Weight Loss: A Role for Growth Hormone and Anabolic Steroids?

Severe weight loss is a common and serious problem in people
with advanced AIDS. Its relation to mortality has long been
noted. Four years ago, an article by Donald Kotler, M.D., and
colleagues(1) described a nutritional assessment of 32
deceased AIDS patients. The investigators found that these
persons' final weight was about one-third their ideal weight.
Total body cell mass was 54 percent of normal. These results
were independent of the immediate cause of wasting, which
could be any of a number of opportunistic infections. They
suggested that maintaining body mass could prolong survival.

Obviously, the first thing to do to minimize weight loss is
to treat the underlying infections that trigger it. But
people with AIDS may not regain the weight dissipated during
acute illness. And wasting may occur without any apparent
opportunistic infection.

Karl Grunfeld, M.D., Ph.D., is an endocrinologist based at
the San Francisco Veterans Administration Medical Center who
has researched and written extensively on HIV-associated
wasting. He says "Wasting is not inevitable, but a reflection
of disease complications. People who rapidly lose weight
almost always have opportunistic infections. And two-thirds
of those with slow weight loss have gastrointestinal
disorders. Everyone with HIV should have their weight
charted, and when things change, the physician should look
very carefully at the underlying condition."

There are two therapies approved specifically for HIV-related
weight loss, Marinol (or THC, the active ingredient in
marijuana) and Megace (a progesterone analog), which are both
appetite stimulants. There also are a number of dietary
supplements, both oral and intravenous, for people with
problems absorbing enough nutrients to maintain the
heightened level of metabolic activity that occurs during HIV
infection. (See AIDS TREATMENT NEWS #133 for a review of
gastrointestinal conditions affecting nutrient intake.)

Although appetite stimulation and nutritional supplementation
are effective when the sole problem is insufficient
nutrition, in people with HIV they usually contribute added
pounds of fat, not the desperately needed protein stores in
lean tissues such as muscle.

Wasting in AIDS is not like starvation, where the body
reduces its metabolic rate and utilizes fat stores to make up
for reduced food intake. Marc Hellerstein, M.D., Ph.D., a
University of California Berkeley endocrinologist who
frequently works with Dr. Grunfeld observed, "In AIDS, and
other diseases, too, the body switches to preferring to
metabolize protein over fat. And it's hard to put lean tissue
back on just by consuming more nutrients."

As far as wasting is concerned, AIDS acts like any chronic
disease. The body mobilizes its resources to meet the needs
of emergency immune response and repair critical damaged
tissue. This response, which includes breaking down existing
cellular protein, is appropriate in the short-run but becomes
literally self-destructive when extended in reaction to a
chronic stressor like HIV.(2)

Tumor necrosis factor and a number of other immune system
activation chemicals (cytokines) as well as changes in
hormonal balance, such as increased production of
cortisol,(3) are thought to influence the shift to a wasting
mode. Researchers more and more are turning to hormone-based
therapies that overcome these basic wasting factors while, it
is hoped, leaving valuable immune activity intact.

Human Growth Hormone

Recombinant human growth hormone (rHGH) has been approved for
several years now to correct small stature in children. This
synthetic biotechnology product, which mimics the natural
hormone produced by the pituitary gland, has a two-fold mode
of action. It reduces protein breakdown and nitrogen
excretion while increasing fat metabolism. The availability
of rHGH has led to considerable research into its use in
adults to treat a wide variety of problems involving either
lean tissue loss or obesity.

Two preliminary studies published this year found that human
growth hormone triggered significant weight gain in people
with HIV wasting. The first was a University of New Mexico
trial(4) comparing high dose versus low dose rHGH in a total
of ten people with AIDS or ARC. The 12-week trial found that
weight loss was reversed in the high-dose group, with trial
participants gaining an average of 3.8 kg of lean body mass
and losing an average of 1.3 kg in fat mass. (Including extra
water retention, total average weight gain was 3.2 kg.)
Muscle power and endurance also improved significantly. Six
weeks after the trial's completion, most of these gains had
disappeared, however.

In a San Francisco trial published just last month,(5) six
HIV-positive men and six HIV-negative controls were kept in a
metabolic hospital ward for two weeks, where they were fed a
uniform, controlled diet and received rHGH for a week. In the
course of the treatment week, the HIV-positive men, who
previously had lost nearly 20 percent of their original body
weight, averaged a gain of 2.0 kg, compared to 1.6 kg in the
HIV-negative men. Protein use as fuel decreased significantly
in the HIV-positive group, while their use of fat increased
-- hopefully sparing the body's protein.

