OnLine First

[Michael Scally MD]

In order to improve their performances, even professional sportsmen are often tempted to take dietary supplements, as is evidenced by a considerable number of surveys documenting the prevalence of supplement use among athletes. An important factor stimulating this widespread use of supplements is of course the easy availability of these products through numerous Internet sites. Unfortunately, the athletes who take supplements are often largely unaware of the risks involved in the intake of these so-called ‘natural’ supplements. It appears to be common for sportsmen to exceed the recommended dosages, even though some of these substances, such as iron and zinc, are known to be harmful in higher doses. Another significant risk related to the intake of dietary supplements is that these products might be contaminated with anabolic steroids and could therefore lead to athletes failing a doping test or cause health risks to consumers. In order to clarify the extent of the problem, a broad-based investigation of the international nutritional supplement market was conducted.

From October 2000 until November 2001, a total of 634 non-hormonal dietary supplements were obtained from 215 different suppliers in 13 countries. These supplements were analyzed by means of a targeted gas chromatography–mass spectrometry (GC–MS) method, screening for testosterone, nandrolone, boldenone and their respective prohormones. Out of these 643 supplements, 94 (14.6%) were found to contain one of these anabolic steroids and one or more of their respective prohormones, none of which were identified on the label. This study shows that the contamination of dietary supplements is indeed an internationally prevalent problem, warranting the need for adequate screening methods to detect these anabolic steroids. In this manner, the risks of both positive doping tests and potentially serious health problems in athletes who take large amounts of these supplements can be minimized.

The aim of the present study was to develop such a new in-house mass spectral library of 88 steroids, along with a fast ultra-performance liquid chromatography (UPLC)–MS method, as a potentially attractive alternative to GC–MS, accurate mass measurements and bioactivity screening. In order to highlight the possibilities and limits of these libraries, the method was also tested on a number of samples already analyzed by means of a targeted LC–MS/MS method.


Becue I, Poucke CV, Peteghem CV. An LC-MS screening method with library identification for the detection of steroidsin dietary supplements. J Mass Spectrom 2011;46(3):327-35. An LC-MS screening method with library identificat... [J Mass Spectrom. 2011] - PubMed result

For many years anabolic-androgenic steroids (AAS) are by far the most frequently detected pharmacological substances in doping control. In order to improve their performances, professional sportsmen are often tempted to take dietary supplements. However, due to the frequent and widespread occurrence of contaminated supplements, the use of such products is not without risk for the athletes involved. In order to minimize the chances of an unattended positive doping test or serious health problems, fast and reliable screening methods for the detection of anabolic steroids in dietary supplements are needed. A general screening procedure requires the fast and unambiguous detection of a large range of steroids. Gas chromatography-mass spectrometry (GC-MS) has been used intensively in the detection of doping substances for the past 40 years. Over time, many laboratories have delivered spectra to be included in standard reference databases, one of which is maintained by the National Institute of Standards and Technology (NIST) (Gaithersburg, MD, USA). In recent years, however, liquid chromatography coupled to mass spectrometry (LC-MS) has gained popularity. Unfortunately, existing GC-MS libraries are not applicable to LC-MS analysis. In the present study, a new mass spectral library of 88 steroids was developed, along with a fast UPLC-MS method. For the construction of this mass spectral library, three different mass spectra were measured for each steroid, with a sample cone voltage of 30, 60 and 100 V, respectively. This method was then successfully tested on contaminated dietary supplements which had previously been tested by means of a targeted LC-MS/MS method. Overall, the library search was shown to identify the same compounds as the MRM method.

 

[Michael Scally MD]

A great deal of research is available to demonstrate that creatine supplementation is effective in improving both muscle and cognitive function. In supplemental form, this nutrient is inexpensive and data are available supporting a track record of excellent safety. The purpose of this review is to describe the fundamentals of creatine metabolism, age-associated changes to the creatine- phosphocreatine energy system, effects of creatine supplementation on muscle function in older adults, and the effects of creatine supplementation on cognitive processing.


Rawson ES, Venezia AC. Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids. Use of creatine in the elderly and evidence for ef... [Amino Acids. 2011] - PubMed result

The ingestion of the dietary supplement creatine (about 20 g/day for 5 days or about 2 g/day for 30 days) results in increased skeletal muscle creatine and phosphocreatine. Subsequently, the performance of high-intensity exercise tasks, which rely heavily on the creatine-phosphocreatine energy system, is enhanced. The well documented benefits of creatine supplementation in young adults, including increased lean body mass, increased strength, and enhanced fatigue resistance are particularly important to older adults. With aging and reduced physical activity, there are decreases in muscle creatine, muscle mass, bone density, and strength. However, there is evidence that creatine ingestion may reverse these changes, and subsequently improve activities of daily living. Several groups have demonstrated that in older adults, short-term high-dose creatine supplementation, independent of exercise training, increases body mass, enhances fatigue resistance, increases muscle strength, and improves the performance of activities of daily living. Similarly, in older adults, concurrent creatine supplementation and resistance training increase lean body mass, enhance fatigue resistance, increase muscle strength, and improve performance of activities of daily living to a greater extent than resistance training alone. Additionally, creatine supplementation plus resistance training results in a greater increase in bone mineral density than resistance training alone. Higher brain creatine is associated with improved neuropsychological performance, and recently, creatine supplementation has been shown to increase brain creatine and phosphocreatine. Subsequent studies have demonstrated that cognitive processing, that is either experimentally (following sleep deprivation) or naturally (due to aging) impaired, can be improved with creatine supplementation. Creatine is an inexpensive and safe dietary supplement that has both peripheral and central effects. The benefits afforded to older adults through creatine ingestion are substantial, can improve quality of life, and ultimately may reduce the disease burden associated with sarcopenia and cognitive dysfunction.

 

[Michael Scally MD]

Could Giftedness Be Linked to Prenatal Exposure of Higher Levels of Hormones?
Could giftedness be linked to prenatal exposure of higher levels of hormones?

ScienceDaily (Mar. 12, 2011) — A longstanding debate as to whether genius is a byproduct of good genes or good environment has an upstart challenger that may take the discussion in an entirely new direction. University of Alberta researcher Marty Mrazik says being bright may be due to an excess level of a natural hormone.

Mrazik, a professor in the Faculty of Education's educational psychology department, and a colleague from Rider University in the U.S., have published a paper in Roeper Review linking giftedness (having an IQ score of 130 or higher) to prenatal exposure of higher levels of testosterone. Mrazik hypothesizes that, in the same way that physical and cognitive deficiencies can be developed in utero, so, too, could similar exposure to this naturally occurring chemical result in giftedness.

"There seems to be some evidence that excessive prenatal exposure to testosterone facilitates increased connections in the brain, especially in the right prefrontal cortex," said Mrazik. "That's why we see some intellectually gifted people with distinct personality characteristics that you don't see in the normal population."

Mrazik's notion came from observations made during clinical assessments of gifted individuals. He and his fellow researcher observed some specific traits among the subjects. This finding stimulated a conversation on the role of early development in setting the foundation for giftedness.

"It gave us some interesting ideas that there could be more to this notion of genius being predetermined from a biological perspective than maybe people gave it credit for," said Mrazik. "It seemed that the bulk of evidence from new technologies (such as Functional MRI scans) tell us that there's a little bit more going on than a genetic versus environmental interaction."

Based on their observations, the researchers made the hypothesis that this hormonal "glitch" in the in-utero neurobiological development means that gifted children are born with an affinity for certain areas such as the arts, math or science. Mrazik cautions that more research is needed to determine what exact processes may cause the development of the gifted brain.

