Sarcopenia & Testosterone (Beyond Hypogonadism)

[Michael Scally MD]

Sarcopenia is defined as the progressive decline of skeletal muscle mass and strength, which occurs with aging. The rate of muscle loss is estimated to be 1–2% per year after the age of 50 yr and can affect even healthy physically active adults. Secondary to loss of skeletal muscle mass, there is a corollary decrease in functional independence and the ability to perform activities of daily living within the elderly population. Approximately 25% of people above the age of 70 yr and 40% of those who have reached the age of 80 yr are clinically sarcopenic. Additionally, aging-associated skeletal muscle loss also leads to an increased risk of falls, fractures, dependency, and all-cause mortality.

Mechanisms that regulate age-related loss of skeletal muscle mass are not well defined, but the pathogenesis is likely multifactorial. With age, in a process similar to that occurring in many other tissues, there is a gradual decline of regenerative potential in skeletal muscle. Studies suggest that the intrinsic regenerative capacity of aged satellite cells remains intact.

Apoptosis, or programmed cell death, increases in skeletal muscle cells with aging and may also contribute to aging-associated sarcopenia. Thus, a combined approach targeting both diminished satellite cell regenerative potential and increased muscle cell apoptosis may present a framework for therapeutic intervention of aging-associated sarcopenia.

Testosterone, through its anabolic effects on muscle, is an important determinant of body composition in humans. Therefore, it is not surprising that testosterone supplementation increases muscle mass in healthy young and old men, healthy hypogonadal men, older men with low testosterone levels, and men with chronic illness and low testosterone levels. A recent multicenter study of testosterone therapy in older men further documented significant gains in total and appendicular lean mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. The testosterone-induced increase in muscle size in both young and old men is associated with hypertrophy of muscle fibers and significant increases in myonuclear and satellite cell numbers. The mechanisms by which testosterone increases satellite cell number and promotes muscle growth in aging are not well understood.


Kovacheva EL, Sinha Hikim AP, Shen R, Sinha I, Sinha-Hikim I. Testosterone Supplementation Reverses Sarcopenia in Aging through Regulation of Myostatin, c-Jun NH2-Terminal Kinase, Notch, and Akt Signaling Pathways. Endocrinology;151(2):628-38.

Aging in rodents and humans is characterized by loss of muscle mass (sarcopenia). Testosterone supplementation increases muscle mass in healthy older men. Here, using a mouse model, we investigated the molecular mechanisms by which testosterone prevents sarcopenia and promotes muscle growth in aging. Aged mice of 22 months of age received a single sc injection of GnRH antagonist every 2 wk to suppress endogenous testosterone production and were implanted subdermally under anesthesia with 0.5 or 1.0 cm testosterone-filled implants for 2 months (n = 15/group). Young and old mice (n = 15/group), of 2 and 22 months of age, respectively, received empty implants and were used as controls. Compared with young animals, a significant (P < 0.05) increase in muscle cell apoptosis coupled with a decrease in gastrocnemius muscles weight (by 16.7%) and muscle fiber cross-sectional area, of both fast and slow fiber types, was noted in old mice. Importantly, such age-related changes were fully reversed by higher dose (1 cm) of testosterone treatment. Testosterone treatment effectively suppressed age-specific increases in oxidative stress, processed myostatin levels, activation of c-Jun NH2-terminal kinase, and cyclin-dependent kinase inhibitor p21 in aged muscles. Furthermore, it restored age-related decreases in glucose-6-phosphate dehydrogenase levels, phospho-Akt, and Notch signaling. These alterations were associated with satellite cell proliferation and differentiation. Collectively these results suggest involvement of multiple signal transduction pathways in sarcopenia. Testosterone reverses sarcopenia through stimulation of cellular metabolism and survival pathway together with inhibition of death pathway.

 

[Michael Scally MD]

As I have stated, there is a rapid push for androgen research of a much higher caliber than ever before. Whether this will lead to androgen treatments for the “Baby Boomers” is yet to be seen. The research into SARMs, in my opinion, is part of this push. Can you believe the statements, "Testosterone (T) increases muscle mass and strength in hypogonadal patients. It is unclear whether T has similar effects in intermediate-frail and frail elderly men with low to borderline-low T," are still being made? This is a slow methodical process, but it is finally moving forward.


Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of Testosterone on Muscle Strength, Physical Function, Body Composition, and Quality of Life in Intermediate-Frail and Frail Elderly Men: A Randomized, Double-Blind, Placebo-Controlled Study. J Clin Endocrinol Metab;95(2):639-50.

Context: Physical frailty is associated with reduced muscle strength, impaired physical function, and quality of life. Testosterone (T) increases muscle mass and strength in hypogonadal patients. It is unclear whether T has similar effects in intermediate-frail and frail elderly men with low to borderline-low T. Objective: Our objective was to determine the effects of 6 months T treatment in intermediate-frail and frail elderly men, on muscle mass and strength, physical function, and quality of life. Design and Setting: We conducted a randomized, double-blind, placebo-controlled, parallel-group, single-center study. Participants: Participants were community-dwelling intermediate-frail and frail elderly men at least 65 yr of age with a total T at or below 12 nmol/liter or free T at or below 250 pmol/liter. Methods: Two hundred seventy-four participants were randomized to transdermal T (50 mg/d) or placebo gel for 6 months. Outcome measures included muscle strength, lean and fat mass, physical function, and self-reported quality of life. Results: Isometric knee extension peak torque improved in the T group (vs. placebo at 6 months), adjusted difference was 8.6 (95% confidence interval, 1.3-16.0; P = 0.02) Newton-meters. Lean body mass increased and fat mass decreased significantly in the T group by 1.08 {+/-} 1.8 and 0.9 {+/-} 1.6 kg, respectively. Physical function improved among older and frailer men. Somatic and sexual symptom scores decreased with T treatment; adjusted difference was -1.2 (-2.4 to -0.04) and -1.3 (-2.5 to -0.2), respectively. Conclusions: T treatment in intermediate-frail and frail elderly men with low to borderline-low T for 6 months may prevent age-associated loss of lower limb muscle strength and improve body composition, quality of life, and physical function. Further investigations are warranted to extend these results.

 

[BBC3]

So I think the moral is T=Healthy muscle.

