Sarcopenia & Testosterone (Beyond Hypogonadism)

[greenddog1]

Thanks Dr Scally for this article, since I'm well into that age group I find interesting. I noticed most all current protocols are designed for women, but what I'm seeing here is possible helpful therapy for men in their latter years. By the way, I ran across this article in, of all places, WebMD:


Symptoms and Causes of Sarcopenia
Symptoms of muscle loss include musculoskeletal weakness and loss of stamina, which can interfere with physical activity. Reduced physical activity, in turn, further reduces muscle mass.

Although sarcopenia is mostly seen in people who are inactive, the fact that it also occurs in people who stay physically active throughout life suggests there are other factors involved in the development of sarcopenia.

Continue reading below...
Researchers believe the following factors play a role:

• Age-related reduction in nerve cells responsible for sending signals from the brain to the muscles to initiate movement
• A decrease in the concentrations of some hormones, including growth hormone, testosterone, and insulin-like growth factor
• A decrease in the body's ability to synthesize protein
• Inadequate intake of calories and/or protein to sustain muscle mass

Treatments for Sarcopenia
The primary treatment for sarcopenia is exercise. Specifically, resistance training or strength training -- exercise that increases muscle strength and endurance with weights or resistance bands -- has been shown to be useful for both the prevention and treatment of sarcopenia.

Resistance training has been reported to positively influence the neuromuscular system, hormone concentrations, and protein synthesis rate. Research has shown that a program of progressive resistance training exercises can increase protein synthesis rates in older adults in as little as two weeks.

For optimal benefits with minimal risk of injury, the proper number, intensity, and frequency of resistance exercise is important. For that reason, you should work with an experienced physical therapist or trainer to develop an exercise plan.

Although drug therapy is not the preferred treatment for sarcopenia, a few medications are under investigation. They include:

Urocortin II. This peptide has been shown to stimulate the release of a hormone called adrenocoticotropic hormone (ACTH) from the pituitary gland. Intravenous urocortin II has been shown to prevent muscle atrophy from being in a cast or taking certain medications; it has also been shown to cause muscle growth in healthy rats. But its use for building muscle mass in humans has not been studied and is not recommended.

Hormone Replacement Therapy (HRT). When a woman's production of hormones is diminished at menopause, hormone replacement therapy has been shown to increase lean body mass, reduce abdominal fat short-term, and prevent bone loss. However, in recent years there has been controversy surrounding the use of HRT due to increased risk of certain cancers and other serious health problems among HRT users.

Other treatments under investigation for sarcopenia include testosterone supplementation, growth hormone supplementation, and medication for treatment of metabolic syndrome (insulin-resistance, obesity, hypertension, etc.). If found useful, all of these would complement the effects of resistance exercise, not replace them.

Which, IMO also validates my use of Androgens, weight training and cardio on regular basis. I plan on pursuing this regimem until I drop. So far, it has served me well. Look forward to more research oxytocin for males.

 

[jp4355]

Dr. Scally, I have a question for You.
I'm 61 and recently Diagnosed with Sarcopenia.
I Fractured my T-4 and 6 Vertebrae doing DB Pullovers. Had MRI and DEXA Scan.
I also have Muscle Wasting (Cachexia) of my Thighs from 8 Total Intra-Articular Injections of Corticosteroids for Degenerative Hip Disease.

So my Question is which would be Better to Address the Bone and Muscle Issue.
HGH or Testosterone........................... JP
P.S.
I have Read Two Schools of thought on this Subject.
P.S.S.
Thanks for the Article, it was very interesting to read, on top of All the reading that I had already done.
I will also be Talking with my Rheumatologist, the beginning of next month, and would like to have some kind of an Idea, which is the Better Alternative.

 

[Michael Scally MD]

Urban RJ, Dillon EL, Choudhary S, et al. Translational studies in older men using testosterone to treat sarcopenia. Trans Am Clin Climatol Assoc 2014;125:27-44. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112698/

Sarcopenia is the loss of skeletal muscle mass and strength that occurs with aging. Our research group has found an efficacious administration paradigm using testosterone to combat sarcopenia in humans.

In addition, our research has uncovered an important regulatory enzyme of inflammation, nuclear factor-kappaB-inducing kinase that may regulate human skeletal muscle catabolism, and that appears to be counter-regulated by administration of standard doses of testosterone. This is important because a number of age-related clinical circumstances trigger acute and chronic muscle loss including cancer, chronic obstructive pulmonary disease, hospitalization, acute and chronic illness, and diseases in which systemic inflammation occurs.

