart patients and the benefits are well established. However, there is less evidence that statins are beneficial for preventing heart problems in those who have no history of CVD. Given that low cholesterol has been shown to increase the risk of death from other causes, statins may do more harm than good in some patients.

The researchers reviewed data from 14 trials involving 34,272 patients. Outcomes in patients given statins were compared to outcomes in patients given placebos or usual care. Combined data from eight trials involving 28,161 patients that provided data on deaths from all causes showed that statins reduced the risk of dying from 9 to 8 deaths for every 1000 people treated with statins each year. Statins reduced fatal and non-fatal events, including heart attack, stroke and revascularization surgery, as well as blood cholesterol levels.

However, the researchers say that the conclusions of their review are limited by unclear, selective and potentially biased reporting and that careful consideration should be given to patients' individual risk profiles before prescribing statins.

"It is not as simple as just extrapolating the effects from studies in people who have a history of heart disease," said lead researcher Fiona Taylor, from the Cochrane Heart Group at the London School of Hygiene and Tropical Medicine in London, UK. "This review highlights important shortcomings in our knowledge about the effects of statins in people who have no previous history of CVD. The decision to prescribe statins in this group should not be taken lightly."

The researchers point out that all but one of the trials they reviewed were industry-sponsored. "We know that industry-sponsored trials are more likely to report favourable results for drugs versus placebos, so we have to be cautious about interpreting these results," said Taylor. "The numbers eligible for treatment with statins are potentially great so there might be motivations, for instance, to stop trials earlier if interim results support their use."

A separate Cochrane Systematic Review, conducted by some of the same authors, considered the effects of combined approaches to reducing the risk of heart disease, including using education and counselling to encourage people to change their diets and stop smoking. The authors concluded that combined interventions had little or no impact on deaths or disease caused by CVD. In an editorial accompanying the reviews, Carl Heneghan, University of Oxford, concluded that, "Although various multiple prevention strategies exist, the most effective and cost-effective intervention for primary prevention in adults at low risk currently remains unclear."

 

[Michael Scally MD]

Leipzig RM, Whitlock EP, Wolff TA, et al. Reconsidering the approach to prevention recommendations for older adults. Ann Intern Med 2010;153(12):809-14. http://www.annals.org/content/153/12/809.full.pdf

The U.S. Preventive Services Task Force (USPSTF) bases its recommendations on an evidence-based model of clinical prevention that focuses on specific diseases, well-defined preventive interventions, and evidence of improved health outcomes. Applying this model to prevention for very old patients has been problematic for several reasons: Many geriatric disorders have multiple risk factors, interventions, and expected outcomes; older adults are not often represented in clinical trials; and important outcomes may not be measured and reported in ways that are conducive to evidence synthesis and interpretation. In 2005, the USPSTF convened a geriatrics workgroup to refine USPSTF methodology and processes to better address the preventive needs of older adults. The USPSTF has begun to apply these new approaches to the review and recommendation on interventions to prevent falls in older adults.


Michael YL, Whitlock EP, Lin JS, Fu R, O'Connor EA, Gold R. Primary care-relevant interventions to prevent falling in older adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2011;153(12):815-25. http://www.annals.org/content/153/12/815.full.pdf

BACKGROUND: Falls among older adults are both prevalent and preventable.

PURPOSE: To describe the benefits and harms of interventions that could be used by primary care practitioners to prevent falling among community-dwelling older adults.

DATA SOURCES: The reviewers evaluated trials from a good-quality systematic review published in 2003 and searched MEDLINE, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL from the end of that review's search date to February 2010 to identify additional English-language trials.

STUDY SELECTION: Two reviewers independently screened 3423 abstracts and 638 articles to identify randomized, controlled trials (RCTs) of primary care-relevant interventions among community-dwelling older adults that reported falls or fallers as an outcome. Trials were independently critically appraised to include only good- or fair-quality trials; discrepancies were resolved by a third reviewer.

DATA EXTRACTION: One reviewer abstracted data from 61 articles into standardized evidence tables that were verified by a second reviewer.

DATA SYNTHESIS: Overall, the included evidence was of fair quality. In 16 RCTs evaluating exercise or physical therapy, interventions reduced falling (risk ratio, 0.87 [95% CI, 0.81 to 0.94]). In 9 RCTs of vitamin D supplementation, interventions reduced falling (risk ratio, 0.83 [CI, 0.77 to 0.89]). In 19 trials involving multifactorial assessment and management, interventions with comprehensive management seemed to reduce falling, although overall pooled estimates were not statistically significant (risk ratio, 0.94 [CI, 0.87 to 1.02]). Limited evidence suggested that serious clinical harms were no more common for older adults in intervention groups than for those in control groups. Limitations: Interventions and methods of fall ascertainment were heterogeneous. Data on potential harms of interventions were scant and often not reported.

CONCLUSION: Primary care-relevant interventions exist that can reduce falling among community-dwelling older adults.

PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

 

[Michael Scally MD]

ANTIOXIDANTS FOR MALE SUBFERTILITY: Oxidative stress may cause sperm cell damage. This damage can be reduced by the body's own natural antioxidant defences. Antioxidants can be part of our diet and taken as a supplement. It is believed that in many cases of unexplained subfertility, and also in instances where there may be a sperm-related problem, taking an oral antioxidant supplement may increase a couple's chance of conceiving when undergoing fertility treatment. This review identified 34 randomised controlled trials involving 2876 couples. Pooled findings support increases in live births and pregnancy rates with the use of antioxidants by the male partner. Further work is recommended to confirm these findings. http://www.posters2view.com/eshre2010/data/6.pdf


Showell Marian G, Brown Julie, Yazdani Anusch, Stankiewicz Marcin T, Hart Roger J. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews: Reviews 2011 Issue 1 John Wiley & Sons, Ltd Chichester, UK DOI: 10.1002/14651858.CD007411.pub2. Antioxidants for male subfertility

Background - Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm. Oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress.

Objectives - This Cochrane review aimed to evaluate the effect of oral supplementation with antioxidants for male partners of couples undergoing assisted reproduction techniques (ART).

Search strategy - We searched the Cochrane Menstrual Disorders and Subfertility Group Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from their inception until Febuary 2010), trial registers, sources of unpublished literature, reference lists and we asked experts in the field.

Selection criteria - We included randomised controlled trials comparing any type or dose of antioxidant supplement (single or combined) taken by the male partner of a couple seeking fertility assistance with placebo, no treatment or another antioxidant. The outcomes were live birth, pregnancy, miscarriage, stillbirth, sperm DNA damage, sperm motility, sperm concentration and adverse effects.

Data collection and analysis - Two review authors independently assessed studies for inclusion and trial quality, and extracted data.

Main results - We included 34 trials with 2876 couples in total.

Live birth: three trials reported live birth. Men taking oral antioxidants had an associated statistically significant increase in live birth rate (pooled odds ratio (OR) 4.85, 95% CI 1.92 to 12.24; P = 0.0008, I2 = 0%) when compared with the men taking the control. This result was based on 20 live births from a total of 214 couples in only three studies.

Pregnancy rate: there were 96 pregnancies in 15 trials including 964 couples. Antioxidant use was associated with a statistically significant increased pregnancy rate compared to control (pooled OR 4.18, 95% CI 2.65 to 6.59; P < 0.00001, I2 = 0%).

Side effects: no studies reported evidence of harmful side effects of the antioxidant therapy used.

Authors' conclusions - The evidence suggests that antioxidant supplementation in subfertile males may improve the outcomes of live birth and pregnancy rate for subfertile couples undergoing ART cycles. Further head to head comparisons are necessary to identify the superiority of one antioxidant over another.

 

[Michael Scally MD]

Jaskelioff M, Muller FL, Paik JH, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011;469(7328):102-6. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice : Nature : Nature Publishing Group

An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2(+) neural progenitors, Dcx(+) newborn neurons, and Olig2(+) oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.

 

[Michael Scally MD]

The need for more effective prevention of melanoma is recognized around the world as climbing incidence and high mortality in white populations persist. In the United States, approximately 68,700 new melanoma occurrences and more than 8,600 deaths were expected to occur in 2009. Exposure to solar ultraviolet (UV) radiation is the only established modifiable cause of melanoma. Despite the known etiologic role of sun exposure, the question regarding sunscreen use to prevent melanoma remains open and controversial. Here, they present new evidence from the follow-up of a community-based, pragmatic trial of sunscreen to prevent skin cancer in Queensland, Australia.


Green AlC, Williams GM, Logan V, Strutton GM. Reduced Melanoma After Regular Sunscreen Use: Randomized Trial Follow-Up. Journal of Clinical Oncology 2011;29(3):257-63. Sign In — JCO

Purpose Regular sunscreen use prevents cutaneous squamous cell carcinoma long term, but the effect on melanoma is highly controversial. We evaluated whether long-term application of sunscreen decreases risk of cutaneous melanoma.

Participants and Methods In 1992, 1,621 randomly selected residents of Nambour, a township in Queensland, Australia, age 25 to 75 years, were randomly assigned to daily or discretionary sunscreen application to head and arms in combination with 30 mg beta carotene or placebo supplements until 1996. Participants were observed until 2006 with questionnaires and/or through pathology laboratories and the cancer registry to ascertain primary melanoma occurrence.

Results Ten years after trial cessation, 11 new primary melanomas had been identified in the daily sunscreen group, and 22 had been identified in the discretionary group, which represented a reduction of the observed rate in those randomly assigned to daily sunscreen use (hazard ratio

---

, 0.50; 95% CI, 0.24 to 1.02; P = .051). The reduction in invasive melanomas was substantial (n = 3 in active v 11 in control group; HR, 0.27; 95% CI, 0.08 to 0.97) compared with that for preinvasive melanomas (HR, 0.73; 95% CI, 0.29 to 1.81).

Conclusion Melanoma may be preventable by regular sunscreen use in adults.

 

[Michael Scally MD]

Statins for the primary prevention of cardiovascular disease

Cardiovascular disease (CVD) is ranked as the number one cause of mortality and is a major cause of morbidity world wide. Reducing high blood cholesterol which is a risk factor for CVD events is an important goal of medical treatment. Statins are the first-choice agents. Since the early statin trials were reported, several reviews of the effects of statins have been published highlighting their benefits particularly in people with a past history of CVD. However for people without a past history of CVD (primary prevention), the evidence is less clear.