He notes that more is known about what derails the brain's normal development, thus charting what makes gifted people gifted is very much a new frontier. Mrazik hopes that devices such as the Functional MRI scanner will give them a deeper understanding of the role of neurobiology in the development of the gifted brain.

"It's really hard to say what does put the brain in a pathway where it's going to be much more precocious," he said. "The next steps in this research lay in finding out what exact stimuli causes this atypical brain development.”


Mrazik M, Dombrowski SC. The Neurobiological Foundations of Giftedness. Roeper Review 2011;32(4):224 - 34. The Neurobiological Foundations of Giftedness - Roeper Review

Case studies of extremely gifted individuals often reveal unique patterns of intellectual precocity and associated abnormalities in development and behavior. This article begins with a review of current neurophysiological and neuroanatomical findings related to the gifted population. The bulk of scientific inquiries provide evidence of unique patterns of right prefrontal cortex and inferior frontal activation implicated in gifted intelligence, although additional studies suggest enhanced neural processing and cerebral bilateralism. Geschwind, Behan, and Galaburda (GBG) first hypothesized the possible neurodevelopmental factors that account for unique brain development. This article explores more recent findings taken from the prenatal exposure literature and offers a proposed model for explaining aberrant developmental forces that may be at work in precocious individuals.

 

[Michael Scally MD]

Growth Hormone & Hypothalamic-Pituitary-Thyroid Axis

Although the interactive functions among GH, IGF system and the hypothalamic-pituitary-thyroid (HPT) axis have been well described, both at central and peripheral levels, the effect of recombinant human growth hormone (rhGH) administration at supraphysiological doses on HPT system in healthy trained humans still needs to be fully elucidated. Indeed, rhGH intake is a common habit among athletes and while many studies focused onto the metabolic effects following rhGH administration – to elucidate whether this hormone could be an athletic performance-enhancing substance – it is still unclear whether and how it could exert undesirable or even noxious effect on health. On this topic there are, in fact, few and controversial results. From previous studies performed in healthy, mainly untrained, individuals, exogenous GH/rhGH intake (0.125mg/kg body weight (BW)/day) resulted either to exert no effect onto HPT axis (except for a small decline in T4-binding globulin binding capacity) or to decline serum TSH, total T4, and free T4 (FT4) level 4 days after treatment, while increasing free T3 (FT3) and/or total T3 serum concentration. Accordingly, two studies performed in endurance athletes/fit adults showed an increased FT3 and a decreased FT4 serum concentration 7 and 28 days, respectively, after rhGH administration (0.067 mg/kg BW and 0.1–0.2 IU/kg BW, daily for 4 weeks, respectively), whereas TSH serum concentration was either unchanged or not reported.

In a previous study performed in healthy trained subjects treated with a slightly supraphysiological dose of rhGH (0.03mg/kg BW/day), researchers observed changes in GH/IGF-I system variables, such as IGF-I and IGFBP-3 serum level increase, early after (3rd and 4th day, respectively) drug administration, without changes in IGF-II and IGFBP-2. In order to evaluate whether changes in pituitary-thyroid function induced by exogenous rhGH administration may trigger a (subclinical) pathological condition, the present study aims to evaluate both the time-lapse between rhGH administration and changes in thyroid-related parameters, and how long after treatment withdrawal altered variables return to baseline values. GH intake effect onto thyroid structure and maximal oxygen uptake (V?O2max) was also investigated.


Sgro P, Guidetti L, Crescioli C, et al. Effect of supraphysiological dose administration of rhGH on pituitary-thyroid axis in healthy male athletes. Regul Pept 2011;165(2-3):163-7. Effect of supra-physiological dose administration ... [Regul Pept. 2010] - PubMed result

The effect of recombinant human growth hormone (rhGH) administration on hypothalamic-pituitary-thyroid (HPT) system in healthy trained humans still needs to be fully clarified. Furthermore, whether rhGH abuse could exert undesirable or noxious effect on health is still unclear. In order to evaluate changes in HPT axis variables in time after rhGH administration, 14 well-trained healthy male athletes were treated with rhGH (0.03 mg/kg body weight/day, sc) administration, 6 days/week for 3 weeks. Morning blood samples were collected immediately before and 3, 4, 8, 15, and 21 days after rhGH administration. A further set of blood samples was taken 3, 6 and 9 days after drug withdrawal. Samples were analyzed for GH-IGF and HPT axis.

Significant TSH serum decrease and IGF-I increase occurred early after rhGH administration, without FT(3) content modification and with FT(4) reduction delayed in time. Serum TSH concentrations negatively correlated with IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratios. rhGH short-term administration in healthy trained subjects induced an early TSH suppression--likely acting at central level through IGF-I--without thyroid function alteration. Further investigations in athletes are necessary to verify whether prolonged TSH suppression, i.e. rhGH intake for longer time, could induce pathologic condition, such as hypothyroidism.

 

[Michael Scally MD]

Comparative Effectiveness and Safety of Medications for Type 2 Diabetes

Context - There is a dizzying array of treatment regimens for type 2 diabetes.

Contribution - This review found little evidence about the relative effects of various antihyperglycemic therapies on long-term clinical outcomes. Most monotherapies reduced hemoglobin A1c levels by similar amounts. Metformin therapy reduced body weight compared with thiazolidinediones and sulfonylureas; decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors; caused less hypoglycemia than sulfonylureas; and caused more diarrhea than thiazolidinediones.

Caution - Evidence on the comparative effects of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, and different drug combinations was scant.

Implication - Consider metformin the initial drug of choice for treating type 2 diabetes.


Bennett WL, Maruthur NM, Singh S, et al. Comparative Effectiveness and Safety of Medications for Type 2 Diabetes: An Update Including New Drugs and 2-Drug Combinations. Annals of Internal Medicine 2011:E-336. Comparative Effectiveness and Safety of Medications for Type 2 Diabetes: An Update Including New Drugs and 2-Drug Combinations — Ann Intern Med

Background: Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.

Purpose: To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes.

Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes.

Study Selection: Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms.

Data Extraction: Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.

Data Synthesis: Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A1c level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about ?2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones.

Limitations: Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits.

Conclusion: Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A1c levels, but some increased risk for hypoglycemia and other adverse events.

 

[Michael Scally MD]

Couples Sometimes Communicate No Better Than Strangers
Couples sometimes communicate no better than strangers

ScienceDaily (Mar. 14, 2011) — Married people may think they communicate well with their partners, but psychologists have found that they don't always convey messages to their loved ones as well as they think -- and in some cases, the spouses communicate no better than strangers.

The same communication problem also is true with close friends, a recent study has found.

"People commonly believe that they communicate better with close friends than with strangers. That closeness can lead people to overestimate how well they communicate, a phenomenon we term the 'closeness-communication bias,'" said Boaz Keysar, a professor in psychology at the University of Chicago and a leading expert on communications.

Keysar's colleague Kenneth Savitsky, professor of psychology at Williams College in Williamstown, Mass., devised an experiment resembling a parlor game to study the issue. In it, two sets of couples sat in chairs with their backs to each other and tried to discern the meaning of each other's ambiguous phrases. In all, 24 married couples participated.

The researchers used phrases common in everyday conversations to see if the spouses were better at understanding phrases from their partners than from people they did not know. The spouses consistently overestimated their ability to communicate, and did so more with their partners than with strangers.

"A wife who says to her husband, 'it's getting hot in here,' as a hint for her husband to turn up the air conditioning a notch, may be surprised when he interprets her statement as a coy, amorous advance instead," said Savitsky, who is lead author of the paper, published in the January issue of the Journal of Experimental Social Psychology.

