Anabolic Steroids in the Treatment
of HIV-Related Wasting
by Mark Bowers
Researchers and clinicians have increasingly recognized and described
endocrine abnormalities in people with HIV infection. Men with HIV, particularly
men with AIDS, are likely to be hypogonadal. Serum levels of testosterone
are found to be below average in up to 50% of these men. Several strategies
have been considered and implemented to restore testosterone levels to
the normal range, including the use of testosterone and other anabolic
agents.
Clinicians who specialize in HIV disease have begun to appreciate the
early manifestations of HIV-related wasting and the correlation between
wasting and the loss of lean body mass (muscle). Many clinicians intervene
early in the course of HIV infection to ensure that lean body mass is
preserved for the longest possible time. Some of the more commonly prescribed
interventions to restore or increase lean body mass include testosterone
and other anabolic agents. Researchers at the XI International Conference
on AIDS in Vancouver (July 7-12, 1996) suggested that combinations of
testosterone and one or more other anabolic agents may provide the most
effective intervention for HIV-related wasting.
This feature will briefly describe the history and biology of anabolic
steroids for HIV-related wasting and hypogonadism in the United States,
the use of established and novel anabolic agents in the treatment of hypogonadism
and wasting, side effects, legal considerations, current clinical research
and development, and the contribution of progressive resistance exercise
to increasing lean body mass when anabolic agents are used.
History of Anabolic Steroids
Anabolic steroids are synthetic derivatives of testosterone. Testosterone
itself is the sex hormone produced by specialized cells in the testes
of males and in smaller quantities by the adrenal glands of both males
and females. Charles Edouard Brown is credited with the discovery of testosterone
and with helping to found modern endocrinology with his 1889 report that
he had reversed the aging process by injecting himself with liquid derived
from the testicles of dogs and guinea pigs.
The first real synthesis of testosterone was accomplished in 1935 by
3 different European research teams. Noting that androgens (of which testosterone
is one) could relieve pain, increase appetite and promote a sense of well-being,
researchers in the 1940s studied testosterone therapy in the treatment
of hypogonadism, impotence, metastatic cancer and even attempted to change
the sexual orientation of male homosexuals (the intervention increased
libido but did not change orientation).
Since the 1940s, testosterone and synthetic derivatives, now collectively
referred to as anabolic steroids, began to be used to stimulate growth
and initiate puberty in boys whose development is slowed, to treat chronic
wasting in survivors of concentration camps and to reduce trauma associated
with burns, surgery and radiation therapy. Until the development of synthetic
erythropoietin and the perfection of bone marrow transplants, anabolic
steroids were widely used for increasing red blood cell production in
the treatment of anemia.
Investigation of testosterone derivatives for increasing muscular capacity
in soldiers, athletes and bodybuilders began in earnest in the 1940s and
continues today, mostly supporting a $1 billion international black market.
Since 1970, drug-testing programs have been initiated by Olympics governing
committees and by sports organizations to discourage use of anabolic steroids.
In March 1991, the Federal Anabolic Steroid Control Act went into effect.
Anabolic steroids were classified with narcotics and drugs with serious
addictive potential, despite a lack of clinical data to support such a
classification. Also in the 1990s, anabolic steroids have been used medically
to decrease bone resorption (the decrease in bone mass that increases
with age), increase reported sexual desire and function, and improve spatial
cognition and word memory. Aware that consistent use of anabolic steroids
reduces sperm production, the World Health Organization conducted a 10
center global study of anabolic steroids as a male contraceptive.
Biologic Effects
The endocrine system of the body provides fine tuning of the activities
of bodily systems through the release of various hormones, including amines,
amino acids, polypeptides, proteins and steroids. The slow process by
which the body breaks down carbohydrates, fats and proteins to make energy
is called catabolism, while the process by which the body uses energy
to create new protein, fats and complex carbohydrates is called anabolism.
Anabolic steroids are the hormones (and synthetic hormones) that build
new lean body tissue, among other functions.