I was not sure how to interpret this statement in the second study. Testosterone reverses sarcopenia through stimulation of cellular metabolism and survival pathway together with inhibition of death pathway By dead pathway, were they simply referring to as unused, as not T was currently, or recently been endogenously produced?

 

[Michael Scally MD]

So I think the moral is T=Healthy muscle.

I was not sure how to interpret this statement in the second study. Testosterone reverses sarcopenia through stimulation of cellular metabolism and survival pathway together with inhibition of death pathway By dead pathway, were they simply referring to as unused, as not T was currently, or recently been endogenously produced?

They are referring to the inhibition of apoptosis. Apoptosis, or programmed cell death, increases in skeletal muscle cells with aging and may also contribute to aging-associated sarcopenia.

 

[Michael Scally MD]

The Brave New World of Function-Promoting Anabolic Therapies

The literature and commentary are accumulating for anabolic therapies, but the obstacles are providing clear patient reported outcomes (PRO) as benefit. There will be the added problem of androgen induced hypogonadism (AIH). GTx recently terminated its SARM R&D with Merck [ https://thinksteroids.com/community/threads/134287288 ]. I think it was more likely Merck's decision and not GTx. LGND, however, recently announced a successful completion of a phase 1 SARM trial [ https://thinksteroids.com/community/posts/682650 ]. I am working on the AIH aspect. It is hopeful that all of these might come together in a timely manner.


EDITORIAL

Bhasin S. The Brave New World of Function-Promoting Anabolic Therapies: Testosterone and Frailty. J Clin Endocrinol Metab;95(2):509-11.

Boston University School of Medicine, Claude D. Pepper Older Americans Independence Center for Function Promoting Therapies, and Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Shalender Bhasin, M.D., Chief, Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, 670 Albany Street, Second Floor, Boston, Massachusetts 02118. E-mail:Bhasin@bu.edu.

Physical function is an excellent marker of an individual’s health (1). Limitations in physical function are an important public health problem because of their high prevalence and their association with adverse health outcomes, including the increased risk of disability, poor quality of life, hospitalization, and mortality (2, 3). In the USA alone, 12–14% of the noninstitutionalized population—approximately 35–38 million people—have a disability due to a chronic health condition (4). For people over age 65 yr, 35 to 40% experience activity limitations or disability. Because the U.S. population is aging, the percentage of population aged 65 yr or over will increase from 12% in 2000 to 20% in 2030—to more than 69 million. The number of people 85 or older is expected to grow from 3 million (2.1%) to 6.2 million (3.4%) in the United States alone. The majority of individuals who reach this age will experience some limitation in function (4, 5). The costs of support services, lost productivity associated with disabling conditions, and the impact of disability on an individual’s quality of life will have enormous societal consequences (6).

Currently, the practicing physicians have few therapeutic choices for the treatment of older individuals with functional limitations and physical disability. Exercise, physical rehabilitation, and behavioral modalities have had limited impact at a population level. Therefore, there is growing need for developing pharmacological function promoting therapies for the treatment of functional limitations.

It has become apparent that a small number of intersecting signaling pathways are crucial for regulating muscle growth through their effects on ribosomal protein translation (AkT/mammalian target of rapamycin pathway), mesenchymal progenitor cell differentiation (Wnt and Smad signaling), and muscle protein degradation (ubiquitin-proteasome pathway and the FoXo family of transcription factors). Pharmacophores that selectively modulate these signaling pathways, such as androgens, myostatin antagonists, and GH/IGF-I mimetics are being explored for their potential as function-promoting anabolic therapies; of these, androgens are the farthest along in development.

The idea that androgens have anabolic effects on the skeletal muscle is not new. Athletes and recreational body builders who abuse androgens do so because of the widely held perception that androgens increase muscle mass, muscle strength, and athleticperformance. However, systematic investigations of androgens as function-promoting therapies have been limited largely to the past 15 yr (7). Epidemiological studies have shown that circulating testosterone levels are associated with skeletal muscle mass, muscle strength, and self-reported as well as performance-based measures of physical function (8, 9, 10). Cawthon et al. (11) reported in a recent issue of the Journal that low levels of bioavailable testosterone in men participating in the Osteoporotic Fractures in Men Study (MrOS) were associated independently with worse frailty status. In longitudinal analysis, the men in the lowest quartile of bioavailable testosterone levels had approximately 1.5-fold higher odds of greater frailty status 4.1 yr later (11). However, neither total nor free testosterone levels were associated with frailty status. Mohr et al. (12) in a separate analysis of the data from the Massachusetts Male Aging Study (MMAS) also found no significant association of total or free testosterone levels with overall frailty status. However, in the MMAS, total testosterone levels were associated with some frailty components—grip strength and physical activity—but not with other components such as exhaustion, slow walking, or weight loss (12). In light of the known effects of testosterone on muscle mass and strength, it is not surprising that testosterone levels would be associated with frailty components that are more tightly linked to skeletal muscle mass and strength. Undoubtedly, frailty is a heterogeneous construct, and not all of its components share a common biological or pathophysiological basis or have the same prognostic significance (13).

In this issue of the Journal, Srinivas-Shankar et al. (14) report the results of the first randomized clinical trial of the effects of testosterone therapy in older men with one or more components of the frailty syndrome, total testosterone less than 12 nmol/liter, or free testosterone less than 250 pmol/liter. The study had several features of good clinical trial design: randomization, blinding of subjects and investigators, parallel group design, and inclusion of a placebo group as the reference for comparison (14). Unlike some other important studies that did not achieve robust increments in testosterone concentrations (15, 16), Srinivas-Shankar et al. (14) adjusted the testosterone dose to achieve testosterone concentrations in the target range. Testosterone therapy was associated with greater improvements in isokinetic knee extension peak torque and lean body mass (14). Although performance-based measures of physical function did not improve to a greater extent than placebo, in secondary analysis, physical function improved in subsets of older and frailer men. Importantly, somatic and sexual symptoms improved to a greater extent with testosterone therapy than with placebo. The overall frequency of adverse events was relatively low given the age and frail status of the participants. It is important to recognize that frailty was not an efficacy outcome of this trial.