"Although speakers expected their spouse to understand them better than strangers, accuracy rates for spouses and strangers were statistically identical. This result is striking because speakers were more confident that they were understood by their spouse," Savitsky said.

"Some couples may indeed be on the same wavelength, but maybe not as much as they think. You get rushed and preoccupied, and you stop taking the perspective of the other person, precisely because the two of you are so close," he said.

Savitsky conducted a similar experiment with 60 Williams College students. In the study, the students overestimated their effectiveness in communicating with friends, replicating the pattern found with married couples.

Closeness can create 'illusion of insight'

Communication problems arise when a speaker assumes that a well-known acquaintance has all the information the speaker has, removing the need for a long explanation, Keysar said. When people meet a stranger, they automatically provide more information because they don't have a "closeness bias" in that encounter. In the same way, listeners may wrongly assume that a comment or request from a close acquaintance is based on knowledge that the two have in common -- a mistake the listener would not make with a stranger.

In order to test that idea, a team at Keysar's lab set up an experiment in which two students would sit across from each other, separated by a box with square compartments that contained objects. Some of the objects were not visible to one of the students. That student, the speaker, would ask the partner to move one of the objects -- but the speaker did not know that the request could be interpreted in two different ways. For example, if the speaker asked the partner to move a mouse, the partner would have two options: a computer mouse that the speaker could see, or a stuffed mouse that the speaker could not see.

The study found that when partners were asked to move an object with an ambiguous name, they would hesitate longer when the speaker was a friend. But when the speaker was a stranger, the partner would be faster to focus on the object that the speaker could see, and ignore the object that the speaker did not know about. This showed that the participants were more likely to take an egocentric position when working with a friend, neglecting to consider the possibility that the friend didn't share the same information they had.

"Our problem in communicating with friends and spouses is that we have an illusion of insight. Getting close to someone appears to create the illusion of understanding more than actual understanding," said co-author Nicholas Epley, a professor of behavioral science at the University of Chicago Booth School of Business.

"The understanding, 'What I know is different from what you know' is essential for effective communication to occur," Savitsky said. "It is necessary for giving directions, for teaching a class or just for having an ordinary conversation. But that insight can be elusive when the 'you' in question is a close friend or spouse."


Savitsky K, Keysar B, Epley N, Carter T, Swanson A. The closeness-communication bias: Increased egocentrism among friends versus strangers. Journal of Experimental Social Psychology 2011;47(1):269-73. http://psychology.uchicago.edu/people/faculty/CommBias.pdf

People commonly believe that they communicate better with close friends than with strangers. We propose, however, that closeness can lead people to overestimate how well they communicate, a phenomenon we term the closeness-communication bias. In one experiment, participants who followed direction of a friend were more likely to make egocentric errors--look at and reach for an object only they could see--than were those who followed direction of a stranger. In two additional experiments, participants who attempted to convey particular meanings with ambiguous phrases overestimated their success more when communicating with a friend or spouse than with strangers. We argue that people engage in active monitoring of strangers' divergent perspectives because they know they must, but that they "let down their guard" and rely more on their own perspective when they communicate with a friend.

 

[Michael Scally MD]

Painkiller Prescribing Varies Dramatically Among Family Physicians
Painkiller prescribing varies dramatically among family physicians

ScienceDaily (Mar. 14, 2011) — Some physicians are prescribing opioids such as OxyContin 55 times as often as others, according to a new study led by St. Michael's Hospital and the Institute for Clinical Evaluative Sciences (ICES). The study found most opioid-related deaths occur among patients treated by physicians who frequently prescribe opioids, suggesting doctors who prescribe a lot of opioids may not be doing so safely.

"We found that the 20 per cent of family doctors who are frequent prescribers wrote 55 times as many prescriptions as the 20 per cent of family doctors who prescribe opioids the least. This large variation in practice is concerning," says Dr. Irfan Dhalla, a general internist at St. Michael's Hospital and an adjunct scientist at ICES.

The study, published in the March edition of the journal Canadian Family Physician, examined opioid prescribing rates among family physicians in Ontario. Researchers found doctors who frequently prescribe opioids are also more likely to write the patient's final prescription before death.

"Family physicians are caught in the middle. On the one hand, there are many patients suffering terribly from chronic pain who can't get relief from other treatments. On the other hand, the evidence for long-term treatment with opioids is very weak," says St. Michael's family physician Dr. Philip Berger. "If the drugs were safe, it wouldn't be an issue. But unfortunately they do carry significant risks -- most notably addiction and death from overdose. And it is important to recognize that one reason opioids are prescribed so often is that the pharmaceutical industry has marketed these drugs very aggressively."

Deaths related to opioids in Ontario have more than doubled -- from 13.7 deaths per million residents in 1991 to 33.3 deaths per million residents in 2006. Of the 423 deaths that occurred in 2006, oxycodone -- the active ingredient in OxyContin -- was the opioid most frequently associated with an overdose death.
In 2010, the provincial government passed the Narcotics Safety and Awareness Act, which will enable the Ministry of Health and Long-Term Care to better track opioid prescribing in Ontario.


Dhalla IA, Mamdani MM, Gomes T, Juurlink DN. Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario. Can Fam Physician 2011;57(3):e92-6. Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario -- Dhalla et al. 57 (3): e92 -- Canadian Family Physician

Objective - To examine whether variation in prescribing at the level of? the individual physician is associated with opioid-related mortality.

Design - A population-based cross-sectional analysis linking prescription? data with records from the Office of the Chief Coroner.

Setting - The province of Ontario.?

Participants - Family physicians in Ontario and Ontarians aged 15 to 64 who? were eligible for prescription drug coverage under the Ontario Public Drug Program.

Main outcome measures - Variation in family physicians’ opioid prescribing and opioid-related mortality among their patients.

Results - The 20% of family physicians (n = 1978) who prescribed opioids? most frequently issued opioid prescriptions 55 times more often than the 20% who prescribed opioids least frequently. Family physicians in the uppermost quintile also wrote the final opioid prescription before death for 62.7% of public drug plan beneficiaries whose deaths were related to opioids. Physician characteristics associated with greater opioid prescribing were male sex (P = .003), older age (P < .001), and a greater number of years in practice (P < .001).

Conclusion - Opioid prescribing varies remarkably among family physicians,? and opioid-related deaths are concentrated among patients treated by physicians who prescribe opioids frequently. Strategies to reduce opioid-related harm should include efforts focusing on family physicians who prescribe opioids frequently.

 

[Michael Scally MD]

Association of Alcohol Intake With Pancreatic Cancer Mortality in Never Smokers [Pancreatic Cancer is one of the worst cancers to have. For all of the reasons not to drink alcohol to excess this might be one of the most powerful an persuasive.]

Findings from the prospective study presented herein strongly support the hypothesis that alcohol consumption, in particular heavy intake, also is an independent risk factor for pancreatic cancer, the fourth most common cause of cancer mortality [death] in the United States.

Heavy alcohol consumption causes acute and chronic pancreatitis but has never been linked definitively to pancreatic cancer. Indeed, a panel of experts convened by the International Agency for Research on Cancer in 2009 designated the evidence supporting a causal relationship between alcoholic beverage consumption and pancreatic cancer as limited. The lack of convincing evidence includes concerns about study design, inconsistencies in results of epidemiological studies, and potential residual confounding by smoking. Case-control investigations of this association are limited by sample size, potential recall bias, or possible selection bias owing to the high fatality of pancreatic cancer. Although some individual cohort studies and 3 pooled assessments or meta-analyses of prospective studies reported statistically significant positive associations between alcohol consumption and pancreatic cancer risk, other cohort studies showed no association. However, few studies had adequate statistical power to examine associations for high levels (>2-3 drinks per day) of alcohol consumption. In addition, residual confounding by smoking could explain a weak association, as a high proportion of heavy alcohol drinkers also smoke and tobacco smoking is a well-established modifiable risk factor for pancreatic cancer. Moreover, among the prospective studies that assessed the associations of specific beverage types with risk of pancreatic cancer, some showed a stronger risk for liquor consumption than for beer or wine consumption.