The San Francisco research group is now part of a new
national trial that involves 160 men and women at ten sites.
After an initial, placebo-controlled three-month period, all
the trial participants will receive open-label rHGH for an
indefinite period.

"The FDA is calling this study 'pivotal,'" said Morris
Schambelan, M.D., one of the study's investigators. "Besides
being of longer duration and placebo-controlled, it will
include endurance testing, better measurements of body
composition, and quality of life data." There will also be
immunological measurements -- several reports have indicated
that human growth hormone has immune-stimulating effects.
[Note: This study, sponsored by Serono Laboratories, Inc., of
Narwell, Massachusetts, is now recruiting at two sites in San
Francisco -- San Francisco General Hospital, and the VA
Medical Center -- and at eight other sites in the U.S.
Recruiting is expected to continue through 1993.]

The University of New Mexico group is now conducting one of
several studies that combine human growth hormone with
insulin-like growth factor (IGF-1). IGF-1 is produced by the
liver in response to human growth hormone. Many, but not all,
of growth hormone's effects seem to be really the result of
IGF. "We're just in the early data-gathering phase for IGF,"
said Dr. Grunfeld. "We started with growth hormone because it
has a track record. Once we get preliminary data we can try
combinations of the two in order to avoid particular side
effect profiles."

Side effects of rHGH can include swelling in the limbs, joint
stiffness and increases in blood sugar and fat levels.
Reversible carpal tunnel syndrome has been seen in people
taking high doses of rHGH. Growth hormone is also reported to
stimulate immune cell proliferation, but one group found
that, in the test tube at least, rHGH also enhanced HIV
replication.(6) For this reason, volunteers in the national
ten-site rHGH study are required to be taking AZT or a
similar antiviral medication.

Among the reported side effects of IGF are jaw tenderness and
low blood sugar. But long-term use of either of these drugs
is an uncharted area.

Anabolic Steroids

It is noteworthy that the two completed growth hormone trials
took two years to get into print after they were completed.
This was true despite the fact that rHGH and IGF are both hi-
tech, high-visibility products with very active corporate
sponsors.

As growth hormone research grinds on, alternatives exist at
the grassroots level that cost one-tenth of what rHGH does.
These are anabolic steroids, which body builders and other
athletes use to increase their muscle mass and stamina. The
anabolic steroid family includes testosterone and synthetic
derivatives with fewer androgenic (masculinizing) effects.

A number of knowledgeable AIDS specialists have been
prescribing testosterone to patients complaining of weight
reductions plus loss of libido [see the interview with Lisa
Capaldini, M.D., in AIDS TREATMENT NEWS #184]. But just
correcting the frequent mild testosterone deficiencies is
often not enough, and boosting testosterone levels above
normal can have adverse consequences, including liver
toxicities. This is where the synthetic anabolic steroids
come in.

Despite anabolic steroids' "schedule III" legal status (they
are controlled substances on the same level as aspirin-
codeine combinations), a considerable anabolic steroid lore
has accumulated in the sports world,(7) and HIV-positive body
builders have brought that information to the AIDS community.

One such bridge is Brian Chadsey, M.D., a Los Angeles
physician who is a former football player and body builder.
Chadsey has been looking at anabolic steroids' effect on HIV
wasting for eight years. He currently has almost 100 patients
using the substances. "I've had phenomenal results," said Dr.
Chadsey, "with patients commonly gaining 20 or 30 pounds.
Anabolic steroids are useful when people have unintentional
weight losses of ten percent, low testosterone levels and
decreases in daily functioning. Most doctors tell their
patients to just live with weight loss, that it's part of the
disease process. But wasting syndrome is probably an
escalating event that leads to early death." [See AIDS
TREATMENT NEWS #150 and #166 for two other physicians'
experience with anabolic steroids.]

Dr. Chadsey also reports significant improvements in his
patients' immune cell populations while on anabolic steroids.
Three-quarters of his patients witnessed rises in their CD8
(cytotoxic lymphocyte) counts and 40 percent have had
increases in CD4, or T-helper cell levels.