There is much to be learned from this pioneering study by Srinivas-Shankar et al. (14), which represents the first randomized clinical trial of testosterone in men with frailty or intermediate frailty. This trial reaffirmed a common theme emerging from previoustestosterone trials: that testosterone therapy is associated with improvements in skeletal muscle mass and maximal voluntary muscle strength (7), but that the improvements in muscle mass and strength during testosterone therapy are not consistently translated into functional improvements (17). The improvements in muscle strength in testosterone-treated men in this trial, although statistically significant, were relatively small, and it is debatable whether they were clinically meaningful. Testosterone therapy raised serum testosterone concentrations into the mid to normal range. Because gains in skeletal muscle mass and strength are correlated with testosterone dose and testosterone concentrations (17, 18), it may be necessary to raise serum testosterone concentrations to even higher levels than those achieved in this trial to realize clinically meaningful gains in muscle mass and strength; the long-term safety of such an approach remains to be demonstrated.

Also, translation of muscle mass and strength gains into physical function improvements may require additional neuromuscular, cognitive, and behavioral adaptations that are not induced by testosterone administration alone. It is possible that concurrent functional training may be required to induce such adaptations. Although strength training is known to augment the anabolic effects of testosterone on muscle mass and strength, functional training protocols may need to incorporate additional cognitive, behavioral and task-specific training components.

The field of function-promoting therapies has become stymied by a number of regulatory uncertainties. One major issue is how to operationalize the clinical indications for which efficacy trials of function promoting therapies should be conducted. A therapeutic indication should ideally be a condition that is recognized by clinicians, affects health outcomes, and can be ascertained precisely and accurately by self-reported or performance-based measures. Additionally, there should be some mechanistic plausibility that the drug being tested would improve the condition for which the indication is being sought. As an example, mobility limitation is a common condition in older individuals, widely recognized by geriatricians as an important clinical condition that renders the affected individual at higher risk of disability, hospitalization, and death (1, 2, 3). Mobility limitation can be ascertained by self-reported difficulty in walking and verified by measuring the gait speed. Testosterone levels have been associated with gait speed. Therefore, onecould argue that mobility limitation is a good indication for promyogenic function-promoting molecules such as testosterone, other androgens, or selective androgen receptor modulators.

Fried et al. (19) have defined frailty as a syndrome consisting of three or more of the following: unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity. Frailty, defined by these criteria, is predictive of adverse health outcomes. Although geriatricians quibble about the definition of frailty, there is agreement that frailty is an important geriatric syndrome. The problem with frailty operationalized in this manner is that it is a heterogeneous construct not unified by a common pathophysiological mechanism. Neither MrOS nor MMAS epidemiological studies revealed an association of total or free testosterone with frailty phenotype (11, 12). MMAS data suggested that testosterone levels may be associated with some frailty components, such as strength and physical activity, but not others (12). Therefore, it is possible that testosterone therapy may improve some, but not other components of the frailty syndrome. A large fraction of participants in the frailty trial by Srinivas-Shankaret al. (14) met only one criterion of the five-component frailty definition—most frequently only exhaustion. This trial illustrates the conceptual as well as practical difficulties inherent in using frailty as an indication for efficacy trials of promyogenic function-promoting therapies.

The remarkable momentum in the discovery of novel, promyogenic function-promoting therapies, such as selective androgen receptor modulators, myostatin antagonists, and GH secretagogues, contrasts sharply with the near paralysis of pharmaceutical efforts inconducting efficacy trials of candidate molecules. Regulatory uncertainty about the appropriate approvable indications, efficacy outcomes, and clinical trial design issues has stifled clinical development of candidate function-promoting molecules. A collaborativeeffort of academia, industry, and regulatory agencies is needed to facilitate a consensus resolution of these complex issues and to jump-start the clinical development of function-promoting anabolic therapies.

Footnotes

Disclosure Summary: The author has nothing to declare.

For article see page 639

Received November 30, 2009.

Accepted December 2, 2009.

References

1. Studenski S, Perera S, Wallace D, Chandler JM, Duncan PW, Rooney E, Fox M, Guralnik JM 2003 Physical performance measures in the clinical setting. J Am Geriatr Soc 51:314–322

2. Newman AB, Simonsick EM, Naydeck BL, Boudreau RM, Kritchevsky SB, Nevitt MC, Pahor M, Satterfield S, Brach JS, Studenski SA, Harris TB 2006 Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 295:2018–2026

3. Guralnik JM, Ferrucci L, Pieper CF, Leveille SG, Markides KS, Ostir GV, Studenski S, Berkman LF, Wallace RB 2000 Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. J Gerontol A Biol Sci Med Sci 55:M221–M231

4. Spillman BC 2004 Changes in elderly disability rates and the implications for health care utilization and cost. Milbank Q 82:157–194

5. Centers for Disease Control and Prevention 2003 Trends in aging—United States and worldwide. MMWR Morb Mortal Wkly Rep 52:101–104, 106

6. Freedman VA, Martin LG, Schoeni RF 2002 Recent trends in disability and functioning among older adults in the United States: a systematic review. JAMA 288:3137–3146

7. Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, Montori VM, Gao W, Dalton JT 2006 Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2:146–159

8. Roy TA, Blackman MR, Harman SM, Tobin JD, Schrager M, Metter EJ 2002 Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab 283:E284–E294

9. Orwoll E, Lambert LC, Marshall LM, Blank J, Barrett-Connor E, Cauley J, Ensrud K, Cummings SR 2006 Osteoporotic Fractures in Men Study Group. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med 166:2124–2131

10. Araujo AB, Travison TG, Bhasin S, Esche GR, Williams RE, Clark RV, McKinlay JB 2008 Association between testosterone and estradiol and age-related decline in physical function in a diverse sample of men. J Am Geriatr Soc 56:2000–2008

11. Cawthon PM, Ensrud KE, Laughlin GA, Cauley JA, Dam TT, Barrett-Connor E, Fink HA, Hoffman AR, Lau E, Lane NE, Stefanick ML, Cummings SR, Orwoll ES; Osteoporotic Fractures in Men (MrOS) Research Group 2009 Sex hormones and frailty in older men: the osteoporotic fractures in men (MrOS) study. J Clin Endocrinol Metab 94:3806–3815