The aim of this systematic review is to assess the effects, both in terms of benefits and harms of statins for the primary prevention of CVD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE until 2007. We found 14 randomised control trials with 16 trial arms (34,272 patients) dating from 1994 to 2006. All were randomised control trials comparing statins with usual care or placebo. Duration of treatment was minimum one year and with follow up of a minimum of six months. All cause mortality. coronary heart disease and stroke events were reduced with the use of statins as was the need for revascularisations. Statin treatment reduced blood cholesterol. Taking statins did not increase the risk of adverse effects such as cancer. and few trials reported on costs or quality of life. This current systematic review highlights the shortcomings in the published trials and we recommend that caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.


Taylor F, Ward K, Moore THM, Burke M, Davey Smith G, Casas J-P, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2011, Issue 1. Statins for the primary prevention of cardiovascular disease

Background - Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of coronary heart disease (CHD) is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with coronary artery disease. The case for primary prevention, however, is less clear.

Objectives - To assess the effects, both harms and benefits, of statins in people with no history of CVD.

Search strategy - To avoid duplication of effort, we checked reference lists of previous systematic reviews. We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007). There were no language restrictions.

Selection criteria - Randomised controlled trials of statins with minimum duration of one year and follow-up of six months, in adults with no restrictions on their total low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD, were included.

Data collection and analysis - Two authors independently selected studies for inclusion and extracted data. Outcomes included all cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), change in blood total cholesterol concentration, revascularisation, adverse events, quality of life and costs. Relative risk (RR) was calculated for dichotomous data, and for continuous data pooled weighted mean differences (with 95% confidence intervals) were calculated.

Main results - Fourteen randomised control trials (16 trial arms; 34,272 participants) were included. Eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (RR 0.83, 95% CI 0.73 to 0.95) as was combined fatal and non-fatal CVD endpoints (RR 0.70, 95% CI 0.61 to 0.79). Benefits were also seen in the reduction of revascularisation rates (RR 0.66, 95% CI 0.53 to 0.83). Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life.

Authors' conclusions - Although reductions in all-cause mortality, composite endpoints and revascularisations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.

 

[Michael Scally MD]

Fukuda DH, Smith AE, Kendall KL, Stout JR. The possible combinatory effects of acute consumption of caffeine, creatine, and amino acids on the improvement of anaerobic running performance in humans. Nutr Res 2010;30(9):607-14. The possible combinatory effects of acute consumpt... [Nutr Res. 2010] - PubMed result

Preexercise nutritional investigations have recently become a popular avenue of examining the interaction of multiple ingredients on exercise and training methods. The critical velocity (CV) test is used to quantify the relationship between total running distance and time to exhaustion (TTE), yielding aerobic (CV) and anaerobic parameters (anaerobic running capacity [ARC]). The purpose of this study was to examine the hypothesis that a preexercise supplement containing caffeine, creatine, and amino acids (Game Time; Corr-Jen Laboratories Inc, Aurora, CO) would positively impact CV and ARC in college-aged men and women. In a single-blind crossover design, 10 participants consumed the preexercise supplement (ACT) or placebo (PL) before each testing session. Each participant completed runs to exhaustion on a treadmill at 110%, 90% (day 1), and 105% and 100% (day 2) of the peak velocity (PV) determined from a graded exercise test. The ACT elicited a 10.8% higher ARC (P = .02) compared with the PL, whereas no difference was found in CV (0.6%, P = .38). The TTE was greater for the ACT than the PL at 110% (ACT = 125.7 +/- 9.6 seconds, PL = 117.3 +/- 12.6 seconds), 105% (ACT = 156.9 +/- 11.0 seconds, PL = 143.8 +/- 12.9 seconds), and 100% PV (ACT = 185.7 +/- 10.7 seconds, PL = 169.7 +/- 12.8 seconds) (P = .01-.04); but there was no difference for the TTE at 90% PV (ACT = 353.5 +/- 52.7 seconds, PL = 332.7 +/- 54.0 seconds) (P = .08).

These findings suggest that the acute ingestion of this preexercise supplement may be an effective strategy for improving anaerobic performance, but appears to have no effect on aerobic power.

 

[Michael Scally MD]

[THIS IS A MUST READ. NOTE THE THRESHOLD TESTOSTERONE LEVEL FOR MUSCLE GAIN.]

Sattler F, Bhasin S, He J, et al. Testosterone threshold levels and lean tissue mass targets needed to enhance skeletal muscle strength and function: the HORMA trial. J Gerontol A Biol Sci Med Sci 2011;66(1):122-9. Testosterone Threshold Levels and Lean Tissue Mass Targets Needed to Enhance Skeletal Muscle Strength and Function: The HORMA Trial — J Gerontol A Biol Sci Med Sci

BACKGROUND: In the HORMA (Hormonal Regulators of Muscle and Metabolism in Aging) Trial, supplemental testosterone and recombinant human growth hormone (rhGH) enhanced lean body mass, appendicular skeletal muscle mass, muscle performance, and physical function, but there was substantial interindividual variability in outcomes.

METHODS: One hundred and twelve men aged 65-90 years received testosterone gel (5 g/d vs 10 g/d via Leydig cell clamp) and rhGH (0 vs 3 vs 5 mug/kg/d) in a double-masked 2 x 3 factorial design for 16 weeks. Outcomes included lean tissue mass by dual energy x-ray absorptiometry, one-repetition maximum strength, Margaria stair power, and activity questionnaires. We used pathway analysis to determine the relationship between changes in hormone levels, muscle mass, strength, and function.