In Sacramento, California, Michael Dullnig, M.D., a
psychiatrist, also drew on his weightlifting past when trying
to control his own HIV-associated weight loss. Dr. Dullnig
started personally taking anabolic steroids last spring, when
a bout of mycobacterium avium left him 50 pounds below normal
weight, extremely weak, and disabled in one leg. After
following an individual regimen since May that includes
anabolic steroids, extensive use of nutritional supplements,
and a rigorous weight-training schedule, Dullnig said, "I'm
back to the way I looked before, and my energy has returned.
I feel like my life was given back to me."

Dullnig thinks that "exercise is the key. Steroids make cells
receptive to building tissue, but you need exercise to
stimulate the anabolic process. The right nutrients are also
very important. This is like another period of adolescence."
He does warn against overtraining, though. People need to pay
attention to their physical limitations. Dr. Chadsey says
that not all his patients are on exercise programs, although
those who are get better results.

The murky social and legal atmosphere surrounding anabolic
steroids makes it difficult for people with HIV to obtain the
substances or even reliable information about their proper
use. Expert supervision when using anabolic steroids is
especially important for women, who should take lower doses
than men and need to follow a regimen with little potential
for androgenic side effects.

And following an extensive exercise and food supplementation
program is an obstacle for many people who are sick and lack
stamina or digestive capacity. These are just the people who
need the most protection from wasting.

Researchers justify focusing their attention on growth
hormone because of such objections, but more clinical trials
of anabolic steroids could also provide important
information. Dr. Kotler, at St. Luke's/Roosevelt Hospital in
New York, is in a unique position in that he is conducting
separate clinical trials on both anabolic steroids and human
growth hormone. Dr. Kotler says that, although the data has
not been analyzed yet, the results of the two trials seem
similar, with about half the people showing considerable
improvement in body composition. Those who do not are people
who come down with severe opportunistic infections.
Meanwhile, no major side effects with either the anabolic
steroid (in this case oral oxandrolone) or rHGH have been
observed.

So which therapy is more appropriate? Dr. Kotler said, "We
can't tell yet whether anabolic steroids, human growth
hormone, or just testosterone replacement, is best. I don't
even know whether any of these are good long term or have
hidden side effects."

Dr. Chadsey is also looking into using growth hormone to
combat wasting. He thinks a combination of anabolic steroids
and growth hormone may be desirable. "You need some
androgenic effect to increase the reaction to growth
hormone," he said.

Future therapies may well be tailored to the individual,
based on an analysis of each person's hormonal and immune
activity as well as overall disease state. Personal tolerance
to the different therapies would be a factor, too.

Dr. Hellerstein speculated, "We may use a mixture of
approaches depending on what people need: anabolic steroids
for those with low testosterone, human growth hormone to
correct metabolic imbalances, immune modulators to balance
the immune system's effects, nutritional supplementation for
malabsorbers, plus exercise for those who are able to do it."

References

1. Kotler DP, Tierney AR, Wang J, and Pierson RN Jr.
Magnitude of body-cell-mass depletion and the timing of death
from wasting in AIDS. American Journal of Clinical Nutrition.
September 1989; volume 50, number 3, pages 444-447.

2. Grunfeld C, and Feingold KR. Metabolic disturbances and
wasting in the acquired immunodeficiency syndrome. The New
England Journal of Medicine. July 30 1992; volume 327, number
5, pages 329-337.

3. Christeff N, Gharakhanian S, Thobie N, Rozenbaum W, and
Nunez EA. Evidence for changes in adrenal and testicular
steroids during HIV infection. Journal of Acquired Immune
Deficiency Syndromes. August 1992; volume 5, number 8, pages
841-846.

4. Krentz AJ, Koster FT, Crist DM, and others.
Anthropometric, metabolic and immunological effects of
recombinant human growth hormone in AIDS and AIDS-related
complex. Journal of Acquired Immune Deficiency Syndromes.
March 1993; volume 6, number 3, pages 245-251.

5. Mulligan K, Grunfeld C, Hellerstein M and others. Anabolic
effects of recombinant human growth hormone in patients with
wasting associated with human immunodeficiency virus
infection. Journal of Clinical Endocrinology and Metabolism.
October 1993; volume 77, number 4, pages 956-962.

6. Laurence J, Grimison B, and Gonenne A. Effect of
recombinant human growth hormone on acute and chronic human
immunodeficiency virus infection in vitro. Blood. Jan 15
1992; volume 79, number 2, pages 467-72.

7. Phillips WN. Anabolic reference guide. Mile High
Publishing, Golden Colorado, 1991.