12. Mohr BA, Bhasin S, Kupelian V, Araujo AB, O'Donnell AB, McKinlay JB 2007 Testosterone, sex hormone-binding globulin, and frailty in older men. J Am Geriatr Soc 55:548–555

13. Rothman MD, Leo-Summers L, Gill TM 2008 Prognostic significance of potential frailty criteria. J Am Geriatr Soc 56:2211–2116

14. Srinivas-Shankar U, Roberts SA, Connollay MJ, O'Connell MD, Adams J, Oldham JA, Wu FC 2010 Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized double-blind placebo-controlled study. J Clin Endocrinol Metab 95:639–650

15. Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton 3rd LJ, Smith GE, Khosla S, Jensen MD 2006 DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 355:1647–1659

16. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT 2008 Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA [Erratum (2008) 299:634] 299:39–52

17. Storer TW, Woodhouse L, Magliano L, Singh AB, Dzekov C, Dzekov J, Bhasin S 2008 Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men. J Am Geriatr Soc 56:1991–1999

18. Woodhouse LJ, Reisz-Porszasz S, Javanbakht M, Storer TW, Lee M, Zerounian H, Bhasin S 2003 Development of models to predict anabolic response to testosterone administration in healthy young men. Am J Physiol Endocrinol Metab 284:E1009–E1017

19. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA; Cardiovascular Health Study Collaborative Research Group 2001 Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56:M146–M156

 

[HeadDoc]

Re: The Brave New World of Function-Promoting Anabolic Therapies

great find doc. I noticed that they left out reference to the Rudman study involving HGH in elderly men. As I recall though, Rudman did not use the same frailty definition as this study incorporated. If you are not familiar with the Redman study, I will dig it out.

Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldenberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE. Effects of human growth hormone in men over 60 years old, N Engl J Med1990 Jul 5:323(1):1-6.

 

[Millard]

Re: The Brave New World of Function-Promoting Anabolic Therapies

I'm encouraged. None of that "muscle and strength is bad" bs from Bhasin.

 

[cvictorg]

Re: The Brave New World of Function-Promoting Anabolic Therapies

Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

 

[Michael Scally MD]

Re: The Brave New World of Function-Promoting Anabolic Therapies

Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

For those so inclined, the following is the article (attached) abstract. This article from four years earlier brings up the problem of clinically relevant endpoints. Muscle mass and muscle strength are NOT clinically relevant outcomes. The R&D appears that the primary target will be the frail and wasting. The GTx studies made use of the 6-minute walk test.


Bhasin S, Calof OM, Storer TW, et al. Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2006;2(3):146-59.

Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with beta-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.

 

[Michael Scally MD]

Re: The Brave New World of Function-Promoting Anabolic Therapies

great find doc. I noticed that they left out reference to the Rudman study involving HGH in elderly men. As I recall though, Rudman did not use the same frailty definition as this study incorporated. If you are not familiar with the Redman study, I will dig it out.

Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldenberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE. Effects of human growth hormone in men over 60 years old, N Engl J Med1990 Jul 5:323(1):1-6.

The NEJM article on hGH began the mad rush as hGH the ultimate anti-aging potion. This false belief continues to this day. Earlier, in 1996, a NEJM article by Bhasin et al [Bhasin S, Storer TW, Berman N, et al. The Effects of Supraphysiologic Doses of Testosterone on Muscle Size and Strength in Normal Men. N Engl J Med 1996;335(1):1-7.] set off a similar flurry of androgen therapy in a number of conditions. The most widely known of these is in HIV+.


The NEJM editors became acutely aware of this problem regarding hGH. The hGH and testosterone articles are attached. Also included are the articles on the use of hGH.

Editor's Note, posted February 26, 2003: This article has been cited in potentially misleading e-mail advertisements. To give readers more complete information, the full text of the article, its accompanying editorial, and more recent articles about advertising dietary supplements and the question of growth hormone's role in the aging process have been made available online at no charge. Effects of Human Growth Hormone in Men Over 60 -- Original Article on HGH from New England Journal of Medicine


Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990;323(1):1-6.

Background The declining activity of the growth hormone-insulin-like growth factor I (IGF-I) axis with advancing age may contribute to the decrease in lean body mass and the increase in mass of adipose tissue that occur with aging.

Methods To test this hypothesis, we studied 21 healthy men from 61 to 81 years old who had plasma IGF-I concentrations of less than 350 U per liter during a six-month base-line period and a six-month treatment period that followed. During the treatment period, 12 men (group 1) received approximately 0.03 mg of biosynthetic human growth hormone per kilogram of body weight subcutaneously three times a week, and 9 men (group 2) received no treatment. Plasma IGF-I levels were measured monthly. At the end of each period we measured lean body mass, the mass of adipose tissue, skin thickness (epidermis plus dermis), and bone density at nine skeletal sites.

Results In group 1, the mean plasma IGF-I level rose into the youthful range of 500 to 1500 U per liter during treatment, whereas in group 2 it remained below 350 U per liter. The administration of human growth hormone for six months in group 1 was accompanied by an 8.8 percent increase in lean body mass, a 14.4 percent decrease in adipose-tissue mass, and a 1.6 percent increase in average lumbar vertebral bone density (P<0.05 in each instance). Skin thickness increased 7.1 percent (P=0.07). There was no significant change in the bone density of the radius or proximal femur. In group 2 there was no significant change in lean body mass, the mass of adipose tissue, skin thickness, or bone density during treatment.

Conclusions Diminished secretion of growth hormone is responsible in part for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thinning of the skin that occur in old age. (N Engl J Med 1990; 323:1-6.)


Bhasin S, Storer TW, Berman N, et al. The Effects of Supraphysiologic Doses of Testosterone on Muscle Size and Strength in Normal Men. N Engl J Med 1996;335(1):1-7.

Background Athletes often take androgenic steroids in an attempt to increase their strength. The efficacy of these substances for this purpose is unsubstantiated, however.

Methods We randomly assigned 43 normal men to one of four groups: placebo with no exercise, testosterone with no exercise, placebo plus exercise, and testosterone plus exercise. The men received injections of 600 mg of testosterone enanthate or placebo weekly for 10 weeks. The men in the exercise groups performed standardized weight-lifting exercises three times weekly. Before and after the treatment period, fat-free mass was determined by underwater weighing, muscle size was measured by magnetic resonance imaging, and the strength of the arms and legs was assessed by bench-press and squatting exercises, respectively.