Androgens are hormones secreted by the gonads and adrenal cortex that
masculinize, while estrogens are hormones that bring about female secondary
sexual characteristics. Androgens increase the body's retention of nitrogen
and increase lean body mass and body weight. No androgen is completely
anabolic; all stimulate male secondary sexual characteristics to some
degree, although some do so to a lesser extent than others. Androgens
include dihydroepiandrosterone (DHEA), DHEA sulfate, androstendione and
testosterone, all of which are anabolic to some extent. The class of anabolic
steroids includes drugs that are more or less anabolic and more or less
androgenic.Estrogens are not anabolic.
Androgens and estrogens do not work in isolation in the body. Hormones
are secreted by many endocine glands in the body, and each hormone potentially
affects the release of many other hormones by feedback loops or direct
inhibition. Endocrinologists are trying now to completely understand and
manipulate the feedback loops that are relevant to many different diseases
and syndromes, including thyroid disease, obesity, diabetes, hypogonadism
and HIV-related wasting.
An important hormone that can affect levels of testosterone production
in males is gonadotropin-releasing hormone (GnRH), produced by the hypothalamus
in the brain. When GnRH is released into the blood, it targets cells that
produce gonadotropins, luteinizing hormone (LH) and follicle-stimulating
hormone (FSH). LH binds to receptors on the Leydig cells of the testes
to increase the metabolism of cholesterol (from which steroid hormones
are made) and thereby initiate production of testosterone. Follicle-stimulating
hormone finds receptors on the Sertoli cells of the testes to produce
5 necessary proteins and to initiate sperm production.
Androgens and estrogens have an effect on gonadotropin regulation by
either increasing or decreasing the amount of GnRH, LH or FSH that is
released, and in so doing, decreasing or increasing the amount of testosterone
that is produced and released. High enough levels of testosterone will
suppress the release of LH, in turn shutting down production of new testosterone.
Moreover, the administration of exogenous (not produced by the body) testosterone
or estrogens (such as are found in megestrol acetate or crude marijuana)
and some drugs (notably ketoconazole, ganciclovir and cancer chemotherapeutic
agents) can also affect feedback loops and decrease testosterone production.
Testosterone either binds to target cells or is converted to dihydrotestosterone
(DHT) or estradiol. DHT binds to androgen receptors better than testosterone,
and is more androgenic. Both androgens maintain the tissues of the testes,
penis, epididymis, seminal vesicles and prostate. Other binding sites
for androgens include muscle cells, sebaceous (oil) glands and body hair
follicles. Additionally, elevated testosterone or DHT increases the synthesis
of blood clotting factors, decreases high-density lipoprotein concentrations
and maintains or increases bone mass.
Clinical Considerations
HIV disease is increasingly associated with decreases in anabolism and
increases in catabolism in the body. The number of HIV positive men who
complain of decreases in libido and impotence increases with their stage
of disease. Testosterone levels in such men are found to be significantly
lower than normal reference levels, and in many communities including
San Francisco, it is standard of care to restore levels of testosterone
to normal physiologic ranges by administering either periodic intramuscular
injections of testosterone derivatives (see below for types and doses)
or by transdermal patch delivery of testosterone (Testoderm or Androderm).
A more complicated syndrome often present in HIV disease is HIV-related
wasting. Wasting is usually defined as unintentional loss of 10% or more
of usual body weight. Such weight loss may be explained by several factors,
including malnutrition, malnourishment and chronic severe diarrhea, as
well as increased catabolism that selectively seems to target lean body
mass while sparing fat stores. A clinically important consideration is
that the amount of lean body mass correlates with survival, while the
amount of fat mass does not. Studies strongly suggest that moderate to
severe weight loss before an AIDS diagnosis independently predicts survival
after AIDS; those with greater weight loss have significantly poorer survival
times after developing AIDS than those with no such weight loss.
A logical paradigm for evaluating weight loss in the context of HIV disease
is to first assess nutritional status and supplement where it is found
to be deficient. Megestrol acetate (Megace, made by Bristol Labs, 100
20mg tablets for $69.86) and dronabinol (Marinol, made by Roxane Labs,
25 5mg capsules for $160.89) are both approved appetite stimulants for
treating HIV-related weight loss. A common observation about such weight
gain, however, is that seldom is lean body mass increased by the use of
these 2 approved drugs.