The Cancer Prevention Study II (CPS-II) is one of the largest long-term prospective cohort studies conducted to date. In the CPS-II, self-reported alcohol intake, smoking history, and other information was collected from approximately 1.2 million US men and women in 1982. In a previous analysis of the CPS-II cohort that assessed the predictors of pancreatic cancer mortality over 14 years of follow-up, there was no association between alcohol intake and pancreatic cancer mortality. In that analysis, consumption exceeding 1 drink per day was the highest category of intake assessed, and no results were reported by beverage type. The present analysis of alcohol intake and pancreatic cancer mortality in the CPS-II is based on almost 7000 pancreatic cancer deaths identified during 24 years of follow-up and is stratified on smoking history and beverage type.


Gapstur SM, Jacobs EJ, Deka A, McCullough ML, Patel AV, Thun MJ. Association of Alcohol Intake With Pancreatic Cancer Mortality in Never Smokers. Arch Intern Med 2011;171(5):444-51. Arch Intern Med -- Abstract: Association of Alcohol Intake With Pancreatic Cancer Mortality in Never Smokers, March 14, 2011, Gapstur et al. 171 (5): 444

Background An international panel of experts characterized the evidence linking alcoholic beverage consumption to pancreatic cancer as limited. Primary concerns include inconsistent results from underpowered studies, residual confounding by smoking, and the question of whether the association varies by type of alcoholic beverage.

Methods The association of alcohol intake with pancreatic cancer mortality was examined using data from the Cancer Prevention Study II, a prospective study of US adults 30 years and older. Alcohol consumption was self-reported on a 4-page questionnaire in 1982. Based on follow-up through December 31, 2006, there were 6847 pancreatic cancer deaths among 1 030 467 participants. Multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) were computed using Cox proportional hazards regression analysis controlling for age, sex, race/ethnicity, education, marital status, body mass index, family history of pancreatic cancer, and personal history of gallstones, diabetes mellitus, or smoking.

Results The RRs (95% CIs) of pancreatic cancer mortality associated with current intake of less than 1, 1, 2, 3, and 4 or more drinks per day compared with nondrinkers were 1.06 (0.99-1.13), 0.99 (0.90-1.08), 1.06 (0.97-1.17), 1.25 (1.11-1.42), and 1.17 (1.06-1.29), respectively (P < .001 for trend). Consumption of 3 or more drinks per day was associated with pancreatic cancer mortality in never smokers (RR, 1.36; 95% CI, 1.13-1.62) and in ever smokers (RR, 1.16; 95% CI, 1.06-1.27). This association was observed for consumption of liquor (RR, 1.32; 95% CI, 1.10-1.57) but not beer (RR, 1.08; 95% CI, 0.90-1.30) or wine (RR, 1.09; 95% CI, 0.79-1.49).

Conclusion These results strengthen the evidence that alcohol consumption, specifically liquor consumption of 3 or more drinks per day, increases pancreatic cancer mortality independent of smoking.

 

[Michael Scally MD]

Vitamin D Insufficiency High Among Patients With Early Parkinson Disease

High prevalence of hypovitaminosis D has been reported in Parkinson Disease (PD). Researchers found a significant decrease in vitamin D levels in patients with PD compared with matched healthy control subjects and patients with Alzheimer disease, but did not find a correlation with duration of disease symptoms. Other previous reports also noted high prevalence of vitamin D deficiency in PD, but in contrast, the prevalence was higher in patients with later-stage PD than in those with early-stage PD, consistent with the possibility that having PD and reduced mobility contributes to this relatively high prevalence. The Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) cohort is a well-characterized cohort of subjects with early PD. The cohort is well suited for further examining the prevalence of vitamin D insufficiency early in the course of the disease. Subjects in this cohort also experienced clinically significant disease progression, allowing a preliminary examination of whether vitamin D concentration changes as the disease worsens clinically. In this study, they report vitamin D status in patients with early PD and examine changes in 25(OH)D concentration from baseline to the DATATOP study-defined end point or final visit.


Evatt ML, DeLong MR, Kumari M, et al. High Prevalence of Hypovitaminosis D Status in Patients With Early Parkinson Disease. Arch Neurol 2011;68(3):314-9. Arch Neurol -- Abstract: High Prevalence of Hypovitaminosis D Status in Patients With Early Parkinson Disease, March 2011, Evatt et al. 68 (3): 314

Background Vitamin D insufficiency has been reported to be more common in patients with Parkinson disease (PD) than in healthy control subjects, but it is not clear whether having a chronic disease causing reduced mobility contributes to this relatively high prevalence.

Objective To examine the prevalence of vitamin D insufficiency in a cohort of untreated patients with early PD (diagnosed within 5 years of study entry).

Design, Setting, and Patients The Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) cohort is a well-characterized cohort of subjects with early, nondisabling PD. The cohort is well suited for examining the prevalence of vitamin D insufficiency early in the course of the disease. We conducted a survey study of vitamin D status in stored blood samples from patients with PD enrolled in the placebo group of the DATATOP trial. Samples from baseline visits and end point/final visits (mean [SD], 18.9 [13.1] months) were analyzed for 25-hydroxyvitamin D (25[OH]D) concentration in blinded fashion.

Main Outcome Measures The mean vitamin D concentration and the prevalence of vitamin D insufficiency at baseline and end point/final visits.

Results Among 199 subjects, 170 (85.4%) had samples from the baseline and end point visits available for analysis; 13 were excluded (10 with low probability of having PD and 3 with 25[OH]D concentrations >3 SDs above the mean). In the remaining 157 subjects, the mean (SD) 25(OH)D concentrations at the baseline and end point visits were 26.3 (8.6) ng/mL and 31.3 (9.0) ng/mL, respectively (to convert to nanomoles per liter, multiply by 2.496). The prevalence of vitamin D insufficiency (25[OH]D concentration <30.0 ng/mL) was 69.4% at baseline and 51.6% at the end point.

Conclusions The prevalence of vitamin D insufficiency in patients with early PD was similar to or higher than those reported in previous studies. Vitamin D concentrations did not decline during progression of PD. Further studies are needed to elucidate the natural history and significance of vitamin D insufficiency in PD.

 

[Michael Scally MD]

Endocrine Aspects Of Male Sexual Dysfunctions

This article summarizes the main sections of the report on Endocrine Aspects of Male Sexual Dysfunctions, which was prepared by the authors for the Third International Consultation of Sexual Medicine (ICSM, Paris, July 2009), in collaboration with the Standards’ Committee of the International Society of Sexual Medicine (ISSM). This report aimed to provide guidelines focusing on diagnosis and treatment of male sexual dysfunctions, as far as endocrine aspects are concerned. It was drawn up in starting from two previous comprehensive reviews of the corresponding topics: the report by Morales et al. of the committee “Endocrine Aspects of Men Sexual Dysfunctions” of the Second ICSM (Paris, July 2003), which already contained recommendations that were updated and completed, and the chapter “Hormones, Metabolism, Aging and Men’s Health” of the book “Standard Practice in Sexual Medicine” published in 2006 by the Standard’s Committee of the ISSM. These reviews may be consulted for more details on the basic aspects of the corresponding topics. Recent recommendations on investigation, treatment and monitoring of late onset hypogonadism have also been taken in consideration. The article is essentially made of the 30 recommendations of the 2009 ICSM report and of a summary of the evidence supporting them.