Moreover, it is often the treatment itself that can induce muscle loss. For example, glucocorticoids are tremendously effective at reducing inflammation and are a frontline therapy for many inflammatory-based diseases, yet paradoxically trigger muscle loss. We will discuss our research findings and the clinical significance of our human clinical translational research with testosterone.

 

[Michael Scally MD]

O'Connell M, Wu F. Androgen effects on skeletal muscle: implications for the development and management of frailty. Asian Journal of Andrology 2014;16(2):203-12. http://goo.gl/CIQYX1

Androgens have potent anabolic effects on skeletal muscle and decline with age in parallel to losses in muscle mass and strength. This loss of muscle mass and function, known as sarcopenia, is the central event in development of frailty, the vulnerable health status that presages adverse outcomes and rapid functional decline in older adults.

The potential role of falling androgen levels in the development of frailty and their utility as function promoting therapies in older men has therefore attracted considerable attention.

This review summarizes current concepts and definitions in muscle ageing, sarcopenia and frailty, and evaluates recent developments in the study of androgens and frailty.

Current evidence from observational and interventional studies strongly supports an effect of androgens on muscle mass in ageing men, but effects on muscle strength and particularly physical function have been less clear.

Androgen treatment has been generally well-tolerated in studies of older men, but concerns remain over higher dose treatments and use in populations with high cardiovascular risk.

The first trials of selective androgen receptor modulators (SARMs) suggest similar effects on muscle mass and function to traditional androgen therapies in older adults.

Important future directions include the use of these agents in combination with exercise training to promote functional ability across different populations of older adults, as well as more focus on the relationships between concurrent changes in hormone levels, body composition and physical function in observational studies.

 

[Michael Scally MD]

Basualto-Alarcon C, Varela D, Duran J, Maass R, Estrada M. Sarcopenia and androgens: A link between pathology and treatment. Frontiers in Endocrinology 2014;5. http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00217/full

Sarcopenia, the age-related loss of skeletal muscle mass and function, is becoming more prevalent as the lifespan continues to increase in most populations. As sarcopenia is highly disabling, being associated with increased risk of dependence, falls, fractures, weakness, disability, and death, development of approaches to its prevention and treatment are required.

Androgens are the main physiologic anabolic steroid hormones and normal testosterone levels are necessary for a range of developmental and biological processes, including maintenance of muscle mass. Testosterone concentrations decline as age increase, suggesting that low plasma testosterone levels can cause or accelerate muscle- and age-related diseases, as sarcopenia.

Currently, there is increasing interest on the anabolic properties of testosterone for therapeutic use in muscle diseases including sarcopenia. However, the pathophysiological mechanisms underlying this muscle syndrome and its relationship with plasma level of androgens are not completely understood.

This review discusses the recent findings regarding sarcopenia, the intrinsic, and extrinsic mechanisms involved in the onset and progression of this disease and the treatment approaches that have been developed based on testosterone deficiency and their implications.

 

[Michael Scally MD]

Farooqi V, van den Berg ME, Cameron ID, Crotty M. Anabolic steroids for rehabilitation after hip fracture in older people. Cochrane Database Syst Rev. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008887.pub2/abstract

BACKGROUND: Hip fracture occurs predominantly in older people, many of whom are frail and undernourished. After hip fracture surgery and rehabilitation, most patients experience a decline in mobility and function. Anabolic steroids, the synthetic derivatives of the male hormone testosterone, have been used in combination with exercise to improve muscle mass and strength in athletes. They may have similar effects in older people who are recovering from hip fracture.

OBJECTIVES: To examine the effects (primarily in terms of functional outcome and adverse events) of anabolic steroids after surgical treatment of hip fracture in older people.

SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (10 September 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013 Issue 8), MEDLINE (1946 to August Week 4 2013), EMBASE (1974 to 2013 Week 36), trial registers, conference proceedings, and reference lists of relevant articles. The search was run in September 2013.

SELECTION CRITERIA: Randomised controlled trials of anabolic steroids given after hip fracture surgery, in inpatient or outpatient settings, to improve physical functioning in older patients with hip fracture.

DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials (based on predefined inclusion criteria), extracted data and assessed each study's risk of bias. A third review author moderated disagreements. Only very limited pooling of data was possible. The primary outcomes were function (for example, independence in mobility and activities of daily living) and adverse events, including mortality.

