Monaldi Arch Chest Dis

2003; 59: 4, 326-330 PROCEEDINGS OF ADVANCES IN PULMONARY REHABILITATION

Appetite stimulants and anabolic hormones
J.W. Fitting
Introduction
The occurrence of weight loss with advanced
Chronic Obstructive Pulmonary Disease (COPD)
has long been recognized. This observation is clin-
ically highly relevant because a lower than normal
body weight is clearly associated with an increased
mortality in COPD, independent of the severity of
airflow limitation [1-3]. A depleted fat-free mass is
also associated with a decreased skeletal muscle
mass in COPD, and significantly contributes to ex-
ercise intolerance in these patients [4-6]. This in
part explains why nutritional depletion adversely
affects quality of life in COPD [7].
Various attempts have been made to correct the
process of malnutrition in these patients. Nutri-
tional support has been used mostly with oral liq-
uid supplements, and less frequently with enteral
nutrition. Overall, the result of nutritional support
in COPD has been disappointing: a meta-analysis
of nine randomized controlled trials identified no
significant improvement in nutritional or function-
al status [8]. In several studies, the major obstacle
was an inability to increase energy intake suffi-
ciently because of early satiety and anorexia. The
latter phenomenon has been found to be associated
with an elevated systemic inflammatory response
in patients non responding to nutritional supple-
mentation [9]. Thus, it appears logical to couple
nutritional support to other measures such as ap-
petite enhancement or anabolic stimuli.
Mechanisms of appetite control
It is well known from neuroanatomical studies
in animals that the center of weight control, and
therefore of appetite control, is located in the hypo-
thalamus. Various compounds are at play and inter-
act between peripheral organs and the hypothala-
mus. Leptin is a 167 aminoacid hormone tran-
scribed from the ob gene and synthesized by the
adipocytes. Leptin is a marker of fat mass, with loss
of body fat leading to low circulating levels, and in-
crease in adiposity leading to high levels. Leptin
plays a role in food intake, with low levels associ-
ated with increased appetite and high levels with
reduced appetite. The effects of leptin on appetite
are believed to be mediated by two other com-
pounds. Neuropeptide Y (NPY) is a 36 aminoacid
polypeptide, located mainly in hypothalamic in-
terneurons, and which is a powerful appetite stimu-
lant. As NPY synthesis is inhibited by leptin, the
level of NPY activity may well explain the effect of
leptin on food intake. Melanocyte-stimulating hor-
mone (MSH) and the hypothalamic MC-4 receptor
inhibit food intake and appear as well to mediate
the inhibitory effect of leptin on appetite [10-12].
Interactions between the gastrointestinal tract and
the central nervous system exist as well. Ghrelin is
a 28-amino acid peptide which is secreted by the
stomach and circulates in the plasma. Ghrelin se-
cretion increases during fasting and increases food
intake through a gastroprokinetic activity and an
activation of the hypothalamic NPY [13].
Anorexia, or loss of appetite, may have multi-
ple causes: food aversion, altered taste, pain, anxi-
ety, nausea, vomiting, gastrointestinal dysfunction.
Anorexia is frequent during infection and may rep-
resent a defense strategy, in particular via a re-
duced level of plasma free iron. Indeed, it has been
observed that infection is rare in iron-deficient hu-
mans and increases after treatment of iron defi-
ciency, and that mortality increases during refeed-
ing of infected humans or animals. However, pro-
longed anorexia is harmful by decreasing body fat
and protein reserves [14].
