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Drug therapies that combat wasting

by Tadd Scott Lazarus, M.D. and David W. Purdy

There are a variety of options in the treatment of HIV-related wasting syndrome. Probably the most important concept to remember is that one must diagnose and treat what is treatable. Specifically, wasting is often a result of undiagnosed mycrobacterial infection or cytomegalovirus that has become disseminated (extra-ocular). One should never abandon investigating an infectious, neoplastic or mechanical etiology for wasting. During the investigative process, wasting must be treated through a directed effort concentrating on addressing both symptoms and etiology.

Wasting and the nutritional problems associated with HIV/AIDS have for too long been placed as back-burner issues of concern of the dietician or the patient but not the clinician. In 1989, Dr. Donald Kotler and associates published a pivotal study in the American Journal of Clinical Nutrition (50(3);) wherein they described the "magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS." They noted that there was progressive depletion of body cell mass as patients neared death. The extrapolated and observed values for body cell mass at death were 54% of normal. Body weight had a similar relationship to death, with a projected body weight at death of 66% of ideal. We conclude that death from wasting in AIDS is related to the magnitude of tissue depletion and is independent of the underlying cause of wasting. The degree of wasting seen in this study is similar to historical reports of semistarvation, with or without associated infections. This observation suggests that successful attempts to maintain body mass could prolong survival in patients with AIDS." Since that time, multiple studies have clearly shown the correlation between decreased body cell mass and an increase in morbidity and mortality. Yet little of this knowledge has found its way into the practice of HIV medicine.

At the heart of wasting syndrome is the inappropriate use of lean muscle as an oxidative fuel and the inability of the body to appropriately oxidize fat stores. Only anabolic agents can effectively address this conundrum and correct the metabolic course. Agentssuch as appetite stimulantshave an important place in the treatment armamentarium as the intake of calories and nutrients is crucial in replenishing lean body mass.

The following is not meant as an exhaustive treatise on this subject but a place for clinicians and patients unfamiliar with these therapies to augment their knowledge base.

Anabolic Steroids
Thousands of people with HIV are currently being treated successfully with anabolic-androgenic steroids for HIV-associated wasting and hypogonadism. Androgenic steroids (male sex hormones), like anabolic steroids, have a long history of use in treating wasting conditions associated with infectious diseases and cancer.¹,² An article published as early as 1968 strongly supported the use of anabolic steroids in the management of chronic wasting diseases.³

Studies clearly show that anabolic agents may produce far superior and more enduring lean body mass increases than any other available treatment for wasting.⁴ Anabolic steroids improve muscle bulk, body weight, overall strength and sense of well being in HIV-positive patients.⁵ Anabolic steroids also improve nutritional status, stimulate appetite⁶, combat anemia, control depression and significantly improve the patient's overall quality of life.

Anabolic steroids possess anti-catabolic properties in that they can abolish a negative nitrogen balance brought about by the administration of corticosteroids and anti-androgens.⁷,⁸ In placebo-controlled studies using anabolic steroids, not only was there a significant effect on lean body mass, but also muscle strength.⁹ Anabolic-androgenic steroids act directly on skeletal muscle by binding to the androgen receptors.¹⁰

Testosterone and Other Anabolic Steroids
All anabolic-androgenic steroids are derivatives of the human body's natural testosterone. Synthetic preparations of testosterone used in medicine are in fact anabolic-androgenic steroids. All anabolic steroids have anabolic (muscle building) and androgenic (masculinizing) properties. Testosterone has the highest level of androgenic properties. Anabolic steroids were developed for clinical use with the expectation that they would be relatively less androgenic than testosterone.¹¹

Because all anabolic steroids contain androgenic properties which are considered undesirable and unnecessary for many patients, and also may lead to potential side effects, efforts have been made to separate the two properties, with emphasis on creating synthetic anabolic steroids which have higher anabolic than androgenic properties.¹² The anabolic steroids recommended for the treatment of HIV wasting are in fact higher in anabolic properties than androgenic properties.

One study successfully demonstrated that testosterone analogues, like Deca-Durabolin (nandrolone decanoate, Organon) may be more appropriate to prescribe than testosterone itself for HIV wasting.¹³

Oral Anabolic Steroids
There are two oral anabolic steroids that experts recommend in the treatment of HIV-associated wasting. The two medications are Oxandrin (oxandralone, BTG) and Winstrol (stanozolol, Sanofi Winthrop).