Donald Kotler, MD, of Columbia University College of Physicians and Surgeons,
suggests evaluating patients who are wasting for malnutrition related
to oral, pharyngeal or esophageal problems resulting from medications
or other factors. Patients whose metabolic rate is increased should be
evaluated for possible systemic infections, and treated if they are found.
Kotler suggests that patients who do not respond to appetite stimulants
may require nonvolitional approaches (e.g. parenteral nutrition) to offset
eating disorders or malabsorption. When intake is judged to be adequate,
Kotler suggests that anabolic agents may be useful.
Many physicians who provide exogenous testosterone to patients who are
mildly to severely hypogonadal find that lean body mass increases, particularly
when testosterone supplementation is accompanied by progressive resistance
exercise. In cases where frank hypogonadism is not found, some physicians
will choose another anabolic steroid to increase the ratio of lean body
mass to fat and promote survival. Although the hormone is only available
through expanded access and is not yet FDA-approved for HIV wasting, some
physicians rely on human growth hormone (HGH) to respond to wasting in
their patients who are losing weight too rapidly and fail to respond to
other interventions. Anecdotally, combinations of testosterone, other
anabolic steroids and growth hormone yield the greatest gains in lean
body mass, but this strategy has not yet been evaluated in rigorously
controlled clinical studies.
An important hormone that regulates the production of testosterone is
human chorionic gonadotropin (HCG, made by Steris Labs, 10ml at 10,000
units/vial for $22.71), administered as treatment for hypogonadism in
some instances. Most information about the use of HCG is anecdotal, and
involves periodic injections at the end of a "steroid cycle,"
a period of several weeks during which combinations of testosterone and
anabolic steroids are taken to increase lean body mass. HCG is thought
to provide the needed hormonal impetus to restart endogenous testosterone
production after exogenous steroids have down-regulated testicular production
for several weeks. HCG has not been evaluated in treating hypogonadism
in HIV positive individuals.
What is Available?
Testosterone is available in oral, intramuscular, transdermal, subcutaneous
and sublingual preparations. Oral preparations of testosterone are quickly
inactivated by the liver and may have unacceptable liver toxicities. However,
some oral anabolic steroids such as Winstrol (stanozolol, made by Sanofi
Winthrop, 100 2mg tabs for $65.87), and Oxandrin (oxandrolone, made by
BTG Pharmaceuticals, 100 2.5mg tablets for $375.00) are not as quickly
broken down in the liver and may be useful in repleting lean body mass.
Anadrol (oxymetholone, made by Syntex, 100-50mg tablets for $88.06) and
Halotestin (fluoxymesterone, made by Upjohn Pharmaceuticals, 100-5mg tablets
for $109.96) are very toxic to the liver.
Esters of testosterone in an oil base are available by prescription for
intramuscular injection: propionate or phenyl-propionate (short range
of effectiveness, injections 5 days apart), cypionate (mid range of effectiveness,
injections about 7 days apart) and enanthate, decanoate or undecanoate
(longer range of effectiveness, injections 10-14 days apart). Many synthetic
anabolic steroids are also intended for intramuscular injection: nandrolone
decanoate (Deca-Durabolin, made by Organon, 1 ml injection at 200mg/ml
for $19.30 or made by Steris Labs, 1 ml at 200mg/ml for $6.29) or nandrolone
phenylpropionate (Durabolin, made by Organon, 2 ml injection at 50mg/ml
for $14.15 or made by Haber Pharmaceuticals, 2 ml injection at 50mg/ml
for $4.75).
What to Measure?
Only 1 to 2% of all testosterone in circulation is free; the rest is
bound to sex hormone-binding globulins, which cannot bind to target cells.
Clinicians measure total testosterone, including both bound and free fractions,
to determine whether an individual is hypogonadal.
Data reported by Adrian Dobs, MD, of Johns Hopkins University in Baltimore,
at the 10th annual meeting of the International Congress of Endocrinology
in San Francisco June 12-15, 1996, suggest that declining levels of testosterone
in HIV positive men may predict weight loss and wasting. Twenty-six participants
in the Multicenter AIDS Cohort Study were tested to see if decreases in
testosterone levels preceded or were linked with wasting or if weight
loss caused decreases in testosterone levels. Baseline measures showed
13 men had lost more than 10% of their original weight independent of
diarrhea or opportunistic infections, while 13 men gained weight. After
6 months, testosterone levels decreased in the 13 who had significant
weight loss, and remained stable in those with stable weight. Dobs concluded
that decreases in testosterone levels may predict which male patients
are at risk for rapid weight loss and wasting.
