Catabolic Wasting - Cachexia and Sarcopenia
Conventional medicine generally does not treat muscle wasting until it has reached a moderate to advanced state involving unintentional loss of at least 5% of body weight within 12 months (Muscaritoli 2013; Evans 2008). The usual therapies include encouraging food and fluid intake and drug treatment. A number of interventions may be used in the treatment of people with catabolic wasting, including testosterone, dehydroepiandrosterone (DHEA), progestins, growth hormone, cannabinoids, and thalidomide (Gordon 2004; Khan 2003; Dunn 2009; Fearon 2013; Zacker 2006; Siddiqui 2006; Nicolini 2013). It is also important to utilize proper conventional treatment for the underlying cause of cachexia/sarcopenia such as cancer, HIV/AIDS, or respiratory or kidney failure. If cancer is successfully treated, the underlying cachexia is often resolved (Merck 2013).
Testosterone and DHEA
Testosterone plays a critical role in muscle building, and many muscle-wasted patients (men and women) are deficient in testosterone. One study reported that testosterone was deficient in over 70% of men with cancer cachexia. Total testosterone levels were lower in patients who had cancer with cachexia compared to patients who presented with cancer without cachexia (Burney 2012). A number of studies have reported that testosterone treatment has been useful in promoting lean weight gain for people with HIV/AIDS- or COPD-related cachexia (Gullett 2010; Kong 2002).
Injected testosterone (eg, Andro LA 200®, Delatestryl®, Depandro 100® and Depo-Testosterone®) and related oral compounds (eg, oxandrolone [Oxadrin®]) are often useful for individuals with catabolic wasting and low testosterone levels. Testosterone can also be applied in gel form (eg, AndroGel®, Testim®, Axiron®) or as skin patches (Androderm® and Testoderm®). A review of published studies of people with HIV/AIDS-related wasting reported that both testosterone injections and patches led to lean weight gain (Kong 2002). A Texas study treated healthy men aged 60 to 85 years who had low testosterone (<500 ng/dL) with testosterone or placebo. After 5 months, men treated with testosterone injections gained an average of 6.9 pounds of lean mass and lost an average of 2.7 pounds of fat, while men given placebo lost an average of 2.4 pounds of lean mass and gained an average of 2.6 pounds of fat (Sheffield-Moore 2011). Studies have also reported that testosterone can improve protein synthesis and muscle mass in older women (Sheffield-Moore 2006; Smith 2014).
The oral testosterone derivative oxandrolone has been used for decades as a therapeutic intervention against unintentional weight loss associated with such causes as HIV/AIDS-related muscle wasting, severe burns, infections, and major surgery. It has demonstrated efficacy in a variety of studies and has a favorable side effect and safety profile compared to some other oral anabolic agents (Orr 2004). Importantly, oxandrolone has less of a tendency to promote virilization (expression of male characteristics) in females, making it a reasonable option for the treatment of wasting conditions in women (Gullett 2010). In a double-blind, randomized study carried out across multiple centers, oxandrolone at doses of either 5 mg or 15 mg daily improved body weight and well-being more so than placebo in 63 HIV-positive men who had experienced weight loss of more than 10% of initial body weight (Berger 1996). In another trial published in the Journal of the American Medical Association, 24 HIV-positive men exhibiting an average 9% weight loss were randomized to receive 20 mg oxandrolone or placebo daily. All the subjects were also participating in a progressive resistance training program during the study and received supraphysiologic doses of intramuscularly-injected testosterone (100 mg per week). Twenty-two men completed the 8-week study (11 men in each group). Both the placebo group and the oxandrolone group exhibited improvements in body mass and measures of muscle anabolism. However, the improvements were significantly greater among the men who received oxandrolone. The researchers concluded “A moderately supraphysiologic androgen regimen that included an anabolic steroid, oxandrolone, substantially increased the lean tissue accrual and strength gains from [progressive resistance exercise], compared with … testosterone replacement alone, in … men with HIV-associated weight loss” (Strawford 1999). In a larger double-blind, placebo-controlled trial, 262 HIV-infected men who either had a body mass index (BMI) ≤20 or had experienced 10-20% weight loss were assigned to receive 20, 40, or 80 mg of oxandrolone or a placebo daily. After 12 weeks, men receiving 40 or 80 mg oxandrolone exhibited greater body mass gains than those who took a placebo, prompting the study investigators to remark “Oxandrolone administration is effective in promoting dose-dependent gains in body weight … in HIV-infected men with weight loss” (Grunfeld 2006). Oxandrolone can cause some side effects such as potentially significant increases in liver enzymes, increases in LDL cholesterol, and decreases in HDL cholesterol, but these generally are outweighed by the benefits for those experiencing significant wasting (Grunfeld 2006).