Oxandrin appears to be one of the few oral anabolic steroids with a history of use in treating wasting disorders. It differs from other testosterone analogues in that it contains an oxygen rather than a carbon atom. This may account for its anabolic potency that is approximately three to ¹³ times that of testosterone.¹⁴

Oxandrin is indicated as adjunctive therapy to promote weight gain after weight loss following extensive surgery, chronic infections or severe trauma.¹⁵ Clinical trials have demonstrated that Oxandrin is a safe and effective oral anabolic steroid with low androgenic properties. It appears that unlike other oral anabolic steroids, Oxandrin undergoes little overall metabolic transformation in the liver and is well tolerated in men and women.¹⁶

A 1995 double-blind study conducted at six different U.S. sites concluded that HIV-positive men who were severely wasting (10% or below their normal body weight), experienced significant and sustained weight gain with Oxandrin. The study subjects were prescribed 15 mg/day or 140 mg a week, for 16 weeks. There were no apparent side effects.¹⁷ In other studies, Oxandrin has been prescribed at much higher dosages than 15 mg/day without significant side effects. Oxandrin appears to be one of the few safe oral anabolic steroids, because unlike other anabolic-androgenic steroids, Oxandrin undergoes little metabolism and is not aromatized into estrogen.¹⁸

Winstrol, the other anabolic steroid recommended for HIV-associated wasting, has a history of use in wasting disorders as well, but appears to be slightly more androgenic than Oxandrin. When prescribed at small therapeutic dosages, however, as recommended in the treatment of wasting, this should not be a problem or cause negative side effects.

Anabolic Steroid Patches
Some health care providers and patients prefer the anabolic steroid patch as a convenient alternative to injections or oral anabolic steroid preparations.

There are currently two anabolic steroid patches. One is Testoderm (testosterone transdermal system, ALZA). The patch is a thin flexible film that adheres to the scrotum by utilizing a heat-activated adhesive. Testosterone passes from the system through the scrotal skin and into the bloodstream. The scrotal skin appears to allow 10 times more testosterone to pass through than other skin sites on the body trunk and arm.

Another anabolic steroid patch is Androderm (testosterone transdermal system, SmithKline Beecham). Unlike Testoderm, Androderm is applied as two patches to the back of the arm or shoulder upon retiring.

Anabolic Steroid Gels
Dihydrotestosterone Gel is in development as a novel delivery mechanism for testosterone. It is applied to the patient's abdominal area. The appropriate dosage of this product for the treatment of HIV-associated wasting is not yet clear, but it could be a convenient and effective alternative hormone therapy for the future.

Human Growth Hormone
Much attention has been focused on the use of Serostim (recombinant human growth hormone, Serono) for the treatment of HIV-associated wasting. Serostim is an effective agent causing prompt reversal of negative nitrogen balance and increases in lean body mass. Unfortunately, the cost of therapy has made it difficult to justify this agent as first-line therapy for wasting. Serostim requires a daily injection during the course of therapy and side-effects can include flu-like symptoms including myalgias and arthralgias as well as peripheral edema. In trials of Serostim in the elderly, there was evidence of reversal of gains in lean body mass with cessation of the agent. it should be remembered the Serostim has no androgenic activity and a hypogonadal male will still need exogenous testosterone replacement.

What's the right dose?

High dosages vs. Low Dosages
There is some discussion regarding the appropriate dosage level of anabolic steroids in combating wasting and hypogonadism. There is little doubt that low doses of anabolic steroids will produce a modest effect, while large doses will result in a progressive augmentation of lean body mass.¹⁹

However, the goal of optimum dosage is to achieve the appropriate effect at the lowest possible dosage. The appropriate dosage level of anabolic steroids also depends on the individual patient's sensitivity to the dosage used and the androgenic properties of the anabolic steroid.²⁰

The recommended dosage level of injectable anabolic steroids, like nandralone decanoate, is 100 mg per week.

The recommended dosage level for an oral anabolic steroid, like Oxandrin, is 140 mg per week. At this recommended dosage level there have been no reports of negative side effects. Approximately 30% of oxandralone is excreted in the urine unconjugated and unchanged, which accounts for the higher recommended dosage level in comparison to nandrolone decanoate.²¹

Too High a Dose Is Dangerous
There are a number of individuals advocating the use of hormone therapies that recommend protocols of as much as 300 mg to 600 mg of medication administered weekly. Experts agree that this is not only a bad idea, but also dangerous in the long term.

Pyramiding Medication Dosage
The practice of escalating and then de-escalating the dosage level, sometimes referred to as "pyramiding" the medication, is, again, a common practice among bodybuilders. The idea is that it is safer to utilize the medication by prescribing smaller dosages within the first few weeks of the treatment period, and then increasing and decreasing the dose in a "pyramid" fashion, and eventually weaning the patient off the medication. While no formal scientific studies support this practice, experts agree that when using dosages higher than 100 mg of Deca-Durabolin or injected testosterone or 140 mg per week of an oral anabolic agent, a "pyramid" regimen is safer than starting the patient on a high dosage.

Monotherapy vs. Combination therapy
Skeletal muscle contains androgen receptors to which anabolic steroids bind.²²,²³ Steroid receptors are therefore regarded as mediators of hormone action. The presence of such receptors in tissues reflects their hormone sensitivity and the receptor levels are an indictor of potential hormone action.²⁴

Anabolic steroid receptors are sensitive which is the reason why there is reversal of negative nitrogen balance even after very low doses of anabolic agents are utilized. Like all receptors, tolerance to the stimulating agent develops over time if the medication is used without any treatment breaks. This may lead to the medication becoming ineffective or having reduced efficacy.