A related study reported at the same meeting suggested that the loss
of testosterone may contribute to decreased lean body mass, and further
suggested that increased resistance to growth hormone accompanies testosterone
decreases. From a field of 65 men with AIDS, 20 hypogonadal men were selected
for study. Free testosterone levels were highly correlated with lean mass,
and increased growth hormone levels were inversely correlated with weight.
Acquired growth hormone resistance is considered a classical factor in
the loss of lean body mass. Both studies suggest that monitoring an HIV
positive man's testosterone levels and supplementing when they are deficient
may be an easy, cost-effective means of preventing HIV wasting syndrome.
A study of the nutritional and testosterone status of HIV positive women,
done by Donald Kotler, MD, and colleagues at St. Luke's-Roosevelt hospital
in New York and reported at the XI International AIDS Conference in Vancouver,
concluded that serum testosterone levels are frequently low in pre-menopausal
HIV positive women and are associated with malnutrition defined by low
body cell mass (Tu.B.2382).
Side Effects and Risks
The number of side effects associated with the use of anabolic steroids
varies depending on the source and the individual steroid. Entries in
the Physician's Desk Reference may pre-date newer research and
may incorrectly portray the primary and side effects of anabolic steroids.
The most complete list of side effects appears in Anabolic Reference
Guide, which lists skin reactions (acne, virilization, hirsutism,
male pattern baldness and seborrhea), endocrine, urinary and genital involvement
(gynecomastia, enlarged prostate, sterility, adrenal genital syndrome,
excessive frequency of urination and duration of penile erections), fluid
and electrolye effects (sodium, chloride, water, potassium, calcium and
inorganic phosphate retention), gastrointestinal effects (stomach aches,
nausea), hepatic effects (alterations in liver function tests, hepatocellular
neoplasms and peliosis hepatitis), hematologic effects (suppression of
clotting factors II, V, VII and X, bleeding in users who also take anticoagulants,
and polycythemia), cardiac effects (hypertension, cardiovascular disease,
palpitations, enlarged heart), cancer, headaches, muscle tears, immune
system depression, insomnia and anaphylactic shock as independent risks
associated with the use of steroids.
Not all synthetic testosterone derivatives have the same safety profile.
Oral steroids are associated with reduced high-density lipoprotein cholesterol,
increased low-density lipoprotein cholesterol and increased risk of liver
damage. Jaundice, a yellowing of the skin, the whites of the eyes and
other tissues because of excess circulating bilirubin (a waste product
resulting from the breakdown of red blood cells), may be a sign of toxic
side effects from the use of an anabolic steroid or a symptom of liver
disease, such as hepatitis.
Novel delivery systems for anabolic steroids are accompanied by additional
novel side effects, including rare incidences of rash, rectal lesions
over the prostate, scrotal cellulitis and papilloma on the scrotum associated
with the use of Testoderm subscrotal testosterone patches. Androderm,
which is applied to non-scrotal skin, is associated with the additional
side effects of pruritis (itching), blister reactions, erythema (redness),
allergic dermatitis, burning or vesicles at the patch application site.
Most anabolic steroids are delivered by intramuscular injection; they
must not be injected into veins. Testosterone is suspended in cottonseed
oil or sesame oil so that the hormone diffuses slowly. Oil is thicker
than most fluids that are injected, so the delivery needle should be larger,
preferably 21 or 22 gauge, and longer, 1 or 1.5 inches. The needle should
be used only once, then safely discarded or exchanged. Needle exchange
programs frequently exchange appropriately sized syringes and needles.
Sharing needles can result in the transmission of many infections, including
HIV, hepatitis, papilloma virus, cytomegalovirus and others.