RESULTS: Increases in total testosterone of 1046 ng/dL (95% confidence interval = 1040-1051) and 898 ng/dL (95% confidence interval = 892-904) were necessary to achieve median increases in lean body mass of 1.5 kg and appendicular skeletal muscle mass of 0.8 kg, respectively, which were required to significantly enhance one-repetition maximum strength (>/= 30%). Co-treatment with rhGH lowered the testosterone levels (quantified using liquid chromatography-tandem mass spectrometry) necessary to reach these lean mass thresholds. Changes in one-repetition maximum strength were associated with increases in stair climbing power (r = .26, p = .01). Pathway analysis supported the model that changes in testosterone and insulin-like growth factor 1 levels are related to changes in lean body mass needed to enhance muscle performance and physical function. Testosterone's effects on physical activity were mediated through a different pathway because testosterone directly affected Physical Activity Score of the Elderly.

CONCLUSIONS: To enhance muscle strength and physical function, threshold improvements in lean body mass and appendicular skeletal muscle mass are necessary and these can be achieved by targeting changes in testosterone levels. rhGH augments the effects of testosterone. To maximize functional improvements, the doses of anabolic hormones should be titrated to achieve target blood levels.

 

[Michael Scally MD]

There are problems with this study, particularly the finding for LH and FSH presence. In ALL AAS users I have treated these hormones are undetectable, but here they are found. Also, the TT difference is barely significant. These show that the study might be measuring something else altogether. It would be better to measure AAS directly. [It is comical they used BMI.]

The reason this study is important is QT prolongation and increased QT dispersion are predictors of risk of arrhythmias in different patient populations, and their data suggest AAS induced repolarization ventricular abnormalities in AAS users and this could contribute to the early identification of AAS users with high risk of ventricular arrhythmias and sudden death. In light of prior negative findings and the poor methodology the study contributes nothing new.


A total of 22 male subjects who regularly engaged in strength training (mean 6 days per week) and low aerobic training (mean 2 days per week) at fitness academies in Niteroi city (Rio de Janeiro state, Brazil) volunteered to participate in the present study. Individuals were selected based on the results of a screening questionnaire and all of them were non-smokers, non-alcoholics and non-users of cocaine, marijuana or heroin. Eleven subjects, included in the AAS group, were individuals who declared they had taken AAS for periods as long as 4 years. The reported self-administration regimens were in cycles of 6.7 +/- 1.1 weeks, with the use of two or more drugs in the same cycle. The orally self-administered drugs were oxymetholone and stanozolol, and the injectable steroids were nandrolone, stanozolol and testosterone propionate. The control group consisted of 11 individuals who declared that they did not use and had never before taken AAS. To indirectly assess anabolic steroid use, hormonal examinations were taken from blood samples. Serum testosterone, estradiol, follicle stimulating hormone and luteinizing hormone were measured by electrochemiluminescence immunoassays (Roche Diagnostics, Basel, Switzerland). The subjects’ bodyweight and height were measured and the body mass index (BMI) was calculated as bodyweight divided by squared height (kg ?m2). No clinical problems occurred during the study.


Maior AS, Menezes P, Pedrosa RC, Carvalho DP, Soares PP, Nascimento JH. Abnormal cardiac repolarization in anabolic androgenic steroid users carrying out submaximal exercise testing. Clin Exp Pharmacol Physiol 2010;37(12):1129-33. Abnormal cardiac repolarization in anabolic androg... [Clin Exp Pharmacol Physiol. 2010] - PubMed result

1. The aim of the present study was to investigate the cardiovascular effects of anabolic androgenic steroid (AAS) abuse by comparing the electrocardiographic parameters before and after submaximal exercise between AAS users and non-AAS users.

2. A total of 22 men who regularly engaged in both resistance and aerobic exercise at fitness academies volunteered for the study (control group: n = 11, age 25 +/- 4 years; AAS group: n = 11, age 27 +/- 5 years). All subjects were submitted to submaximal exercise testing using an Astrand-Rhyming protocol. Heart rate and electrocardiography parameters were measured at rest and at the third minute of the post-exercise recovery time.

3. AAS users presented higher QTc and QTd at rest (10% and 55%, respectively) and at the post-exercise period (17% and 43%, respectively), compared with control subjects. The maximal and minimum QTc interval of the AAS group was significantly prolonged at the post-exercise period (12% and 15%, respectively). The haemodynamic parameters were similar in both groups (P > 0.05). The AAS group showed a lower heart rate recovery at the first minute after the test (P = 0.0001), and a higher exertion score (P < 0.0001) at a lower workload, compared with the control group.

4. Our results show that the QTc interval and dispersion are increased in individuals who abuse AAS, suggesting the presence of ventricular repolarization abnormalities that could potentially increase the risk of cardiac arrhythmias and sudden cardiac death.

 

[Michael Scally MD]

The controversy continues. If not for the HUGE amounts of money now being made by PhRMA, testosterone would be an almost nonexistent prescription. Currently, obtaining a testosterone prescription is as easy as getting one for an antibiotic. I am doubtful that it will get hard anytime soon to get testosterone, but there continues to be a call for a more restrictive or limited use until large trials are conducted. Following is the article conclusion; the full-text is at the link.