MAIN RESULTS: We screened 1290 records and found only three trials involving 154 female participants, all of whom were aged above 65 years and had had hip fracture surgery. All studies had methodological shortcomings that placed them at high or unclear risk of bias. Because of this high risk of bias, imprecise results and likelihood of publication bias, we judged the quality of the evidence for all primary outcomes to be very low.These trials tested two comparisons. One trial had three groups and contributed data to both comparisons. None of the trials reported on patient acceptability of the intervention.Two very different trials compared anabolic steroid versus control (no anabolic steroid or placebo). One trial compared anabolic steroid injections (given weekly until discharge from hospital or four weeks, whichever came first) versus placebo injections in 29 "frail elderly females". This found very low quality evidence of little difference between the two groups in the numbers discharged to a higher level of care or dead (one person in the control group died) (8/15 versus 10/14; risk ratio (RR) 0.75, 95% confidence interval (CI) 0.42 to 1.33; P = 0.32), time to independent mobilisation or individual adverse events. The second trial compared anabolic steroid injections (every three weeks for six months) and daily protein supplementation versus daily protein supplementation alone in 40 "lean elderly women" who were followed up for one year after surgery. This trial provided very low quality evidence that anabolic steroid may result in less dependency, assessed in terms of being either dependent in at least two functions or dead (one person in the control group died) at six and 12 months, but the result was also compatible with no difference or an increase in dependency (dependent in at least two levels of function or dead at 12 months: 1/17 versus 5/19; RR 0.22, 95% CI 0.03 to 1.73; P = 0.15). The trial found no evidence of between-group differences in individual adverse events.

Two trials compared anabolic steroids combined with another nutritional intervention ('steroid plus') versus control (no 'steroid plus'). One trial compared anabolic steroid injections every three weeks for 12 months in combination with daily supplement of vitamin D and calcium versus calcium only in 63 women who were living independently at home. The other trial compared anabolic steroid injections every three weeks for six months and daily protein supplementation versus control in 40 "lean elderly women". Both trials found some evidence of better function in the steroid plus group. One trial reported greater independence, higher Harris hip scores and gait speeds in the steroid plus group at 12 months. The second trial found fewer participants in the anabolic steroid group were either dependent in at least two functions, including bathing, or dead at six and 12 months (one person in the control group died) (1/17 versus 7/18; RR 0.15, 95% CI 0.02 to 1.10; P = 0.06). Pooled mortality data (2/51 versus 3/51) from the two trials showed no evidence of a difference between the two groups at one year. Similarly, there was no evidence of between-group differences in individual adverse events. Three participants in the steroid group of one trial reported side effects of hoarseness and increased facial hair. The other trial reported better quality of life in the steroid plus group.

AUTHORS' CONCLUSIONS: The available evidence is insufficient to draw conclusions on the effects, primarily in terms of functional outcome and adverse events, of anabolic steroids, either separately or in combination with nutritional supplements, after surgical treatment of hip fracture in older people. Given that the available data points to the potential for more promising outcomes with a combined anabolic steroid and nutritional supplement intervention, we suggest that future research should focus on evaluating this combination.

 

[Michael Scally MD]

Camerino GM, Desaphy JF, De Bellis M, Capogrosso RF, Cozzoli A, et al. Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation. PLoS One. 2015;10(6):e0129686. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129686

[Nandrolone Decanoate (ND) 5 mg/kg, once a day, 6 days a week, for 4 weeks]

Muscle disuse produces severe atrophy and a slow-to-fast phenotype transition in the postural Soleus (Sol) muscle of rodents. Antioxidants, amino-acids and growth factors were ineffective to ameliorate muscle atrophy.

Here we evaluate the effects of nandrolone (ND), an anabolic steroid, on mouse skeletal muscle atrophy induced by hindlimb unloading (HU). Mice were pre-treated for 2-weeks before HU and during the 2-weeks of HU.

Muscle weight and total protein content were reduced in HU mice and a restoration of these parameters was found in ND-treated HU mice.

The analysis of gene expression by real-time PCR demonstrates an increase of MuRF-1 during HU but minor involvement of other catabolic pathways. However, ND did not affect MuRF-1 expression.

The evaluation of anabolic pathways showed no change in mTOR and eIF2-kinase mRNA expression, but the protein expression of the eukaryotic initiation factor eIF2 was reduced during HU and restored by ND.

Moreover we found an involvement of regenerative pathways, since the increase of MyoD observed after HU suggests the promotion of myogenic stem cell differentiation in response to atrophy.

At the same time, Notch-1 expression was down-regulated. Interestingly, the ND treatment prevented changes in MyoD and Notch-1 expression.

On the contrary, there was no evidence for an effect of ND on the change of muscle phenotype induced by HU, since no effect of treatment was observed on the resting gCl, restCa and contractile properties in Sol muscle.