Results Among the men in the no-exercise groups, those given testosterone had greater increases than those given placebo in muscle size in their arms (mean [{+/-}SE] change in triceps area, 424{+/-}104 vs. -81{+/-}109 mm2; P<0.05) and legs (change in quadriceps area, 607{+/-}123 vs. -131{+/-}111 mm2; P<0.05) and greater increases in strength in the bench-press (9{+/-}4 vs. -1{+/-}1 kg, P<0.05) and squatting exercises (16{+/-}4 vs. 3{+/-}1 kg, P<0.05). The men assigned to testosterone and exercise had greater increases in fat-free mass (6.1{+/-}0.6 kg) and muscle size (triceps area, 501{+/-}104 mm2; quadriceps area, 1174{+/-}91 mm2) than those assigned to either no-exercise group, and greater increases in muscle strength (bench-press strength, 22{+/-}2 kg; squatting-exercise capacity, 38{+/-}4 kg) than either no-exercise group. Neither mood nor behavior was altered in any group.

Conclusions Supraphysiologic doses of testosterone, especially when combined with strength training, increase fat-free mass and muscle size and strength in normal men.

 

[HeadDoc]

Re: The Brave New World of Function-Promoting Anabolic Therapies

well given that the heart is a muscle, strength may be an issue.

 

[Michael Scally MD]

The study cited in the article is probably the follow up on the study above. And, why do you think the benefits were not maintained. Do I hear AIH? I hope they include serum T in the study.


Beneficial effects of testosterone for frailty in older men are short-lived
Beneficial effects of testosterone for frailty in older men are short-lived | Science Blog

NOVEMBER 4, 2010

Chevy Chase, MD — The beneficial effects of six months of testosterone treatment on muscle mass, strength and quality of life in frail elderly men are not maintained at six months post-treatment, according to a study accepted for publication in The Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM).

Frailty is an age-related state of physical limitation caused by the loss of muscle mass and function and can lead to adverse clinical outcomes such as dependency, institutionalization and death. Testosterone levels naturally decline with aging and testosterone replacement is a common therapy. Short-term testosterone treatment in frail elderly men has been shown to improve muscle mass and strength, but until now it has been unclear whether these effects could be maintained post-treatment.

“Since the use of testosterone in elderly men raises concerns regarding adverse effects on the prostate and cardiovascular system, it’s important to determine if short-term treatment can lead to prolonged benefits beyond the duration of testosterone exposure,” said Frederick Wu, MD, of the University of Manchester in the United Kingdom and lead author of the study. “Our findings suggest it may not be possible to break or interrupt the cycle of decline in physical function in frailty by short-term anabolic pharmacological intervention using testosterone supplementation for six months.”

In this study, researchers evaluated 274 intermediate-frail and frail elderly men aged 65-90 years with low testosterone levels. Study participants received either a testosterone gel or placebo for six months. Assessments were carried out at baseline, the end of treatment and six months after treatment cessation. Researchers found that the increased lean body mass, muscle strength and quality of life after six months of testosterone treatment were not maintained six months after treatment.

“At present, the optimal duration of anabolic hormonal intervention to produce sustained benefits in treating frailty in older men is unknown,” said Wu. “To best interrupt the downward spiral into frailty a greater emphasis should be placed on a multi-disciplinary interventional approach including resistance exercise, diet and other lifestyle options, in conjunction with pharmacological agents.”

Other researchers working on the study include: Matthew O’Connell, Steven Roberts, Upendram Srinivas-Shankar, Abdelouahid Tajar, Judith Adams and Jackie Oldham of the University of Manchester in the United Kingdom; and Martin Connolly of the University of Auckland in New Zealand.

The article, “Do the Effects of Testosterone on Muscle Strength, Physical Function, Body Composition and Quality of Life Persist Six Months Post-treatment in Intermediate-Frail and Frail Elderly Men,” will appear in the February 2011 issue of JCEM.

 

[2yung4this]

wish this was more common knowlege. I am only 24, but have no muscle mass, and only have a bf of 13% i say only becasue I was 130, but the docs think im literally skin an bones....my arms a like twigs its like im an AIDS patient so not funny. Finally found a doc willing to try Super levels of T to get me into the 1100-1300 range and try HGH and what not to get me normal....

 

[HeadDoc]

The study cited in the article is probably the follow up on the study above. And, why do you think the benefits were not maintained. Do I hear AIH? I hope they include serum T in the study.


Beneficial effects of testosterone for frailty in older men are short-lived
Beneficial effects of testosterone for frailty in older men are short-lived | Science Blog

NOVEMBER 4, 2010

Chevy Chase, MD — The beneficial effects of six months of testosterone treatment on muscle mass, strength and quality of life in frail elderly men are not maintained at six months post-treatment, according to a study accepted for publication in The Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM).

Frailty is an age-related state of physical limitation caused by the loss of muscle mass and function and can lead to adverse clinical outcomes such as dependency, institutionalization and death. Testosterone levels naturally decline with aging and testosterone replacement is a common therapy. Short-term testosterone treatment in frail elderly men has been shown to improve muscle mass and strength, but until now it has been unclear whether these effects could be maintained post-treatment.

“Since the use of testosterone in elderly men raises concerns regarding adverse effects on the prostate and cardiovascular system, it’s important to determine if short-term treatment can lead to prolonged benefits beyond the duration of testosterone exposure,” said Frederick Wu, MD, of the University of Manchester in the United Kingdom and lead author of the study. “Our findings suggest it may not be possible to break or interrupt the cycle of decline in physical function in frailty by short-term anabolic pharmacological intervention using testosterone supplementation for six months.”

In this study, researchers evaluated 274 intermediate-frail and frail elderly men aged 65-90 years with low testosterone levels. Study participants received either a testosterone gel or placebo for six months. Assessments were carried out at baseline, the end of treatment and six months after treatment cessation. Researchers found that the increased lean body mass, muscle strength and quality of life after six months of testosterone treatment were not maintained six months after treatment.