Conclusions

It is still unclear whether age-related declines in serum testosterone are benign or whether there are thresholds below which these declines are associated with adverse health consequences. If testosterone therapy is to be considered for alleviating deleterious effects of such a decline, it remains to be determined whether it is effective and safe in older men, what testosterone levels should be indications for therapy, and what levels should be therapeutic targets. At present, although numerous testosterone formulations are increasingly being utilized to treat a constellation of symptoms potentially related to low testosterone levels, the syndrome is not clearly defined; furthermore, it is still unknown whether the therapy will benefit elderly men or expose them to unnecessary and unjustified risks. Observational studies cannot definitively answer these questions, and until they are answered with robust, large-scale randomized trials, physicians and patients—especially older men—will continue to make treatment decisions based on limited information about the risks and benefits of testosterone therapy.

Cook NL, Romashkan S. Why do we need a trial on the effects of testosterone therapy in older men? Clin Pharmacol Ther 2011;89(1):29-31. Clinical Pharmacology & Therapeutics - Why Do We Need a Trial on the Effects of Testosterone Therapy in Older Men?

Decreases in levels of sex hormones occur with aging. Observational studies have found associations of low testosterone concentrations in older men with adverse symptoms; however, these associations do not prove causality. Therefore, the question arises whether to treat older men whose serum testosterone is low. In 2009, the Testosterone Trial (T Trial) was funded to examine the efficacy of therapy in 800 elderly men with low testosterone levels; potentially associated symptoms; and abnormalities in physical, sexual, or cognitive function or vitality.

 

[Michael Scally MD]

Email me for the full-text article. Include the article title.

West DW, Phillips SM. Anabolic processes in human skeletal muscle: restoring the identities of growth hormone and testosterone. Phys Sportsmed 2010;38(3):97-104. Anabolic processes in human skeletal muscle: resto... [Phys Sportsmed. 2010] - PubMed result

Testosterone supplementation acts via numerous mechanisms as a highly potent anabolic agent to skeletal muscle. Although growth hormone (GH) strongly affects collagen synthesis and lipolysis, as well as increasing lean body mass, it is not anabolic toward the contractile (ie, myofibrillar) muscle tissue in healthy individuals. However, there is a persistent belief (both in scientific literature and among recreational weightlifters) that exercise-induced release of GH and testosterone underpins muscular hypertrophy with resistance training. This is a premature assumption because although pharmacological GH supplementation can increase muscle strength or size in individuals with clinical GH deficiency, there is no evidence that transient exercise-induced changes in GH have the same effects in individuals with normal GH levels. Exercise paradigms are designed based on the assumption (not necessarily evidenced-based mechanisms) that GH and testosterone facilitate anabolic processes that lead to skeletal muscle protein accretion and hypertrophy. Our recent work disputes this assumption. Instead, our data indicate that exercise-induced hormonal elevations do not enhance intracellular markers of anabolic signaling or the acute postexercise elevation of myofibrillar protein synthesis. Furthermore, data from our training study demonstrate that exercise-induced increases in GH and testosterone availability are not necessary for and do not enhance strength and hypertrophy adaptations. Instead, our data lead us to conclude that local mechanisms that are intrinsic to the skeletal muscle tissue performing the resistive contractions (ie, weightlifting) are predominant in stimulating anabolism.

The purpose of this article is 1) to provide a brief overview of the mechanisms of action of testosterone and GH; 2) to discuss the inability of physiological exercise-induced elevations in these hormones to have a measurable impact on skeletal muscle anabolism; and 3) to describe factors that we believe are more important for stimulating hypertrophy in human skeletal muscle. Clarifying both the role of hormones in regulating muscle mass as well as the underlying basis for adaptation of skeletal muscle to resistance exercise will hopefully enhance and support the prescription of resistance exercise as an integral component of a healthy lifestyle.

 

[Michael Scally MD]

Because men experience more incidents of cardiovascular disease (CVD) than women of a similar age, it has been suggested that testosterone may influence the development of CVD. However, the literature has shown that low rather than high testosterone levels are associated with CVD risk factors, atherosclerosis, and the increased risk of both CVD and all-cause mortality in men.

The incidence of adverse thrombotic events such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism increases with age. At the same time, despite large interindividual variations, an age-related decline of testosterone occurs. The reduction in testosterone levels is suggested to be a normal part of the aging process, but there are no age-specific criteria for a diagnosis of hypogonadism in older men. In addition, lifestyle factors such as obesity are more strongly associated with the reduction of testosterone levels than age. To what extent testosterone deficiency affects hemostasis and CVD in men, or if testosterone supplementation could be useful in the treatment of hemostasis and CVD, is an area of great interest with many unanswered questions.

Recent experimental cross-sectional and case control studies have shown that testosterone may have an impact on the hemostatic/fibrinolytic system in men. This review considers the coagulation system and CVD from the perspective of testosterone. Most of the data available in this regard are still limited to observational and small interventional studies, and hence the conclusion from the review of these data is largely hypothetical. [Email for the full-text article.]


Brodin E, Vikan T, Hansen JB, Svartberg J. Testosterone, hemostasis, and cardiovascular diseases in men. Semin Thromb Hemost 2011;37(1):87-94. Testosterone, hemostasis, and cardiovascular disea... [Semin Thromb Hemost. 2011] - PubMed result

Men have a higher incidence of cardiovascular disease (CVD) than women, and adverse thrombotic events increase with age. Recent experimental cross-sectional, and case-control studies have shown that testosterone may affect the hemostatic/fibrinolytic system in men in several ways. It has been hypothesized that physiological doses of testosterone would have a beneficial effect on tissue factor-induced thrombin generation and the development of CVD. The search for eternal youth has created a market for testosterone treatment in aging men during the last few years. However, whether testosterone supplementation could be useful in the treatment of testosterone-deficient elderly men is still controversial. The present review focuses on the coagulation system and CVD from the perspective of testosterone.