Proper injection techniques will help to avoid several risks associated
with injecting steroids. Counterfeit steroids frequently contain impurities
that cause infection or abscesses. Too frequent injection in one area
may also result in the formation of abscesses. Failure to thoroughly clean
the injection site with an alcohol swab before injection may allow skin
bacteria to be injected along with the steroid; the resulting infection
may be difficult to treat and disfiguring. Incorrect selection of an injection
site may lead to the disruption of a major nerve, such as the sciatic
nerve, with considerable pain and temporary paralysis in the area served
by that nerve.
Recent innovations in the delivery of testosterone are subcutaneous pellets
and transdermal patches. One patch, Testoderm (Alza Pharmaceuticals, 30
patches 4mg/24hr $71.76) is in clinical studies for the treatment of HIV
weight loss in men. The patch is applied to the subscrotal area (which
is one reason why women are excluded from the study) and delivers physiologic
levels of testosterone over 24 hours, then is replaced. An advantage of
both delivery systems is that there is no immediate rise in serum testosterone
levels to supraphysiologic (higher than naturally occurring) levels, which
occurs after intramuscular injections. Some evidence has accrued that
supraphysiologic levels of testosterone trigger a feedback mechanism that
down-regulates endogenous (natural, made within the body) production of
testosterone and may perturb the levels of other important hormones in
the feedback loop. Another patch, Androderm (Smith Kline Beecham, 60 patches
of 2.5 mg at $97.50) is also available and can be worn elsewhere than
on subscrotal skin; 5mg (2 patches) per day are recommended to produce
results equivalent to a 200 mg injection of testosterone.
Testosterone cyclodextrin (Androtest SL, Biotechnology General) is a
short-acting sublingual (under the tongue) testosterone preparation that
circumvents most problems with liver toxicity. A clinical study compared
sublingual testosterone at either 2.5 mg or 5 mg 3 times a day to intramuscular
injections of 200 mg of testosterone enanthate every 20 days over a total
of 60 days. The sublingual preparation was found to be as effective as
intramuscular injections for restoring sexual function without significant
side effects. An advantage to the sublingual pill is that testosterone
levels do not become supraphysiologic; however, the effectiveness of sublingual
testosterone in maintaining bone density and muscle mass has not yet been
proven.
Legal Risks
Anabolic steroids are Schedule III controlled substances. The Anabolic
Steroids Control Act of 1990 that added 28 anabolic steroids to Section
102 of the Controlled Substances Act made it a felony in the United States
to distribute or possesss with intent to distribute any anabolic steroid
or human growth hormone for any use other than the treatment of a disease
or other recognized medical condition, punishable by not more than 5 years
in prison or, if a minor under 18 years of age is involved, not more than
10 years in prison. Legally, "anabolic steroid" means any drug
or hormonal substance (other than estrogens, progestins and corticosteroids)
that promotes muscle growth.
The legal system is clear that anabolic steroids promote muscle growth,
a position more clear than the official policy of the Food and Drug Administration.
Progressive Resistance Exercise
Anecdotal evidence has accumulated for many years that shows that persons
who are receiving anabolic steroids increase their lean body mass much
more quickly when they perform progressive resistance exercise than when
they do not. A study by Shalender Bhasin, PhD, of the Charles R. Drew
University of Medicine and Science in Los Angeles, compared lean body
mass gain of 43 HIV negative men in 4 treatment groups. The 30 week, double-blind
study compared testosterone enanthate to placebo, with or without progressive
resistance exercise.
The greatest gains (an average of 13.5 lbs) were seen in men who received
testosterone (600 mg per week intramuscular injections) and exercised,
followed by the group that received only testosterone (an average gain
of 7 lbs), then the placebo plus exercise group (an average of 4 lbs).
The smallest gains were registered in men who received only placebo injections.
All participants ate a controlled diet based on body weight for 2 weeks
prior to the 10- week course of treatment, and were monitored during the
10 week treatment period to adjust caloric intake in response to increases
in body weight. Liver enzymes, hemoglobin, hematocrit and red blood cell
counts remained unchanged in the groups receiving testosterone injections.
Standardized mood and anger inventories were completed for all participants,
and no statistically significant differences were noted among the treatment
groups.