“At present, the optimal duration of anabolic hormonal intervention to produce sustained benefits in treating frailty in older men is unknown,” said Wu. “To best interrupt the downward spiral into frailty a greater emphasis should be placed on a multi-disciplinary interventional approach including resistance exercise, diet and other lifestyle options, in conjunction with pharmacological agents.”

Other researchers working on the study include: Matthew O’Connell, Steven Roberts, Upendram Srinivas-Shankar, Abdelouahid Tajar, Judith Adams and Jackie Oldham of the University of Manchester in the United Kingdom; and Martin Connolly of the University of Auckland in New Zealand.

The article, “Do the Effects of Testosterone on Muscle Strength, Physical Function, Body Composition and Quality of Life Persist Six Months Post-treatment in Intermediate-Frail and Frail Elderly Men,” will appear in the February 2011 issue of JCEM.

So these guys benefited from treatment. It appears that this was a focused study of short term duration. Otherwise you'd wonder why treatment would be stopped! This is typical of the study you'd like to pass around to the local docs.

 

[Michael Scally MD]

I will need to obtain the full-text and see if AIH was observed (in all likelihood) or even if they bothered to measure T during the time off T.

O'Connell MDL, Roberts SA, Srinivas-Shankar U, et al. Do the Effects of Testosterone on Muscle Strength, Physical Function, Body Composition, And Quality of Life Persist Six Months after Treatment in Intermediate-Frail and Frail Elderly Men? J Clin Endocrinol Metab:jc.2010-1167. http://jcem.endojournals.org/cgi/content/abstract/jc.2010-1167v1

Context: Short-term testosterone (T) treatment in frail elderly men improves muscle mass and strength. It is unclear whether these effects can be maintained post treatment.

Objective: To assess the durability of androgen effects in frail men.

Design and Setting: Single center, randomized, double-blind, placebo-controlled trial to investigate the effects of 6 months T (25-75 mg daily) on muscle strength, body composition, physical function, and quality of life (QoL). Participants were assessed at the end of treatment (6 months) and 6 months after treatment cessation (12 months).Participants: 274 intermediate-frail and frail elderly men aged 65-90 years with low T levels.

Results: Mean T increased from 11.1 (3.1) nmol/liter at baseline to 18.4 (3.5) nmol/liter at 6 months, then declined to 10.5 (3.7) nmol/L at 12 months, in the T-treated group. Isometric knee extension peak torque increased in the T-treated group compared with placebo to give an adjusted mean difference (95% CI) between groups of 8.1 (-0.2 to 16.5) Nm at 6 months. Lean mass increased in the T-treated group giving a difference between groups of 1.2 (0.8 to 1.7) kg at 6 months. Somatic and sexual symptoms improved during treatment. None of these differences between groups remained at 12 months. Prostate specific antigen (PSA) levels and haematocrit increased slightly during treatment but returned to baseline by 12 months.

Conclusion: The effects of 6-month T treatment on muscle strength, lean mass, and QoL in frail men are not maintained at 6 months post treatment.

 

[Michael Scally MD]

Apparently, they still do not get it. They state, "It is possible that greater gains in strength with more potent anabolic stimuli administered over a longer period may produce more sustained functional benefits. The effect of increasing T within the physiological range for 6 months may have been too small or too brief to meaningfully affect the functional ability and lifestyle and to influence the cycle of frailty in these subjects."

IT IS AIH!!!

They go on to admit the study limitation, "A limitation in the design of this follow-up phase was the lack of interim measurements between 6 and 12 months. It was therefore not possible to evaluate the decay time course of the offset of treatment effects in this study."

IT IS AIH!!!

The following is from the article: Introduction and Discussion.


Introduction

Frailty describes an age-related state of increased vulnerability, presaging adverse outcomes (1, 2). With the aging population, management of frailty is becoming an increasingly important healthcare issue. While resistance training may lead to functional improvements in the elderly (3, 4), this approach may be burdensome to frail elders. An alternative option is the use of pharmacological anabolic interventions (5). Testosterone (T) replacement in elderly men is among the first wave of these therapies.

T levels decline with aging (6, 7) and may contribute to the age-related physical deterioration in the elderly (8, 9). We recently reported an increase in lean body mass (LBM), muscle strength, and quality of life (QoL) in intermediate frail and frail elderly men in response to 6 months T treatment in a randomized, placebo-controlled study (10).

The anabolic effects of T treatment on muscle mass in elderly men appear to peak after about 6 months; this increase in muscle mass can be maintained with continued treatment for up to 3 yr (11–13). It is unclear whether these effects can be maintained once treatment is withdrawn. Since the use of T in elderly men often raises concern regarding adverse effects (14, 15), it would be important to determine whether short-term treatment can lead to prolonged benefits beyond the duration of T exposure.

The effects of 12-week treatment with the anabolic androgenic steroid, oxandrolone, on muscle mass and strength in healthy elderly men were shown to decline within 12 weeks of treatment cessation (16). However, the persistence of effects of physiological T treatment in frail elderly men has not previously been studied. Frail men may be undergoing a cycle of decline wherein a loss of muscle mass and strength leads to declines in physical function, energy levels, and physical activity, which further aggravate the deficits in muscle mass and function (2). Anabolic interventions like T may halt this frailty cycle, with improved strength allowing maintenance of function and activity thus preventing further decline. Frail men may therefore be more likely to experience prolonged benefits from anabolic interventions. This study sought to evaluate the post-treatment durability of effects at 6 months after the cessation of T treatment in intermediate-frail and frail elderly men.


Discussion

The main finding of this study was that the increased LBM, muscle strength, and QoL after 6-month T treatment in intermediate-frail and frail elderly men were not maintained 6 months post treatment. Our results also indicate that any potentially adverse changes in safety parameters of T treatment did not persist post treatment.

While lower limb muscle strength assessed by IME-PT declined progressively over 12 months in the placebo group, it increased by around 6% with T treatment but then declined to the baseline after treatment by 12 months (Figure 1). Similar trends were seen for the other outcomes (Figure 1). The different trajectories between the T and placebo groups highlight the clear, albeit unsustained, effects of short-term intervention. This suggests that the observed effects of our intervention were due to the direct influence of changing T levels and not to any secondary treatment- related factor. This is consistent with a previous study (16) showing that the anabolic effects of oxandrolone did not persist post-treatment in healthy older men.