 

[Michael Scally MD]

[Email me for the full-text article.]

Stroke is the leading cause of serious long-term disability and the third leading cause of mortality in the United States. Responding to the need for improvements in acute stroke care, the Brain Attack Coalition (BAC) published recommendations for the establishment of primary stroke centers in 2000. In December 2003, the Joint Commission began certifying stroke centers based on BAC criteria. Now, nearly 700 of the 5000 acute care hospitals in the United States are Joint Commission–certified stroke centers. Some states, such as New York, Massachusetts, and Florida, have established their own designation programs using the BAC core criteria.

Despite widespread support for the stroke center concept, there is limited empirical evidence demonstrating that admission to a stroke center is associated with lower mortality. Prior studies have largely focused on stroke processes of care, such as treatment timeline and use of thrombolytic therapy. There is comparably less information on whether better care at stroke centers improves acute or long-term mortality. In this study, among patients with acute ischemic stroke, admission to a designated stroke center was associated with modestly lower mortality and more frequent use of thrombolytic therapy.

When the stroke center concept was launched more than 10 years ago, there was skepticism about whether stroke centers would make a difference. Through the collaborative work of many medical professionals, supportive hospital administrators, EMS personnel, and state legislatures, stroke centers have helped reduce death rates one stroke at a time. [Accompanying Editorial: Alberts MJ. Preventing Death One Stroke at a Time. JAMA: The Journal of the American Medical Association 2011;305(4):408-9. Preventing Death One Stroke at a Time, January 26, 2011, Alberts 305 (4): 408 — JAMA ]


Xian Y, Holloway RG, Chan PS, et al. Association Between Stroke Center Hospitalization for Acute Ischemic Stroke and Mortality. JAMA: The Journal of the American Medical Association 2011;305(4):373-80. Association Between Stroke Center Hospitalization for Acute Ischemic Stroke and Mortality, January 26, 2011, Xian et al. 305 (4): 373 — JAMA

Context Although stroke centers are widely accepted and supported, little is known about their effect on patient outcomes.

Objective To examine the association between admission to stroke centers for acute ischemic stroke and mortality.

Design, Setting, and Participants Observational study using data from the New York Statewide Planning and Research Cooperative System. We compared mortality for patients admitted with acute ischemic stroke (n = 30 947) between 2005 and 2006 at designated stroke centers and nondesignated hospitals using differential distance to hospitals as an instrumental variable to adjust for potential prehospital selection bias. Patients were followed up for mortality for 1 year after the index hospitalization through 2007. To assess whether our findings were specific to stroke, we also compared mortality for patients admitted with gastrointestinal hemorrhage (n = 39 409) or acute myocardial infarction (n = 40 024) at designated stroke centers and nondesignated hospitals.

Main Outcome Measure Thirty-day all-cause mortality.

Results Among 30 947 patients with acute ischemic stroke, 15 297 (49.4%) were admitted to designated stroke centers. Using the instrumental variable analysis, admission to designated stroke centers was associated with lower 30-day all-cause mortality (10.1% vs 12.5%; adjusted mortality difference, ?2.5%; 95% confidence interval [CI], ?3.6% to ?1.4%; P < .001) and greater use of thrombolytic therapy (4.8% vs 1.7%; adjusted difference, 2.2%; 95% CI, 1.6% to 2.8%; P < .001). Differences in mortality also were observed at 1-day, 7-day, and 1-year follow-up. The outcome differences were specific for stroke, as stroke centers and nondesignated hospitals had similar 30-day all-cause mortality rates among those with gastrointestinal hemorrhage (5.0% vs 5.8%; adjusted mortality difference, +0.3%; 95% CI, ?0.5% to 1.0%; P = .50) or acute myocardial infarction (10.5% vs 12.7%; adjusted mortality difference, +0.1%; 95% CI, ?0.9% to 1.1%; P = .83).

Conclusion Among patients with acute ischemic stroke, admission to a designated stroke center was associated with modestly lower mortality and more frequent use of thrombolytic therapy.

 

[Michael Scally MD]

[Email me for the full-text article.]

The currently available replacement for men with testosterone (T) deficiency in the United States includes: 2 biweekly injection options (T enanthate and cypionate), the daily transdermal testosterone patches and gels, and a buccal delivery system. The buccal delivery system requires twice a day application; some men cannot tolerate the gel tablet applied on their gums. The transdermal patches are associated with significant local skin irritation. The gels are an open system with minimal skin irritation, but there is a potential for transfer of the T applied on the skin to women and children; this has resulted in labeling that requires showering or wearing protective clothing before close skin-to-skin contact. Many men currently are relying on biweekly injectables for T replacement. These preparations have less favorable pharmacokinetics, with high peaks and low troughs and, in some men, can produce variations in mood and energy levels and crops of acne after injections. However, these injectables are less costly and have long-term safety records. Some patients have been trained to self administer these injectables, although many patients rely on their health providers to administer the oil-based injections.