DHEA is a hormone and precursor to many other important hormones including testosterone and estrogen (Samaras 2013). Low DHEA levels are common in older adults and are associated with lower muscular mass and strength, higher risk of osteoporosis and bone fractures, depression, cardiovascular disease, and sexual dysfunction (Samaras 2013; Hwang 2013). A number of published studies have reported that DHEA administration (typically 25-50 mg daily) is associated with higher bone densities in osteoporosis patients, with beneficial effects sometimes greater in women than men (Samaras 2013; Weiss 2009). DHEA supplementation may also have beneficial effects on mental abilities (cognition), mood, cardiovascular disease, and sexual function. More information about DHEA is available in the DHEA Restoration Therapy protocol.
Maintaining Optimal Hormone Levels to Prevent Sarcopenia
Levels of growth hormone, testosterone, DHEA, and other hormones important for maintaining muscle mass usually decline with age (Liefke 2000; Jones 2009). By age 70, about 70% of men have low levels of testosterone and may benefit from testosterone replacement therapy (Baer 2012). A double-blind study treated frail elderly men (>65 years) who had low testosterone (below 345 ng/dL) with either 50 mg daily of testosterone gel (130 men) or placebo gel (132 men). After 6 months of treatment, lean muscle mass increased significantly by an average of 2.2 pounds in the testosterone group but stayed the same in the placebo group. In addition, knee extension strength and reported sexual function improved significantly in the testosterone group but not in the control group (Srinivas 2010).
Testosterone levels usually also fall with age in women (Hwang 2013). Testosterone replacement has been used with some success in older women with a number of medical conditions including age-related muscle loss, mood problems, sexual dysfunction, and bone loss (Maclaran 2012; Sheffield 2006).
Any person with suspected muscle wasting should have their hormones tested at least once a year. If necessary, persons with muscle wasting should be treated with bioidentical hormones by a physician trained in hormone replacement therapy.
Growth hormone (brand names Genotropin®, Humatrope®, Norditropin®, Nutropin®, Saizen®, Serostim®) has been approved by the Food and Drug Administration (FDA) for treating HIV/AIDS-related wasting and is sometimes used “off label” to treat other catabolic wasting conditions. Growth hormone is produced by the pituitary gland and its natural production usually declines significantly with age or during severe, chronic illness like AIDS or cancer (Gullet 2010).
Several studies have reported that growth hormone treatment can increase lean weight in people with COPD- or HIV/AIDS-related cachexia (Gullett 2010). A 12-week study of people with HIV/AIDS-related wasting treated 90 subjects with growth hormone (0.1 g/kg body weight per day) and 88 subjects with placebo. After 12 weeks, the growth hormone group had an average gain of 6.6 pounds of lean weight while the placebo group lost an average of 0.2 pounds of lean weight. In addition, subjects given growth hormone had a significantly greater gain in treadmill exercise capacity compared to those receiving placebo. Adverse effects observed more commonly in growth hormone treatment patients than controls included fluid retention (edema), joint pain, and diarrhea (Schambelan 1996). Growth hormone has also been used in older adults with age-related sarcopenia. An analysis of studies which included a total of 220 older adults reported that use of growth hormone for 2 weeks or more was associated with an average 4.6-pound lean weight gain and no significant change in bone density. However, growth hormone treated elders experienced health problems at significantly higher rates (compared to controls) including fluid retention (edema), joint pain, and carpel tunnel syndrome, and were somewhat more likely to experience the onset of type 2 diabetes (Liu 2007).