The decline in muscle mass and strength post treatment suggests that treatment for 6 months may not be sufficient to interrupt the progression of frailty in this heterogeneous cohort of intermediate-frail and frail elderly men. The potential for any intervention to produce prolonged benefits in this population may be related to the size of the treatment effect, and particularly how this affects functional ability. It is possible that greater gains in strength with more potent anabolic stimuli administered over a longer period may produce more sustained functional benefits. The effect of increasing T within the physiological range for 6 months may have been too small or too brief to meaningfully affect the functional ability and lifestyle and to influence the cycle of frailty in these subjects. [They just do not get it!!! AIH] On the other hand, the majority of the study cohort consisted of intermediate-frail (rather than frail) men whose baseline functional impairment may not be severe enough for a small effect of T to engender substantial improvements.

At present, the optimal duration of anabolic hormonal intervention to produce sustained benefits is unknown. Resistance training can produce substantial gains in strength and function even in the very elderly (3, 4). The use of T or other anabolic agents may augment the effects of exercise (17). This underscores the importance of a multi-disciplinary interventional approach including resistance exercise, diet, and other lifestyle options, in conjunction with pharmacological agents in the elderly to interrupt the downward spiral into frailty.

There have been concerns about the health risks associated with the use of T in the elderly (14, 18). In this study, the effects on traditional safety parameters were small during treatment and they returned to baseline after treatment within 6 months. Unlike studies using high doses of T in elderly men (14), the current study reported few and no increase in cardiovascular or other adverse events compared with placebo. The favorable safety profile in our study may be related to: 1) lower doses of T (2.5–7.5 mg daily), 2) careful dose adjustments to ensure physiological levels of T are achieved and maintained during treatment, and 3) the exclusion of men with symptomatic ischemic heart disease. These are important points to note for designing future T interventional studies in elderly men.

The results presented here were based on the subset of men that completed assessments at 12 months to allow clear comparison of the 6-month and 12-month data. In this subset, some results reported previously (10), did not reach statistical significance, but the magnitude of the effects were virtually identical to that reported for the entire cohort (10), and the loss of formal significance simply reflects the smaller numbers analyzed.

A limitation in the design of this follow-up phase was the lack of interim measurements between 6 and 12 months. It was therefore not possible to evaluate the decay time course of the offset of treatment effects in this study. It is possible that some benefits may have remained for a short time post treatment. Furthermore, it is possible that any delay in recovery from suppressed endogenous T secretion resulting in transient T deficiency could have accelerated the decay of treatment effects in the initial post treatment phase. [This is VERY disappointing since a simple T measurement would have shown AIH. How long will it take until they realize AIH importance?]

In summary, the effects of T treatment on body composition, muscle strength, and QoL did not persist by 6 months after treatment withdrawal in intermediate-frail and frail elderly men. This suggests that any benefits of short-term T exposure on these parameters are entirely hormone-dependent and do not propagate secondary derivative pathways that might help break a cycle of frailty in the elderly. [Duuuuuhh!!! You could have blown me over with a feather.]

 

[Michael Scally MD]

Re: The Brave New World of Function-Promoting Anabolic Therapies

Requirements for Androgenic Anabolism Versus Reproductive Physiology

Androgen production declines with age in both genders. Although secondary sexual traits such as facial hair are maintained, lean mass declines, and low testosterone levels are associated with a greater risk for several age-related diseases. An inevitable consequence of aging is the loss of bone and muscle mass, which results in part from a steady decline in anabolic and anti-catabolic hormone signaling. These lean mass and bone deficits confer higher risk for osteoporotic fractures, age related sarcopenia, and loss of independence.

Genetic and pharmacological data have clearly established that androgen restoration therapies promote bone and muscle mass in post-menopausal women and aged men. However, androgens, as male sex hormones, can produce adverse effects, such as hirsutism, acne, deepening of the voice, and reproductive tissue changes. In addition, providing women with testosterone may increase the risk for breast cancer and other health problems due to its metabolic conversion to estradiol. Similarly treatment of men may also present a significant risk factor for benign prostate hyperplasia and prostate cancer.

Given these concerns, tissue-selective androgen receptor modulators (SARMs) that restore healthy bone and muscle but do not cause uterine, prostate, or sebaceous gland hypertrophy would be attractive therapies. The fundamental idea of selective modulation of nuclear receptors is validated by the development of selective estrogen receptor modulators as ligands for the two estrogen receptors. Raloxifene, for example, is a clinically used selective estrogen receptor modulator that slows bone loss and antagonizes estrogen actions in uterus and breast and reduces the risk of the development of estrogen receptor-dependent breast cancers. Preclinical proof of concept for an anabolic SARM with reduced androgenization was established in animal models by several SARMs such as TZP-4238, S-40503, S-1, S-4, LGD2226, LGD2941, JNJ-28330835, and JNJ-37654032. We developed a proof-of-concept SARM, TFM-4AS-1, that increases periosteal bone formation, cortical bone mass, and lean body mass as effectively as DHT but with markedly reduced effects on uterus, prostate, and the pilosebaceous unit (PSU). However, as each SARM has a unique in vivo profile that is rarely linked to a specific in vitro activity profile, the relationship between transcriptional activity and physiological effect has not been established.

Androgens act by binding to the androgen receptor (AR), a member of the nuclear receptor superfamily. Upon ligand binding, AR interacts with DNA sequences or other proteins in the regulatory regions of target genes to recruit transcriptional cofactors and regulate gene expression. Although DHT maximally activates the full repertoire of androgen-responsive genes, synthetic AR ligands range from full agonists to complete antagonists depending on the gene and cellular context. These ligands exert complex activities presumably by differentially modulating the structure of AR co-factor recruitment sites such as the N-terminal-located activation function-1 (AF-1) and the C-terminal-located AF-2, which interact with transcriptional coregulators such as TIF2/SRC-2/GRIP-1/ NCO-2. AR is maximally active when the ligand promotes an interaction between the N- and C-terminal AR domains (the N/C interaction). Interestingly, mutations in the N- or C-terminal domain of AR that impair this interaction were found in incompletely virilized patients with partial androgen insensitivity; some of these mutations also inhibit the recruitment of transcriptional cofactors to AF-2. These genetic data suggest that synthetic ligands that promote the transactivation activity of AR while exhibiting reduced ability to support the N/C interaction or cofactor recruitment could provide tissue selectivity in vivo.