Poster presentations at the XI International Conference on AIDS revealed
that both doctors and their HIV positive patients are beginning to recognize
the importance of weight training or progressive resistance exercise in
building and maintaining adequate stores of lean body mass and increasing
weight, strength and endurance before symptoms of HIV-associated wasting
appear.
In opposition to generally accepted data that indicate that androgen
use without exercise generally does not produce increases in muscle mass
and strength, a Melbourne, Australia study of 13 healthy, non-exercising
men who received 200 mg of testosterone enanthate once a week for 6 months
showed that lean body mass increased about 10% while fat mass decreased
about 16%. The Bhasin study (above) also illustrated gains in muscle strength
and lean body mass among men who received testosterone, but did not engage
in progressive resistance exercise. It is not known whether any of these
results generalize to HIV infected individuals.
Future Directions and Conclusions
The underlying cause of HIV-related wasting should be clinically identified
as soon as possible. Nutritional strategies should be exhausted first,
if appropriate to treat the underlying cause. Then, as with antiretroviral
therapy and the treatment for many opportunistic infections, the best
approach to increasing lean body mass in response to HIV-related wasting
may be a strategy that combines available anabolic agents. Testosterone
replacement is appropriate for males with hypogonadism. If a hypogonadal
man or a woman with HIV also experiences unplanned, unexplained weight
loss, the periodic administration of an additional anabolic steroid may
help to replete lean body mass more quickly, reliably and durably than
testosterone alone. Severe cases of AIDS-related wasting should prompt
the treating physician to consider more heroic rescue efforts, including
administration of human growth hormone (Serostim, made by Serono Laboratories).
Marc Hellerstein, MD, of the University of California at San Francisco,
believes that combinations of testosterone, anabolic steroids and growth
hormone may be the most logical and physiologically appropriate means
to reverse HIV wasting.
Combination therapies for HIV wasting are being evaluated in clinical
studies. Currently, one prospective, placebo-controlled study will evaluate
the body's ability to create lean body mass in response to concurrent
administration of megestrol and either testosterone patches or intramuscular
injections. Combinations of testosterone and other anabolic steroids or
growth hormone have not yet been evaluated clinically.
The safety of the anabolic steroid nandrolone decanoate was prospectively
evaluated in HIV positive volunteers in a 12 week, randomized, double-blind,
placebo-controlled study reported by Gary Bucher, MD, at the AIDS Conference.
Volunteers who had no prior use of anabolic steroids were randomized to
nandrolone (53 volunteers) or placebo (17 volunteers). There was no detrimental
effect on CD4 or CD8 cell counts or on HIV RNA levels, and significant
increases in hemoglobin and hematocrit in the treatment group. White blood
cell counts reflected no changes. One person in the treatment arm was
diagnosed with new Kaposi's sarcoma (KS) lesions during the 12-week study;
Bucher reacted to this occurrence by suggesting that nandrolone decanoate
should be used with caution in patients with KS until larger studies determine
the relationship of anabolic steroids to KS.
Oxandrolone has been proven to be an effective oral therapy to promote
weight gain after extensive surgery, chronic infections and severe trauma,
and offsets protein catabolism associated with long- term use of corticosteroids.
Studies of the effects oxandrolone in HIV positive individuals with wasting
are planned for 1996, but the drug is FDA-approved, available and can
be prescribed now.
Interesting studies that have not been done include the combination of
one or more of the above modalities with anti-catabolic agents, such as
tamoxifen citrate (Nolvadex, Zeneca Pharmaceuticals, 60 10mg tablets at
$86.14). Anti-catabolic agents may reduce unwanted side effects of the
breakdown of testosterone into estrogen, such as gynecomastia (enlargement
of breast tissue), and may prolong the useful effects of exogenous testosterone.
Careful consideration of the effects of anti-catabolics should include
possible drug interactions, side effects, adrenal insufficiency and long
term effects on costisol production in the body. Also of interest are
drugs that are banned by Olympic Committees because of their anabolic
effects: beta 2 agonists (used in the treatment of asthma) such as clenbuterol,
terbutaline sulfate, salmeterol and salbutamol.
Mark Bowers is Managing Editor of Treatment Publications at the San
Francisco AIDS Foundation.
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Page last updated 27 September 1996
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