Megestrol acetate (Megace®) is a synthetic derivative of the hormone progesterone that increases appetite and is used for that purpose in AIDS and cancer patients with weight loss. Some studies have reported that megestrol acetate significantly increases body mass; however, this is largely attributable to gains in fat mass (Gullett 2010; Fox 2009). A 12-week study of frail elders (≥65 years old) in a low-resistance exercise program reported that subjects given 800 mg of megestrol acetate daily gained an average of 20.9 pounds of fat and lost an average of 8.6 pounds of lean tissue, while subjects given placebo gained an average of 1.7 pounds of fat and lost an average of 0.2 pounds of lean tissue. Researchers also noted that the addition of megestrol acetate blunts the beneficial effects of muscle strength training (Sullivan 2007). A 20-week study of 9 elderly men with kidney dialysis-associated cachexia reported that an exercise program coupled with 800 mg of megestrol acetate daily was associated with an average fat gain of 6.2 pounds and an average lean tissue gain of 5 pounds. Subjects on the exercise program with placebo experienced an average loss of 0.4 pounds of fat and 1.2 pounds of lean tissue (Yeh 2010). In a small 12-week study of patients with HIV/AIDS-associated weight loss, subjects were treated with either megestrol acetate (400 mg daily) or nandrolone (ie, an anabolic steroid sometimes used by bodybuilders to increase muscle mass; 100 mg bi-weekly). The megestrol acetate group experienced an average fat weight gain of 17 pounds and an average lean weight gain of 6.1 pounds. The nandrolone group lost an average of 1.4 pounds of fat and gained an average of 7.8 pounds of lean weight (Batterham 2001).
Possible side effects of megestrol acetate include diarrhea, nausea, rash, insomnia, confusion, headache, dizziness, short-term adrenal insufficiency, and edema (water-based swelling of feet, hands, and other areas) (Gullett 2010; Fox 2009). Megestrol acetate treatment may be useful for people with significant loss of both muscle and fat, but it is probably not a good choice for those with significant muscle loss and presence of major fat stores (sarcopenic obesity). Some data suggest that megestrol acetate may increase tumor risk (Tassinari 2003; First Consult 2014). Moreover, although megestrol acetate is often used to promote weight gain in wasting conditions, evidence suggests it may not provide superior benefits compared to other common drugs used in this setting. Given the frequency of potentially serious side effects such as edema, blood clots, and death associated with megestrol acetate and its lack of superiority to other drugs used to treat wasting, it may not be the ideal choice for all individuals. Individuals prescribed megestrol acetate should talk with their health care providers about other drug options that may offer similar benefits and potentially reduced side effects (Ruiz Garcia 2013).
Cannabinoids and Thalidomide
Cannabinoids are compounds derived from the marijuana plant or synthetically produced analogue drugs such as dronabinol (Marinol®). Cannabinoids may be useful for increasing appetite in persons with catabolic wasting. Various studies have found cannabinoids to be very helpful in promoting gain of muscle mass in people with HIV/AIDS-related cachexia but are less useful for people with cancer-related cachexia (Beal 1997; Fearon 2013). Another study of HIV-positive marijuana smokers reported that oral dronabinol (5 or 10 mg four times daily) or 4 marijuana cigarettes smoked daily were associated with a significant increase in daily calorie consumption (Haney 2007). Mild to moderate neurological side effects such as anxiety, confusion, dizziness, and sleepiness are common with the use of cannabinoids (Beal 1997).