Infection and inflammation lead to loss of ap-
petite through several mechanisms involving in par-
ticular interleukin-1 (IL-1), tumor necrosis factor
(TNF-) and interleukin-6 (IL-6). Food intake
rapidly falls in an animal model of peritoneal in-
flammation. This effect is mediated by IL-1 which
stimulates the vagus nerve that extends to the nu-
cleus of solitary tract in the brainstem and which it-
self has projections to the hypothalamus areas in-
volved in appetite control. In this model, anorexia is
prevented by vagotomy. In addition to its actions
through the vagus nerve, IL-1 acts directly on the
hypothalamus by leaking from the bloodstream
through fenestrated capillaries in circumventricular
organs. The result is an inhibitory effect on NPY re-
lease and a reduced food intake. Furthermore, IL-1
reduces the secretion of ghrelin and thereby leads to
early satiety. Finally, administration of bacterial
lipopolysaccharide, of IL-1 or of TNF- increases
circulating leptin in animals and in humans which
contributes to loss of appetite [14, 15].
The role of leptin in COPD has received atten-
tion in recent years. Takabatake et al. [16] report-
ed that circulating leptin was correlated to body
Service de Pneumologie; Centre Hospitalier Universitaire Vaudois; Lausanne; Switzerland.
Correspondence: Prof. J.W. Fitting; Service de Pneumologie; CHUV; 1011 Lausanne; Switzerland; e-mail: jfitting@chuv.hospvd.ch
Monaldi Arch Chest Dis 2003; 59: 4, 326-330.
327
APPETITE STIMULANTS AND ANABOLIC HORMONES
mass index (BMI) and to fat mass in COPD pa-
tients and that this relation did not differ from that
of normal subjects. Leptin levels did not correlate
to serum TNF- or to soluble TNF receptors, sug-
gesting that leptin was not regulated by the TNF
system. In contrast, Schols et al. [17] observed that
leptin levels adjusted for fat mass and corticos-
teroid use were correlated to levels of soluble TNF
receptor (sTNF-R55) in patients with emphysema.
Moreover, leptin concentration was inversely re-
lated to dietary intake and to weight change after
nutritional supplementation. The same group then
reported that leptin was increased at admission for
an exacerbation of COPD, and gradually de-
creased in one week. At day 7, leptin levels were
correlated with circulating sTNF-R55 and were in-
versely correlated with caloric intake [18]. These
observations suggest that leptin is regulated by the
inflammatory response in COPD and may play a
role in the cachexia experienced by some patients.
Appetite stimulants
Several pharmacological agents have been
studied to treat the anorexia-cachexia syndrome
associated with cancer and with AIDS, but only
one was assessed to treat wasting in respiratory
diseases.
Progestins
Megestrol acetate (MA) and medroxyproges-
terone (MPA) are synthetic, orally active deriva-
tives of progesterone. They have an orexigenic ef-
fect in humans which is thought to be mediated by
a stimulation of NPY and by an inhibition of syn-
thesis of IL-1, IL-6 and TNF- [19]. A meta-
analysis of 15 randomized controlled trials in can-
cer cachexia concluded that MA (160-1600
mg/day) and MPA (300-1000 mg/day) have a fa-
vorable effect on appetite and weight gain [20].
However, weight gain has been attributed mainly
to an increase of fat mass and has not been associ-
ated with a functional improvement (19). A posi-
tive effect of MA on body weight was found as
well in Acquired Immuno-deficiency syndrome
(AIDS) -related cachexia [21].
The effect of MA on stable patients with
COPD was first reported in a Chinese journal. Qin
et al. [22] randomized 31 patients to receive either
MA 160 mg/day or no treatment. After two weeks,
the MA treated group showed an increase in
caloric and protein intake, an increase in body
weight, an increase in maximal inspiratory pres-
sure (PImax) and maximal expiratory pressure
(PEmax), and an increase in the 6-minute walking
distance. None of these variables changed signifi-
cantly in the control group. Weisberg et al. [23]
studied the effects of MA on a larger group of
COPD patients in a controlled trial. A group of 145
underweight patients was randomized to receive
either MA 800 mg/day or placebo for 8 weeks. The
MA treated patients showed a weight gain of 3 kg
in 8 weeks which was entirely due to an increase
in fat mass. No benefit was observed for PImax, 6
min walking distance, dyspnea or quality of life,
but the patients expressed satisfaction with regard
to their appetite, weight change and appearance.