Levels of T are expressed either in pmol or nmol/L, or in pg or ng/mL, or in ng/dL (1,000 pg or pmol = respectively, 1 ng or nmol; 100 ng/ dL = 1 ng/mL). The conversion factors are nmol/L or pmol/L = 0.2884 = respectively, ng/mL or pg/mL, and ng/mL or pg/mL = 3.467 = respectively, nmol/L or pmol/L.


Buvat J, Maggi M, Gooren L, et al. Endocrine aspects of male sexual dysfunctions. J Sex Med 2010;7(4 Pt 2):1627-56. Endocrine aspects of male sexual dysfunctions. [J Sex Med. 2010] - PubMed result

INTRODUCTION: Endocrine disorders may adversely affect men's sexual function.

AIM: To provide recommendations based on best evidence for diagnosis and treatment of endocrine-related male sexual dysfunctions.

METHODS: The Endocrine Aspects of Male Sexual Dysfunctions Committee, including 11 members from eight countries and four continents, collaborated with the Endocrine subcommittee of the Standards Committee of the International Society for Sexual Medicine. Medical literature was reviewed in detail, followed by extensive internal committee discussion over 2 years, then public presentation and discussion with the other experts before finalizing the report.

MAIN OUTCOME MEASURE: Recommendations based on grading of evidence-base medical literature and interactive discussion.

RESULTS: From animal studies, it is derived that testosterone modulates mechanisms involved in erectile machinery, including expression of enzymes that both initiate and terminate erection. In addition, testosterone is essential for sexual motivation. Whether these findings could be extrapolated to human erections is unclear. Testosterone plays a broad role in men's overall health. Recent studies have established strong associations between low testosterone and metabolic and cardiovascular imbalances. In some studies, low testosterone decreased longevity; however, longitudinal studies do not support the predictive value of low testosterone for further cardiovascular events. The article proposes a standardized process for diagnosis and treatment of endocrine-related male sexual dysfunctions, updating the knowledge on testosterone and prostate safety. There is no compelling evidence that testosterone treatment causes prostate cancer or its progression in men without severe testosterone deficiency (TD). The possible roles of prolactin and thyroid hormones are also examined.

CONCLUSIONS: Men with erectile dysfunction, hypoactive sexual desire and retarded ejaculation, as well as those with visceral obesity and metabolic diseases, should be screened for TD and treated. Prospective interventional studies are required before screening for TD in more conditions, including cardiovascular diseases, and considering correction as preventive medicine as much data suggests.

 

[Michael Scally MD]

Are you sure you want to take the route of hGH for anti-aging!!! IMO, it is NOT worth the risks (multiple).

Linked to their proliferative, differentiation and apoptotic properties, both growth hormone (GH) and insulin-like growth factor-1 (IGF-I) have been identified as risk factors for certain malignancies, even in the pediatric age group and young adults. There is also evidence that most tumors and transformed cells display increased IGF-I receptor concentration and high IGF-IR mRNA causing enhanced IGF-I binding leading to the axiom that over-expression of IGF-IR is a prerequirement for acquisition or progress of malignant tumors. Further evidence for the link between GH and IGF-I and cancer is the successful use of GH and IGF-I receptor blocking agents in the treatment of malignancy. The above findings led researchers to investigate the reverse situation namely whether congenital defects of GH and IGF-I action would diminish or prevent the development of cancer. In 2007, they reported preliminary data on 169 patients with Laron Syndrome (LS) and on 250 of their first and second-degree relatives and found that none of the homozygous LS patients had developed cancer, whereas 24% of their heterozygous family members had. We also showed that 35 patients with congenital (c) IGHD and 18 with GHRH receptor (R) mutation reported no malignancies. In contradiction, 9-24% of their family members had a history of cancer. The aim of the present study was to extend their findings by enlarging the number of patients with Laron Syndrome and cIGHD and to collect data on patients with, GHRH-R mutations and congenital multiple pituitary hormone deficiency (cMPHD) including GH.


Steuerman R, Shevah O, Laron Z. Congenital IGF-I deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol:EJE-10-0859. Congenital IGF-I deficiency tends to confer protection against post-natal development of malignancies -- Steuerman et al., 10.1530/EJE-10-0859 -- European Journal of Endocrinology

Objective: To investigate whether congenital IGF-I deficiency confers protection against development of malignancies, by comparing the prevalence of malignancies in patients with congenital (secondary) deficiency of IGF-I with the prevalence of cancer in their family members.

Method: Only patients with an ascertained diagnosis of either Laron Syndrome (LS), congenital IGHD, congenital MPHD including GH or GHRH-R defect were included in this study. In addition to our own patients, we performed a world-wide survey and collected data on a total of 538 patients, 752 of their first degree family members, of these 274 siblings, and 131 further family members.

Results: We found that none of the 230 Laron Syndrome patients developed cancer and that only 1/116 patients with congenital IGHD also suffers from xeroderma pigmentosum, had a malignancy. Out of 79 patients with GHRH-R defects and out of 113 patients with congenital MPHD, we found 3 patients with cancer in each group. Among the first-degree family members (most heterozygotes) of LS, IGHD and MPHD, we found 30 cases of cancer and 1 suspected. In addition, 31 malignancies were reported among 131 further relatives.

Conclusions: Our findings bear heavily on the relationship between GH/IGF-I and cancer. Homozygous patients with congenital IGF-I deficiency and insensitivity to GH such as Laron Syndrome seem protected from future cancer development, even if treated by IGF-I. Patients with congenital IGHD also seem protected.

 

[Michael Scally MD]

IMO, the next decade will see knowledge so far beyond the simple AAS/AR. This is exciting.

Testosterones are important sex hormones that regulate animal growth and development, which is known to enhance myogenesis while inhibiting adipogenesis. Testes develop during the early to mid-gestation in ruminant animals, which secrete testosterones to regulate fetal development. In addition, testosterones are also known to enhance muscle growth postnatally. Trenbolone acetate is a synthetic analog of testosterone which is widely used in the United States and Canada. Implanted trenbolone in steers enhances animal growth performance and increases muscle mass. To date, however, the underlying mechanisms for the biological effect of testosterone on muscle growth are not clear.

Wingless and Int (Wnt) is a family of secreted glycoproteins that regulate cell proliferation and differentiation. Wnts exert their effect mainly through the beta-catenin pathway; once Wnt signaling is activated, beta-catenin translocates into nuclei and binds to the Tcell factor/lymphoid-enhancing factor (TCF/LEF) to regulate the expression of target genes. Wnt/beta- catenin signaling pathway is required for myogenesis. Activation of the Wnt signaling pathway enhances myogenesis and inhibits adipogenesis in cultured mesenchymal stem cells.

Adenosine monophosphate–activated protein kinase (AMPK) is a heterotrimeric enzyme with alpha, beta, and gamma subunits. The alpha subunit is the catalytic unit, the gamma subunit has a regulatory function, and the beta unit provides anchorage sites for the alpha and gamma subunits. AMPK is known as a key regulator of energy metabolism and is increasingly recognized as a key mediator of cell differentiation. Activation of AMPK promotes myogenesis. In their previous study, they showed that AMPK cross talks with beta-catenin through phosphorylation of beta-catenin at Ser552. In this study, researchers hypothesized that testosterone activates AMPK and enhances beta-catenin signaling which promotes myogenesis.