As of the time of this writing, 21 U.S. states and the District of Columbia allow for physician-recommended or prescribed marijuana use (NORML 2013). Most of these state laws specifically include HIV/AIDS- and cancer-related cachexia or wasting as approved conditions for allowed marijuana use. However, marijuana smoke contains large amounts of toxic chemicals such as carbon monoxide, particulates, and cancer-causing polycyclic aromatic hydrocarbons (Earleywine 2007; Abrams 2007). Another method for marijuana delivery involves using “vaporization” machines that heat the marijuana up to between 356o F and 392o F to vaporize some of the active compounds without burning (Abrams 2007). Several studies have reported that use of marijuana vaporizers is associated with significantly lower exposure to carbon monoxide and significantly fewer respiratory symptoms (such as coughing) compared to conventional marijuana smoking (Earleywine 2007; Abrams 2007).
Thalidomide (Thalomid®) is a drug that may be helpful to people with cancer-related cachexia and weight loss. Two studies have reported that thalidomide use has been associated with significant gain of total and lean weight in cachectic patients with esophageal or pancreatic cancer (Khan 2003; Gordon 2005). Thalidomide treatment may improve anorexia and nausea, and it inhibits production of the highly inflammatory cytokine TNF-α. Thalidomide treatment has many common adverse side effects including fatigue, peripheral neuropathy, blood clots, respiratory problems, and severe birth defects (Fearon 2013).
Feeding Tubes and Total Parenteral Nutrition (TPN)
Ensuring adequate nutrition is critical for combatting catabolic wasting in severely ill individuals with cachexia. One challenge, however, is that sometimes it is difficult for these people to consume food by mouth. Such barriers as nausea or lack of appetite due to chemotherapy among cancer patients with cachexia, or mechanical difficulties with chewing or swallowing can perturb consumption of adequate nutrition.
A common and effective solution is administration of nutrition via a feeding tube or parenteral nutrition (Arends 2006; Anker 2006).
With a feeding tube, nutrients are delivered through a tube that enters directly into the stomach (“G-tube”) or the segment of the small intestine called the jejunum (“J-tube”); this is called enteral nutrition. This allows semi-solid nutritional solution containing fats, carbohydrates, and proteins, as well as vitamins, minerals, and other micronutrients to be delivered into the patient’s digestive tract while bypassing active eating. Parenteral nutrition involves delivering standardized formulations of liquid nutrients directly into the patient’s bloodstream. Parenteral nutrition can be used to supplement other forms of nutrition consumption, or in cases in which the patient cannot receive any nutrition via their digestive tract, all nutrition may be delivered intravenously – this is called total parenteral nutrition (TPN). Whenever possible, enteral nutrition (as opposed to parenteral nutrition) is preferred, as it more closely mimics natural eating and typically provides better outcomes (Mercadante 1998). Enteral nutrition typically provides 20 – 35 calories per kg (roughly 2.2 pounds) of body weight per day (Nitenberg 2000; Jiménez Jiménez 2011a).
Maintenance of adequate protein and amino acid intake is critical to avert muscle wasting in individuals with cachexia who are receiving enteral nutrition. An enteral and parenteral nutrition research organization based in Spain developed guidelines for enteral feeding of critically-ill cardiac patients indicating that protein intake should be 1.2 – 1.5 g/kg of body weight per day. The formulation should also contain sufficient concentrations of the amino acid glutamine, as it is of critical importance for muscle cell and immune function. In addition, omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) may be added to the enteral formula as well; these Spanish guidelines suggest 1 g per day (Jiménez Jiménez 2011a; Nitenberg 2000).
Although enteral nutrition is not suitable for all patients with wasting or cachexia, guidelines suggest it should be considered if undernutrition is already clinically evident or if food intake is reduced significantly for 7 – 10 days (Arends 2006).