Outside the United States, oral T undecanoate capsules have been available for many years. The twice daily administration of oral testosterone undecanoate (TU) produced peaks of serum T about 5 hours after dosing, and serum levels fall to pretreatment levels in about 8 to 12 hours. Despite the pharmacokinetics profile, hypogonadal men report improvement in symptoms, and oral TU has long-term safety data. Injectable TU in tea seed oil was first reported to be used as a relatively long-acting injectable for hypogonadal men in China, where 500 mg of TU was administered every 4 weeks with serum T levels within the adult range for most hypogonadal men. TU was then reformulated in castor oil and administered as 1000 mg/IM injection. The injections were generally well tolerated and multidose pharmacokinetics showed that the most hypogonadal men would receive adequate replacement with physiological ranges of serum T when TU in castor oil was administered at 6 weeks after the first injection and then followed by injections every 12 week thereafter. If more frequent injections are administered, the trough serum T levels rose progressively. A 30-week study compared T enanthate with TU injections and showed that both injectables improved sexual function and mood in hypogonadal men. A longer term study (over 2 years) showed that 1000 mg of TU administered intramuscularly (IM) increased grip strength and decreased waist to hip ratio and serum total and low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL) cholesterol decreased initially but later increased. Hemoglobin and hematocrit increased in the first 30 weeks and then showed no further increases. Prostate volume and serum prostate-specific antigen (PSA) levels increased in the first 12 months of treatment and then remained stable. The results from these studies indicate that 1000 mg of TU administered at weeks 0 and 6 and then every 12 weeks provides pharmacokinetic profiles of serum T concentrations that would rendered most hypogonadal men eugonadal.


Wang C, Harnett M, Dobs AS, Swerdloff RS. Pharmacokinetics and safety of long-acting testosterone undecanoate injections in hypogonadal men: an 84-week phase III clinical trial. J Androl 2010;31(5):457-65. http://www.ncbi.nlm.nih.gov/pubmed/20133964

Currently available testosterone (T) injections in the United States are administered at 2-3 weekly intervals. Less frequent injections with favorable serum T pharmacokinetics would benefit hypogonadal men. The objective of this study is to assess the pharmacokinetics of long-acting testosterone undecanoate (TU) intramuscular (IM) injection in hypogonadal men. An unblinded, multicenter phase 3 clinical trial was conducted in 31 academic centers and contract research organizations. Males (130) more than 18 years of age with serum total T < 300 ng/dL were enrolled and received 750-mg injections of TU at weeks 0 and 4 and every 10 weeks thereafter for 9 injections over 84 weeks. The main outcome variables were serum total T, free T, dihydrotestosterone (DHT), estradiol (E(2)) levels, and safety parameters. After the first injection, patients maintained average trough T concentrations in the adult male range (300-1000 ng/dL or 10.4-34.7 nmol/L) before each injection and at multiple time points measured after the third and fourth injections. Serum free T, DHT, and E(2) levels and their ratios to serum T remained relatively consistent once steady state was attained. TU injections were generally well tolerated, with safety profiles similar to other T replacement. We conclude that hypogonadal patients treated for 84 weeks with a 750-mg IM injection of TU every 10 weeks demonstrated average concentrations of T, its metabolites (DHT and E(2)), and ratios--DHT:T and E(2):T--within the adult male reference range at all time points measured. TU injections would be an acceptable alternative to the currently available 2-3 weekly injectables.

 

[Michael Scally MD]

Re: Trenbolone

[Email me for the full-text article.]


17?-hydroxyestra-4,9,11-trien-3-one (trenbolone) is a potent synthetic testosterone analogue which does not undergo 5? reduction to more potent metabolites (46). As such, trenbolone may induce less growth in prostate and other androgenic tissues which highly express 5? reductase. This is in contrast to testosterone, which has approximately three fold greater potency in androgenic tissues, which highly express 5? reductase (63), due to its conversion to dihydrotestosterone (DHT).

The primary purpose of this study was to determine the effects of trenbolone-enanthate (TREN; a slowly released trenbolone ester) on a variety of androgen sensitive tissues, including skeletal muscle, bone, visceral adiposity, hemoglobin, and the prostate of rodents. Because trenbolone is selectively metabolized to weaker androgens in vivo, they hypothesized that TREN will produce dose-dependent anabolic effects in skeletal muscle, bone, and fat that are at least equal to those of supraphysiological testosterone, while producing a smaller increase in hemoglobin and less growth of the prostate. Their findings indicate that TREN has advantages over supraphysiologic testosterone and supports the need for future pre-clinical studies examining the viability of TREN as an option for androgen replacement therapy.


Yarrow JF, Conover CF, McCoy SC, et al. 17?-hydroxyestra-4,9,11-trien-3-one (Trenbolone) Exhibits Tissue Selective Anabolic Activity: Effects on Muscle, Bone, Adiposity, Hemoglobin, and Prostate. American Journal of Physiology - Endocrinology And Metabolism. 17?-hydroxyestra-4,9,11-trien-3-one (Trenbolone) Exhibits Tissue Selective Anabolic Activity: Effects on Muscle, Bone, Adiposity, Hemoglobin, and Prostate — AJP - Endo

Selective androgen receptor modulators (SARMs) now under development can protect against muscle and bone loss, without causing prostate growth or polycythemia. 17?-hydroxyestra-4,9,11-trien-3-one (trenbolone), a potent testosterone analogue, may have SARM-like actions because, unlike testosterone, trenbolone does not undergo tissue-specific 5? reduction to form more potent androgens. We tested the hypothesis that trenbolone-enanthate (TREN) might prevent orchiectomy-induced losses in muscle and bone and visceral fat accumulation, without increasing prostate mass or resulting in adverse hemoglobin elevations.