Zhao JX, Hu J, Zhu MJ, Du M. Trenbolone enhances myogenic differentiation by enhancing beta-catenin signaling in muscle-derived stem cells of cattle. Domest Anim Endocrinol. Trenbolone enhances myogenic differentiation by en... [Domest Anim Endocrinol. 2011] - PubMed result

Testosterone is a key hormone regulating animal growth and development, which promotes skeletal muscle growth and inhibits fat deposition; however, the underlying mechanisms remain poorly defined. Because canonical Wingless and Int/beta-catenin signaling promotes myogenesis, we hypothesized that testosterone regulates myogenesis through enhancing the beta-catenin signaling pathway and the expression of its targeted genes. Muscle-derived stem cells were prepared from the skeletal muscle of fetal calf at day 180 of gestation and treated with or without trenbolone (10 nM), a synthetic analog of testosterone, in a myogenic medium. Trenbolone treatment increased the protein levels of MyoD and myosin heavy chain, as well as the androgen receptor content. The myogenic effect of trenbolone was blocked by cyproterone acetate, a specific inhibitor of androgen receptor, showing that the myogenic effect of trenbolone was mediated by the androgen receptor. Immunoprecipitation showed that androgen receptor and beta-catenin formed a complex, which was increased by trenbolone treatment. Trenbolone activated adenosine monophosphate-activated protein kinase, which might phosphorylate beta-catenin at Ser552, stabilizing beta-catenin. Indeed, both cytoplasmic and nuclear beta-catenin levels were increased after trenbolone treatment. As a result, beta-catenin-mediated transcriptional activity was enhanced by trenbolone treatment. In conclusion, these data provide evidence that testosterone increases cellular beta-catenin content which promotes the expression of beta-catenin-targeted genes and myogenesis in the muscle-derived stem cells of cattle.

 

[Michael Scally MD]

Cardiac Aldosterone & Nandrolone Decanoate

do Carmo EC, Fernandes T, Koike D, et al. Anabolic Steroid Associated To Physical Training Induces Deleterious Cardiac Effects. Med Sci Sports Exerc. Anabolic Steroid Associated To Physical Training I... [Med Sci Sports Exerc. 2011] - PubMed result

PURPOSE:: Cardiac aldosterone might be involved in Nandrolone Decanoate (ND) deleterious effects on the heart. Therefore, we investigated the involvement of cardiac aldosterone, by the pharmacological block of AT1 or mineralocorticoid receptors, on cardiac hypertrophy and fibrosis.

METHODS:: Male Wistar rats were randomized into 8 groups (n=14/group): Control (C), Nandrolone Deconoate (ND), Trained (T), Trained ND (TND), ND+Losartan (ND +L), Trained ND +Losartan (TND +L), ND+Spironolactone (ND+S) and Trained ND+Spironolactone (TND+S). ND (10 mg/kg/week), was administered during 10 weeks of swimming training (5 times/wk). Losartan (20mg/kg/day) and Spironolactone (10mg/kg/day) were administered in drinking water.

RESULTS:: Cardiac hypertrophy was increased 10% by using ND and 17% by ND plus training (p<0.05). In both groups, there was an increase in the collagen volumetric fraction (CVF) and cardiac collagen type III expression (p<0.05). The ND treatment increased: LV-ACE activity, AT1 receptor expression, aldosterone synthase (CYP11B2) and 11-beta hydroxysteroid dehydrogenase 2 (11betaHSD2) gene expression and inflammatory markers, TGFbeta and osteopontin. Both Losartan and Spironolactone inhibited the increase of CVF and collagen type III. In addition, both treatments inhibited the increase in LV-ACE activity, CYP11B2, 11betaHSD2, TGFbeta and osteopontin induce by the ND treatment.

CONCLUSION:: We believe this is the first study showing the effects of ND on cardiac aldosterone. Our results suggest that these effects may be associated to TGFbeta and osteopontin. Thus, we conclude that the cardiac aldosterone has an important role on the deleterious effects on the heart induced by ND.

 

[Michael Scally MD]

By studying the effects on lean mass and weight of individual muscles and comparing gene expression after ER- and AR-mediated stimulation in muscle of gonadectomized mice, this study aimed to investigate whether the effect of testosterone on lean tissue could be due to a direct stimulatory effect on the AR or due to aromatization of testosterone to E2.

In conclusion, activation of both ER and AR preserves muscle and lean mass after gonadectomy in male mice, although the effect was more marked after AR activation. Few genes were regulated by both E2 and DHT, and when E2 and DHT regulated the same pathways (IGF1 signaling, increased angiogenesis, and glutathione oxidation), it was done by affecting different sets of genes. However, short-term treatment with E2 partly prevented and with DHT fully prevented the transient increase in Fbxo32 expression observed after gonadectomy. E2 alone had effects on genes involved in glucose and lipid metabolism, likely increasing glycogen synthesis and utilization of FAs for fuel in muscle. DHT alone regulated the expression of genes influencing synaptic formation and transmission, oxygen transport, and polyamine biosynthesis. Based on these findings, it could be hypothesized that the metabolic effects of testosterone in skeletal muscle of male mice are to a large extent dependent on ER activation, whereas other effects of testosterone in skeletal muscle are more dependent on AR activation.


Svensson J, Moverare-Skrtic S, Windahl S, Swanson C, Sjogren K. Stimulation of both estrogen and androgen receptors maintains skeletal muscle mass in gonadectomized male mice but mainly via different pathways. J Mol Endocrinol 2010;45(1):45-57. Stimulation of both estrogen and androgen receptors maintains skeletal muscle mass in gonadectomized male mice but mainly via different pathways -- Svensson et al. 45 (1): 45 -- Journal of Molecular Endocrinology

Testosterone is a major regulator of muscle mass. Little is known whether this is due to a direct stimulation of the androgen receptor (AR) or mediated by aromatization of testosterone to estradiol (E2), the ligand for the estrogen receptors (ERs), in peripheral tissues. In this study, we differentiated between the effects mediated by AR and ER by treating orchidectomized (orx) male mice for 5 weeks with E2 or the non-aromatizable androgen dihydrotestosterone (DHT). Both E2 and DHT increased muscle weight and lean mass, although the effect was less marked after E2 treatment. Studies of underlying mechanisms were performed using gene transcript profiling (microarray and real-time PCR) in skeletal muscle, and they demonstrated that E2 regulated 51 genes and DHT regulated 187 genes, with 13 genes (=25% of E2-regulated genes) being regulated by both treatments. Both E2 and DHT altered the expression of Fbxo32, a gene involved in skeletal muscle atrophy, affected the IGF1 system, and regulated genes involved in angiogenesis and the glutathione metabolic process. Only E2 affected genes that regulate intermediary glucose and lipid metabolism, and only DHT increased the expression of genes involved in synaptic transmission and heme and polyamine biosynthesis. In summary, ER activation by E2 treatment maintains skeletal muscle mass after orx. This effect is less marked than that of AR activation by DHT treatment, which completely prevented the effect of orx on muscle mass and was partly, but not fully, mediated via alternative pathways.

 

[Michael Scally MD]

Ornithine alpha-ketoglutarate (OKG) is a precursor of biologically active amino acids such as glutamine and arginine, and other active compounds that are important in the regulation of protein metabolism in skeletal muscle. Additionally, OKG has a potent secretagogic effect on anabolic hormones like insulin and growth hormone. Therefore, the concept OKG is based on the production of these molecules. Of interest, several studies have highlight that the action of OKG is potentially more efficient that the action of each of its derivative compounds. This observation suggests that OKG is not a simple precursor of active metabolites and hormones but strong interactions exist between each component produced after OKG administration. Although the mechanism of action of OKG is still enigmatic, the interaction between OKG-derived metabolites is a key point in an attempt to shed light on its effect.