Combination therapy (using more than one medication at a time to treat a condition) should be instituted only if a patient is not responding to monotherapy (using only one drug).
The practice of prescribing 100 mg of highly androgenic testosterone, in combination with 100 mg of a different anabolic steroid, is not considered standard protocol; instead, such combination therapy is considered a secondary treatment protocol.

Long Term vs. Short term therapy
Experts feel that to get the best results from hormone therapies the treatment should be prescribed for at least 10 weeks, to give the medication the necessary time to do its work. Nonetheless, hormone therapies are not designed to be long-term and should be prescribed only when necessary. They are specifically designed to control hypogonadism and wasting.

In addition, experts agree that long-term use of hormone therapies may create receptor insensitivity necessitating the use of higher dosages of the medication(s) to receive the same benefit. Impotence and low energy levels are side effects that are potential indicators of either over-medication or a treatment period that is too great a duration.

There is also a risk of psychological dependency on these agents which needs to be clearly articulated. Many men, independent of their HIV status, now view exercise not as an important health activity but concentrate only on their desire for an increase in muscle mass. Of greatest concern is when weight lifting is viewed as ineffective or too slow to get the job done. every healthcare practitioner should discuss the potential for anabolic steroid abuse with his or her patients.

References

1. Gerhardt JJ. Anabolics and HIV. J of Theoretical and Applied Health Tech. 1990.; 6:4.

2. Vague J. Treatment of weight loss. Rev Prat. 1972 Dec 21;22(33):.

3. Wewalka FG. Anabolic steroids in the management of chronic wasting diseases. J Am Med Wom Assoc. 1968 Apr;23(4):339-45.

4. Forbes, et al. Sequences of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA. 1990; V.267, N 3:.

5. Berger JR, Pall L, Winfield D. Effect of anabolic steroids on HIV-related wasting myopathy. South Med J. 1993 Aug;86(8):865-6.

6. Ganesan R, Rosellini RA, Svare B. Investigation of anabolic steroids in two tastes aversion paradigms. Appetite. 1993 Feb; 20 (1):1-11.

7. Van Waygen RG. Metabolic effects of anabolic steroids. Wien Med Wochenschr. 1993;143:368-75.

8. Hausmann DF, et. Al. Anabolic steroids in polytrauma patients. Influence on renal nitrogen and amino acid losses: a double-blind study. JPEN J Parenter Enteral Nutr. 1990 Mar-Apr;14(2):111-4.

9. Soe M, Jensen KL, Gluud C. The effect of anabolic androgenic steroids on muscle strength, body weight and lean body mass in body-building men. Ugeskr Laeger. 1989 Mar 6;151(10):610-3.

10. Gustafsson JA, et. Al. Studies on steroid receptors in human and rabbit skeletal muscle-clues to the understanding of the mechanism of action of anabolic steroids. Prog Clin Biol Res. 1984; 142:261-90.

11. Takada M. Pharmacological action of anabolic steroids. Nippon Rinsho. 1994 Mar;52(3):606-10.

12 Schwartz PL, Miller RJ. Androgens and anabolic steroids. In: Modern Pharmacology. 2nd edition. Boston, Mass: Little, Brown and Company; 1982; .

13. Mendenhall CL, Grossman CJ, Roselle GA, et al. Anabolic steroid effects on immune function: differences between analogues. J Steroid Biochem Molec Biol. 1990; 37: 71-76.

14. Fox M, Minot AS, Liddle GW. Oxandrolone: A potent anabolic steroid. J Clin Endocrin Metabol. 1962; 22:.

15. FDA approved indication as listed in the Oxandrin package insert.

16. Karim A, Ranney RE, Zagarella BA, Maibach HI, Oxandrolone disposition and metabolism in man. Clin Pharmacol Ther. 1973; 14:.

17. Berger JR, et. al. Oxandrolone in AIDS wasting/myopathy. J Neurovirology. 1995.2:32.

18. Massé R, Bi H, Ayotte C, Dugal R. Studies on anabolic steroids II- Gas chromatographic/mass spectrometric characterization of oxandrolone urinary metabolites in man. Biomed Environ Mass Spectrometry. 1989; 18: .

19. Forbes GB. The effect of anabolic steroids on lean body mass: the dose response curve. 1985 Jun;34(6):571-3.

20. Kopera H. Side effects of anabolic steroids and contraindications. Wien Med Wochenschr. 1993; 143(14-15):.

21. Massé R, Bi H, Ayotte C, Dugal R. Studies on anabolic steroids II- Gas chromatographic/mass spectrometric characterization of oxandrolone urinary metabolites in man. Biomed Environ Mass Spectrometry. 1989; 18: .

22. Rogozkin V. Metabolic effects of anabolic steroid on skeletal muscle. Med Sci Sports. 1979 Summer;11(2):160-3.

23. Gustafsson JA, et. Al. Studies on steroid receptors in human and rabbit skeletal muscle-clues to the understanding of the mechanism of action of anabolic steroids. Prog Clin Biol Res. 1984; 142:261-90.

24. Gustafsson JA, et. Al. Studies on steroid receptors in human and rabbit skeletal muscle-clues to the understanding of the mechanism of action of anabolic steroids. Prog Clin Biol Res. 1984; 142:261-90.