Accordingly, PGC1alpha and myosin heavy chain expression, indexes of the phenotype transition, were not restored in ND-treated HU mice.

We hypothesize that ND is unable to directly affect the phenotype transition when the specialized motor unit firing pattern of stimulation is lacking.

Nevertheless, through stimulation of protein synthesis, ND preserves protein content and muscle weight, which may result advantageous to the affected skeletal muscle for functional recovery.

 

[Michael Scally MD]

Morley JE. Pharmacologic Options for the Treatment of Sarcopenia. Calcif Tissue Int. http://link.springer.com/article/10.1007/s00223-015-0022-5

Sarcopenia is now clinically defined as a loss of muscle mass coupled with functional deterioration (either walking speed or distance or grip strength). Based on the FRAX studies suggesting that the questions without bone mineral density can be used to screen for osteoporosis, there is now a valid simple questionnaire to screen for sarcopenia, i.e., the SARC-F.

Numerous factors have been implicated in the pathophysiology of sarcopenia. These include genetic factors, mitochondrial defects, decreased anabolic hormones (e.g., testosterone, vitamin D, growth hormone and insulin growth hormone-1), inflammatory cytokine excess, insulin resistance, decreased protein intake and activity, poor blood flow to muscle and deficiency of growth derived factor-11.

Over the last decade, there has been a remarkable increase in our understanding of the molecular biology of muscle, resulting in a marked increase in potential future targets for the treatment of sarcopenia.

At present, resistance exercise, protein supplementation, and vitamin D have been established as the basic treatment of sarcopenia. High-dose testosterone increases muscle power and function, but has a number of potentially limiting side effects. Other drugs in clinical development include selective androgen receptor molecules, ghrelin agonists, myostatin antibodies, activin IIR antagonists, angiotensin converting enzyme inhibitors, beta antagonists, and fast skeletal muscle troponin activators.

As sarcopenia is a major predictor of frailty, hip fracture, disability, and mortality in older persons, the development of drugs to treat it is eagerly awaited.

 

[Michael Scally MD]

Highlights
· Sarcopenia has a multifactorial pathophysiology in which sleep may be involved in several anabolic and catabolic pathways.
· Age-related sleep deterioration acts on neuroendocrine factors associated with sarcopenia development.
· Poor sleep and sleep disorders may also increase sarcopenia risk through insulin resistance mechanisms.
· Further research should establish potential connections between sleep and age-related muscle loss.
· After confirming this hypothesis, intervention of sleep disturbances may represent a strategy to preserve or recover muscle mass in older adults.

Piovezan RD, Abucham J, dos Santos RVT, Mello MT, Tufik S, et al. The impact of sleep on age-related sarcopenia: possible connections and clinical implications. Ageing Research Reviews. https://www.sciencedirect.com/science/article/pii/S1568163715300052

Sarcopenia is a geriatric condition that comprises declined skeletal muscle mass, strength and function, leading to the risk of multiple adverse outcomes, including death. Its pathophysiology involves neuroendocrine and inflammatory factors, unfavorable nutritional habits and low physical activity.

Sleep may play a role in muscle protein metabolism, although this hypothesis has not been studied extensively. Reductions in duration and quality of sleep and increases in prevalence of circadian rhythm and sleep disorders with age favor proteolysis, modify body composition and increase the risk of insulin resistance, all of which have been associated with sarcopenia.

Data on the effects of age-related slow-wave sleep decline, circadian rhythm disruptions and obstructive sleep apnea (OSA) on hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-gonadal (HPG), somatotropic axes, and glucose metabolism indicate that sleep disorder interventions may affect muscle loss. OSA parameters and recent research associating the risk of conditions closely related to the sarcopenia process, such as frailty and sleep quality impairment, indirectly suggest that sleep can influence skeletal muscle decline in the elderly.

Several protein synthesis and degradation pathways are mediated by growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, cortisol and insulin, which act on the cellular and molecular levels to increase or reestablish muscle fiber, strength and function. Age-related sleep problems potentially interfere intracellularly by inhibiting anabolic hormone cascades and enhancing catabolic pathways in the skeletal muscle.

Nutritional recommendations and specific physical exercises are the current treatment options for sarcopenia. Clinical studies testing exogenous administration of anabolic hormones have not yielded adequate safety profiles. Therapeutic approaches targeting sleep disturbances to normalize circadian rhythms and sleep homeostasis may represent a novel strategy to preserve or recover muscle health in older adults. Promising research results regarding the associations between sleep variables and sarcopenia biomarkers and clinical parameters are required to confirm this hypothesis.