Oral or intravenous OKG supplementation has an anabolic action, i.e. increased body protein retention, during hypercatabolic situations in animal models and in Human. In particular, OKG may exert its effect by regulating protein turnover at skeletal muscle level. The potential benefit of OKG supplementation on skeletal muscle mass and function has never been investigated in sarcopenic non-malnourished older Humans.

Walrand S. Ornithine alpha-ketoglutarate: could it be a new therapeutic option for sarcopenia? J Nutr Health Aging 2010;14(7):570-7. Ornithine alpha-ketoglutarate: could it be a new t... [J Nutr Health Aging. 2010] - PubMed result

Our current knowledge on the causes of sarcopenia is still fragmentary. One of the most evident candidates to explain muscle loss in elderly includes imbalance in protein turnover, i.e. decreased muscle protein synthesis rate, notably in the post-prandial state. Nutritional strategies such as leucine supplementation, use of fast digested proteins or a pulse protein intake have been show to enhance the synthesis rate of muscle proteins in older individuals. Ornithine alpha-ketoglutarate (OKG) is a precursor of amino acids such as glutamine, arginine and proline, and increases the secretion of anabolic hormones, i.e. insulin and growth hormone. A beneficial anabolic action of OKG has been demonstrate in several pathological conditions associated with muscle loss. Therefore, OKG may be of a potential interest to modulate muscle protein metabolism and to maintain muscle mass during aging.

 

[Michael Scally MD]

LB03002 is a new sustained-release formulation consisting of microparticles containing GH incorporated into sodium hyaluronate and dispersed in an oil base of medium- chain triglycerides. The pharmacokinetic and pharmacodynamic properties of this compound have been tested in pediatric and adult patients with GHD. No evident safety concerns emerged with LB03002. On the background of the pharmacokinetic studies, a double-blind, placebo-controlled clinical study in adult GHD patients has been carried out with the once-weekly sustained-release GH formulation, LB03002. The present report documents the efficacy and safety of LB03002 administered once weekly for 26 wk in adult patients with GHD.


Biller BMK, Ji H-J, Ahn H, et al. Effects of Once-Weekly Sustained-Release Growth Hormone: A Double-Blind, Placebo-Controlled Study in Adult Growth Hormone Deficiency. J Clin Endocrinol Metab:jc.2010-819. Effects of Once-Weekly Sustained-Release Growth Hormone: A Double-Blind, Placebo-Controlled Study in Adult Growth Hormone Deficiency -- Biller et al., 10.1210/jc.2010-2819 -- Journal of Clinical Endocrinology & Metabolism

Background: A sustained-release recombinant human GH formulation, LB03002, has been recently developed, with pharmacokinetics and pharmacodynamic activity appropriate for once-weekly administration. LB03002 is a long-acting GH that is administered once a week by sc injection.

Objective: This study evaluated efficacy and safety of LB03002 in adult patients with GH deficiency.
Patients and Methods: A total of 152 patients were randomized to receive LB03002 or placebo once weekly for 26 wk. Changes in body composition were evaluated from DXA (dual-energy x-ray absorptiometry). IGF-I was assessed at each study visit. Safety was assessed from adverse events, glucose homeostasis, and antibody development.

Results: IGF-I increased significantly (P < 0.001) with LB03002 and remained unchanged with placebo. Mean fat mass (FM) decreased by 1.052 kg [95% confidence interval (CI) = –1.614 to –0.491] in the LB03002 group vs. an increase of 0.570 kg (95% CI = –0.205–1.345) in the placebo group; treatment difference was 1.622 kg (95% CI = –2.527 to –0.717; P < 0.001). FM change was mainly due to decreased trunk fat. Least square mean treatment difference was 1.032 kg (95% CI = –1.560 to –0.515; P < 0.001). LBM (lean body mass) was significantly increased with LB03002 vs. placebo (least square mean difference was 1.393 kg; 95% CI = 0.614–2.171; P < 0.001). No concerning safety issues arose during the study.

Conclusions: Weekly GH replacement with the sustained-release preparation LB03002 in adults significantly reduced FM over 6 months and was well tolerated.

 

[Michael Scally MD]

In the last decade, many epidemiological studies on human longevity have shown that parents, siblings and offspring of long-lived subjects have a significant survival advantage compared with the general population in attaining longevity. Although these studies do not distinguish between shared environmental and genetic factors, twin data suggest that genes may have a modest role in achieving longevity. In order to better distinguish the effect of genes from the effect of shared familial environment, researchers analyzed the survival data of the spouses of long-lived subjects as an additional control group. They found that members of this control group, who shared most of their adult life with the long-lived partner, did not show any advantage/benefit in terms of survival, suggesting that a substantial contribution in the familiarity of human longevity is attributable to genetic factors. However, as a complex trait, the heritability of ‘lifespan’ may be influenced by an interplay of genetic, environmental and stochastic factors. In addition, the influence of the genetic component on lifespan is expected to be stronger in populations of areas where environmental factors are harsher as demonstrated in different studies.

Calabria is one of the poorest Italian regions located in the southern part of the peninsula. In the present study researchers aimed (i) to estimate the familial component of human longevity in Calabrian population; (ii) to uncouple within such a familial component the genetic from the environmental component. For these purposes, they reconstructed 202 pedigrees of Calabrian families where at least one nonagenarian individual was present. In order to estimate the presence of a familial component of longevity, they compared the survival data of parents and siblings of long-lived subjects with appropriate Italian birth cohorts. Then, to minimize the variability of familial environmental factors, they compared the survival functions of long-lived siblings with those of their spouses (intrafamily control group). This approach allowed them to estimate how much of the familiarity of the analyzed phenotype is due to genetics.


Montesanto A, Latorre V, Giordano M, Martino C, Domma F, Passarino G. The genetic component of human longevity: analysis of the survival advantage of parents and siblings of Italian nonagenarians. Eur J Hum Genet. The genetic component of human longevity: analysis... [Eur J Hum Genet. 2011] - PubMed result

Many epidemiological studies have shown that parents, siblings and offspring of long-lived subjects have a significant survival advantage when compared with the general population. However, how much of this reported advantage is due to common genetic factors or to a shared environment remains to be resolved.

We reconstructed 202 families of nonagenarians from a population of southern Italy. To estimate the familiarity of human longevity, we compared survival data of parents and siblings of long-lived subjects to that of appropriate Italian birth cohorts. Then, to estimate the genetic component of longevity while minimizing the variability due to environment factors, we compared the survival functions of nonagenarians' siblings with those of their spouses (intrafamily control group).

We found that both parents and siblings of the probands had a significant survival advantage over their Italian birth cohort counterparts. On the other hand, although a substantial survival advantage was observed in male siblings of probands with respect to the male intrafamily control group, female siblings did not show a similar advantage. In addition, we observed that the presence of a male nonagenarians in a family significantly decreased the instant mortality rate throughout lifetime for all the siblings; in the case of a female nonagenarians such an advantage persisted only for her male siblings.

The methodological approach used here allowed us to distinguish the effects of environmental and genetic factors on human longevity. Our results suggest that genetic factors in males have a higher impact than in females on attaining longevity.