Drug development requires the iterative sorting of thousands of compounds through in vitro assays followed by selection of a very small subset for in vivo validation. Thus, medicinal chemistry requires assays that efficiently identify compounds with the highest possible target selectivity and affinity that correspond to desired outcomes in animal models. The process of identifying clinically useful SARMs faces significant challenges as the search is not for the most potent receptor agonist or antagonist but rather for compounds that precisely manipulate transcriptional activities of the receptor producing tissue-selective actions in animals and humans. Currently, there has been no systematic information that defines relationships between the in vitro characteristics of androgens and their effects on tissues.

To establish a rational drug design paradigm for the discovery of novel SARMs, we employed biochemical assays that measure binding to endogenously expressed human AR (AR radioligand competition binding assays (ARBIND)), transactivation of a model promoter via endogenous human AR (TAMAR), AR AF-2 domain recruitment of the coactivator GRIP-1 (TRAF2), and the AR N/C interaction (VIRCON). In addition, we developed a set of gene expression surrogate biomarkers that are predictive for the long term effects of anabolic androgens on bone and in PSUs. This capability enabled testing of a large number of compounds with various in vitro profiles in rats for their effects on cortical bone formation, lean body mass, uterus growth, PSU hypertrophy, and seminal vesicle growth. We established a correlation between the in vitro actions of androgens and these physiological endpoints and, thus, provided a systematic and predictive approach to the development of SARMs. This led to the identification of the SARMs MK-0773 and 2-FPA. MK-0773 was suitable for therapeutic development, and Phase 1b clinical data have provided clinical support for this paradigm for SARM development.


Schmidt A, Kimmel DB, Bai C, et al. Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology. Journal of Biological Chemistry 2010;285(22):17054-64.

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

 

[Michael Scally MD]

Re: The Brave New World of Function-Promoting Anabolic Therapies

A research agenda has been set, but recognition in clinical practice is lagging behind. Sarcopenia is the loss of skeletal muscle mass and strength with age. It is common in men and women, with prevalence ranging from 9% to 18% over the age of 65. Recognition of its serious health consequences in terms of frailty, disability, morbidity, and mortality is increasing. The estimated direct healthcare cost attributable to sarcopenia in the United States in 2000 was $18.5 Billion, about 1.5% of total healthcare expenditure for that year.


Cruz-Jentoft AJ, Baeyens JP, Bauer JrM, et al. Sarcopenia: European consensus on definition and diagnosis. Age and Ageing 2010;39(4):412-23. Sarcopenia: European consensus on definition and diagnosis — Age Ageing

The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. EWGSOP included representatives from four participant organisations, i.e. the European Geriatric Medicine Society, the European Society for Clinical Nutrition and Metabolism, the International Association of Gerontology and Geriatrics—European Region and the International Association of Nutrition and Aging. These organisations endorsed the findings in the final document.

The group met and addressed the following questions, using the medical literature to build evidence-based answers: (i) What is sarcopenia? (ii) What parameters define sarcopenia? (iii) What variables reflect these parameters, and what measurement tools and cut-off points can be used? (iv) How does sarcopenia relate to cachexia, frailty and sarcopenic obesity?

For the diagnosis of sarcopenia, EWGSOP recommends using the presence of both low muscle mass + low muscle function (strength or performance). EWGSOP variously applies these characteristics to further define conceptual stages as ‘presarcopenia’, ‘sarcopenia’ and ‘severe sarcopenia’.EWGSOP reviewed a wide range of tools that can be used to measure the specific variables of muscle mass, muscle strength and physical performance. Our paper summarises currently available data defining sarcopenia cut-off points by age and gender; suggests an algorithm for sarcopenia case finding in older individuals based on measurements of gait speed, grip strength and muscle mass; and presents a list of suggested primary and secondary outcome domains for research.

Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment.

 

[Michael Scally MD]

Re: The Brave New World of Function-Promoting Anabolic Therapies

Many of us have heard the expression the man with the chicken/skinny legs. There might be more to that saying! From this research, skinny legs is associated with arterial stiffness - ?CVD?


Masayuki O, Katsuhiko K, Yasuharu T, et al. Arterial stiffness is associated with low thigh muscle mass in middle-aged to elderly men. Atherosclerosis 2010;212(1):327-32. Arterial stiffness is associated with low thigh mu... [Atherosclerosis. 2010] - PubMed result

OBJECTIVE: Sarcopenia of legs is an important cause of physical dysfunctions, frailty and dependence. Many predisposing and underlying mechanisms of sarcopenia, including age, sedentary life style, oxidative stress, insulin resistance, and low testosterone levels, are also known to be related to atherosclerosis, which is another leading cause of morbidity and mortality in elderly subjects. In this study, we investigated our hypothesis that sarcopenia and atherosclerosis are associated with each other to facilitate mutual abnormalities.

METHODS: Study was performed in apparently healthy 496 middle-aged to elderly persons recruited consecutively among the visitors to the medical check-up program, Anti-Aging Doc, in a University hospital, from March 2006 to December 2007. Mid-thigh muscle cross-sectional area (CSA) was measured by computed tomography and corrected by body weight (CSA/BW). Carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were measured.

RESULTS: Thigh muscle CSA/BW was significantly and negatively associated with carotid IMT and baPWV in men but not in women. After correction for other confounding parameters, baPWV was an independent risk for the presence of sarcopenia in men (odds ratio of 1 m/s increase of baPWV=1.14, 95% CI=1.01-1.30, p<0.05) in addition to age, body height, low physical activity, free testosterone level. Conversely, thigh muscle CSA/BW was an independent determinant of baPWV (beta=-0.15, p<0.01) in addition to age, blood pressure, triglyceride, and antihypertensive drug use in men.

CONCLUSIONS: Arterial stiffness is related to thigh muscle volume in men. Sarcopenia and atherosclerosis may share a common pathway and interact with each other to facilitate mutual abnormalities.

 

[HeadDoc]

Re: The Brave New World of Function-Promoting Anabolic Therapies

what's your deadlift and back squat like these days?