Male F344 rats aged three months underwent orchiectomy or remained intact and were administered graded doses of TREN, supraphysiologic testosterone-enanthate, or vehicle for 29 days. In both intact and orchiectomized animals, all TREN doses and supraphysiologic testosterone-enanthate augmented androgen-sensitive levator ani/bulbocavernosus muscle mass by 35-40% above Shams (p?0.001), and produced a dose-dependent partial protection against orchiectomy-induced total and trabecular bone mineral density losses (p<0.05) and visceral fat accumulation (p<0.05). The lowest doses of TREN successfully maintained prostate mass and hemoglobin concentrations at Sham levels in both intact and orchiectomized animals; whereas supraphysiologic testosterone-enanthate and high-dose TREN elevated prostate mass by 84% and 68%, respectively (p<0.01).

In summary, low dose administration of the non-5? reducible androgen TREN maintains prostate mass and hemoglobin concentrations near the level of Shams, while producing potent myotrophic actions in skeletal muscle and partial protection against orchiectomy-induced bone loss and visceral fat accumulation. Our findings indicate that TREN has advantages over supraphysiologic testosterone and supports the need for future pre-clinical studies examining the viability of TREN as an option for androgen replacement therapy.

 

[Michael Scally MD]

[Email me for the full-text article.]

Vitamin D deficiency is currently considered an important public health problem being associated with musculoskeletal diseases, cardiovascular disease, cancer, and infectious and autoimmune diseases. The vitamin D receptor (VDR), as well as key enzymes for vitamin D metabolism, are widely expressed in human tissues and cells. Previous studies suggest that vitamin D deficiency may contribute to reduced fertility and hypogonadism. These results are of particular interest because both, vitamin D deficiency and hypogonadism are associated with skeletal diseases (e. g., osteoporosis or muscle weakness) as well as extra-skeletal disorders (e. g., cardiovascular disease or obesity). Recently, a study showed in 2,299 men referred for coronary angiography that 25-hydroxyvitamin D [25(OH)D] levels are significantly associated with testosterone levels and that both hormones reveal similar seasonal variations with a peak at the end of summer. Whether there exists a causal link between vitamin D and testosterone status is currently not known. A subgroup analysis of a previously published prospective, randomized vitamin D supplementation trial was performed in overweight subjects. Here, they present results on serum testosterone concentrations in the male participants of this study.


Pilz S, Frisch S, Koertke H, et al. Effect of Vitamin D Supplementation on Testosterone Levels in Men. Horm Metab Res. Effect of Vitamin D Supplementation on Testosteron... [Horm Metab Res. 2010] - PubMed result

The male reproductive tract has been identified as a target tissue for vitamin D, and previous data suggest an association of 25-hydroxyvitamin D [25(OH)D] with testosterone levels in men. We therefore aimed to evaluate whether vitamin D supplementation influences testosterone levels in men. Healthy overweight men undergoing a weight reduction program who participated in a randomized controlled trial were analyzed for testosterone levels. The entire study included 200 nondiabetic subjects, of whom 165 participants (54 men) completed the trial. Participants received either 83 mug (3,332 IU) vitamin D daily for 1 year (n=31) or placebo (n=23). Initial 25(OH)D concentrations were in the deficiency range (<50 nmol/l) and testosterone values were at the lower end of the reference range (9.09-55.28 nmol/l for males aged 20-49 years) in both groups. Mean circulating 25(OH)D concentrations increased significantly by 53.5 nmol/l in the vitamin D group, but remained almost constant in the placebo group. Compared to baseline values, a significant increase in total testosterone levels (from 10.7+/-3.9 nmol/l to 13.4+/-4.7 nmol/l; p<0.001), bioactive testosterone (from 5.21+/-1.87 nmol/l to 6.25+/-2.01 nmol/l; p=0.001), and free testosterone levels (from 0.222+/-0.080 nmol/l to 0.267+/-0.087 nmol/l; p=0.001) were observed in the vitamin D supplemented group. By contrast, there was no significant change in any testosterone measure in the placebo group. Our results suggest that vitamin D supplementation might increase testosterone levels. Further randomized controlled trials are warranted to confirm this hypothesis.

 

[GirlyMan]

Our results suggest that vitamin D supplementation might increase testosterone levels. Further randomized controlled trials are warranted to confirm this hypothesis.

I recall you arguing with HAN not so long ago that this was bullshit. Have you relaxed that position based on this new evidence?

 

[BBC3]

Hey fightseeker. I thought he was just posting copies of articles published by others and courteously bolding operative sentances for the LAZY IMPAIRED>....

I recall you arguing with HAN not so long ago that this was bullshit. Have you relaxed that position based on this new evidence?

 

[GirlyMan]

Hey fightseeker. I thought he was just posting copies of articles published by others and courteously bolding operative sentances for the LAZY IMPAIRED>....

Yeah, I got that. But I still want to know and doing it here attracts more attention from others like you, which raises the likelihood of a response. And I ain't looking for no fights. I'm paid as a scientist and so is Dr. Scally., So relax, he and I both know what that entails. The powers that be can move or delete my comments as they see fit, not a big deal.