 

[Michael Scally MD]

Irwig MS, Kolukula S. Persistent Sexual Side Effects of Finasteride for Male Pattern Hair Loss. The Journal of Sexual Medicine. Persistent Sexual Side Effects of Finasteride for Male Pattern Hair Loss - Irwig - 2011 - The Journal of Sexual Medicine - Wiley Online Library

Introduction.? Finasteride has been associated with reversible adverse sexual side effects in multiple randomized, controlled trials for the treatment of male pattern hair loss (MPHL). The Medicines and Healthcare Products Regulatory Agency of the United Kingdom and the Swedish Medical Products Agency have both updated their patient information leaflets to include a statement that “persistence of erectile dysfunction after discontinuation of treatment with Propecia has been reported in post-marketing use.”

Aim.? We sought to characterize the types and duration of persistent sexual side effects in otherwise healthy men who took finasteride for MPHL.

Methods.? We conducted standardized interviews with 71 otherwise healthy men aged 21–46 years who reported the new onset of sexual side effects associated with the temporal use of finasteride, in which the symptoms persisted for at least 3 months despite the discontinuation of finasteride.

Main Outcome Measures.? The types and duration of sexual dysfunction and the changes in perceived sexual frequency and sexual dysfunction score between pre- and post-finasteride use.

Results.? Subjects reported new-onset persistent sexual dysfunction associated with the use of finasteride: 94% developed low libido, 92% developed erectile dysfunction, 92% developed decreased arousal, and 69% developed problems with orgasm. The mean number of sexual episodes per month dropped and the total sexual dysfunction score increased for before and after finasteride use according to the Arizona Sexual Experience Scale (P < 0.0001 for both). The mean duration of finasteride use was 28 months and the mean duration of persistent sexual side effects was 40 months from the time of finasteride cessation to the interview date. Study limitations include a post hoc approach, selection bias, recall bias for before finasteride data, and no serum hormone levels.

Conclusion.? Physicians treating MPHL should discuss the potential risk of persistent sexual side effects associated with finasteride.

 

[Michael Scally MD]

The use of nutritional supplements continues to increase in sports and physical fitness, with creatine as one of the most widely used substances. Among visitors to Dutch fitness centres, 3.2% had used creatine supplementation in the past year. Creatine is claimed to increase muscle strength and is most popular among bodybuilders. It is considered a harmless product and is not regarded as a performance enhancing drug by the World Anti Doping Agency. Researchers describe a patient who had a substantial elevation of his plasma creatinine level, which normalised after withdrawal of the creatine-containing supplement he was using. Furthermore they explain why serum creatinine is not elevated in all subjects using creatine.

Velema MS, de Ronde W. Elevated plasma creatinine due to creatine ethyl ester use. Neth J Med 2011;69(2):79-81. http://www.njmonline.nl/njm/getpdf.php?t=a&id=10000685

Creatine is a nutritional supplement widely used in sport, physical fitness training and bodybuilding. It is claimed to enhance performance. We describe a case in which serum creatinine is elevated due to the use of creatine ethyl esther. One week after withdrawal, the plasma creatinine had normalised. There are two types of creatine products available: creatine ethyl esther (CEE) and creatine monohydrate (CM). Plasma creatinine is not elevated in all creatine-using subjects. CEE , but not CM, is converted into creatinine in the gastrointestinal tract. As a result the use of CEE may be associated with elevated plasma creatinine levels. Since plasma creatinine is a widely used marker for renal function, the use of CEE may lead to a false assumption of renal failure.


ALSO, SEE:

Spillane M, Schoch R, Cooke M, et al. The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels. J Int Soc Sports Nutr 2009;6:6. http://www.jissn.com/content/pdf/1550-2783-6-6.pdf

Numerous creatine formulations have been developed primarily to maximize creatine absorption. Creatine ethyl ester is alleged to increase creatine bio-availability. This study examined how a seven-week supplementation regimen combined with resistance training affected body composition, muscle mass, muscle strength and power, serum and muscle creatine levels, and serum creatinine levels in 30 non-resistance-trained males.

In a double-blind manner, participants were randomly assigned to a maltodextrose placebo (PLA), creatine monohydrate (CRT), or creatine ethyl ester (CEE) group. The supplements were orally ingested at a dose of 0.30 g/kg fat-free body mass (approximately 20 g/day) for five days followed by ingestion at 0.075 g/kg fat free mass (approximately 5 g/day) for 42 days.

Results showed significantly higher serum creatine concentrations in PLA (p = 0.007) and CRT (p = 0.005) compared to CEE. Serum creatinine was greater in CEE compared to the PLA (p = 0.001) and CRT (p = 0.001) and increased at days 6, 27, and 48. Total muscle creatine content was significantly higher in CRT (p = 0.026) and CEE (p = 0.041) compared to PLA, with no differences between CRT and CEE. Significant changes over time were observed for body composition, body water, muscle strength and power variables, but no significant differences were observed between groups.

In conclusion, when compared to creatine monohydrate, creatine ethyl ester was not as effective at increasing serum and muscle creatine levels or in improving body composition, muscle mass, strength, and power. Therefore, the improvements in these variables can most likely be attributed to the training protocol itself, rather than the supplementation regimen.

 

[Michael Scally MD]

Niacin

In recent years, the thrust of efforts to prevent and treat atherosclerosis has shifted somewhat from nearly exclusive concern for high low-density lipoprotein (LDL) to include the problem of low high density lipoprotein (HDL) cholesterol levels. Statins increase HDL by an average of only 4% to 8%, and may even decrease it in individual patients. There is general agreement that among currently available drugs, niacin is the most potent in the ability to increase HDL. Niacin is presently enjoying somewhat of a revival, almost exclusively in its slow-release (SR) form, which to some extent causes less flushing than crystalline niacin.

Two recent trials have demonstrated the ability of niacin to bring about a regression in carotid atherosclerosis when added to statin therapy. The HATS trial showed that the combination of niacin and simvastatin led to a regression in coronary atherosclerosis. Moreover, HATS and ARBITER-6-HALTS showed reductions in clinical morbid events, whereas long-term follow-up data from the Coronary Drug Project indicated reduced nonfatal myocardial infarction and mortality after 6.5 years of niacin therapy.

As the use of niacin becomes more common in statin-treated patients for the purpose of increasing HDL, as well as achieving a further lowering of LDL in patients who have not reached their LDL goal, we present a case to promote the proper use of niacin in the statin era. We call attention to the significant differences among crystalline, immediate-release (IR) niacin, and SR niacin.

The case described illustrates several important points regarding the clinical use of niacin. First, niacin in large doses is a drug in all respects - with profound therapeutic and toxic effects. Even though it is better known as a vitamin and available over-the-counter, its use to treat dyslipidemia demands medical supervision. Second, contrary to most drugs that come in immediate and sustained-release forms, in which the latter merely allows more convenient dosing, IR and SR niacin have significant differences in therapeutic effects, side effects, and toxicity.


Bassan M. A case for immediate-release niacin. Heart Lung. A case for immediate-release niacin. [Heart Lung. 2011] - PubMed result

Niacin is currently a favored drug for increasing high-density lipoprotein, especially in patients with ischemic heart disease or at high risk of developing it. In addition, niacin further decreases low-density lipoprotein in statin-treated patients and has been shown to reduce morbidity and mortality. Among the available niacin preparations, crystalline, immediate-release niacin is the most effective for increasing high-density lipoprotein and is relatively free of hepatic toxicity. We present the case of a patient who had an excellent clinical and laboratory response to 3 g daily of immediate-release niacin, but who later developed clinical hepatitis when he inadvertently switched to the same dose of slow-release niacin. We encourage the use of niacin in general, immediate-release niacin in particular, and caution that niacin is a drug and not a dietary supplement. We also present practical steps for starting niacin, including close patient contact and support, and beginning with a therapeutic dose of 2 g per day right from the start.