The MA treated group manifested a marked fall in
serum testosterone levels, but the active free
testosterone was not measured. Besides, a stimu-
lant effect was noted on ventilation with a 4.5 mm
Hg fall of PaCO
2
and a corresponding increase of
PaO
2
. Thus, MA alone improves appetite, body
weight and image, but not functional status in
COPD patients. The combination of MA with an
anabolic stimulus like exercise or anabolic hor-
mones may be of interest [23].
Side effects of high dose progestins include a
withdrawal of menstrual bleeding, a reversible im-
potence in 10% of male patients, a glucocorticoid
activity, an adrenal insufficiency on abrupt with-
drawal of the drug, and an increased risk of throm-
boembolism.
Cannabinoids
Cannabis and its derivatives are known to in-
crease appetite. The postulated mechanisms are an
inhibition of IL-1 synthesis, an inhibition of
prostaglandin synthesis, and an interaction with
endorphin receptors. The agent dronabinol (-9
tetrahydrocannabinol), 5-7.5 mg/day, has been
shown to increase appetite and to reduce weight
loss in patients with cancer or with AIDS. The ef-
fect was however less than with megestrol. Side
effects including dizziness and confusion occur in
20% of patients [19, 21, 24].
Thalidomide
Thalidomide is a synthetic derivative of glu-
tamic acid. This agent was introduced as an
antiemetic for pregnant women in the 1950s and
was withdrawn because of a high risk of severe
teratogenesis. Despite this disaster, thalidomide re-
ceived renewed attention because of its im-
munomodulatory properties. In particular, this
drug inhibits production of TNF-, IL-6, interfer-
on-, and adhesion molecules. These mechanisms
probably explain the favorable effect of thalido-
mide on nausea, anorexia and weight loss in pa-
tients with cancer or with AIDS [24, 25].
Anabolic hormones
Growth hormone
Growth hormone (GH) is synthesized by the
antehypophysis and plays a major role in growth
of all tissues. Its anabolic effect on muscle is both
direct and indirect through insulin-like growth fac-
tor 1 (IGF-1), a polypeptide secreted by the liver.
Recombinant human growth hormone (rhGH) is
used for replacement therapy in GH deficient pa-
tients. Administered at physiological doses (0.07
IU/kg/day) for 6 months, rhGH increases fat-free
mass, muscle mass, muscle strength and peak oxy-
gen uptake. Because plasma levels of IGF-1 di-
minish with age, administration of rhGH was at-
328
J.W. FITTING
tempted to reverse the loss of muscle mass. In tri-
als lasting from one week to 6 months, administra-
tion of rhGH increased nitrogen balance, body
weight and fat-free mass. However, no benefit was
obtained in muscle strength or in peak oxygen up-
take [26, 27].
The administration of rhGH has been attempt-
ed to accelerate the weaning process of patients
treated by mechanical ventilation in the ICU.
Pichard et al. [28] studied 20 patients (11 with
COPD) receiving prolonged mechanical ventila-
tion for acute respiratory failure. The administra-
tion of a high dose of rhGH (0.43 IU/kg/day) for
12 days led to a marked improvement in nitrogen
balance, but without any effect on muscle strength
tested by electrical stimulation. Moreover, the
number of hours of mechanical ventilation and the
number of successful weaning attempts were sim-
ilar in the treated group and in the placebo group.
The same authors later reported a case study show-
ing a beneficial effect of 10 weeks of rhGH treat-
ment in a severely malnourished patient waiting on
long-term noninvasive ventilation for a lung trans-
plantation [29].
Several trials of rhGH have been published in
patients with stable COPD. Suchner et al. [30] ad-
ministered rhGH to 6 wasted COPD patients for 8
days. They observed an increased nitrogen bal-
ance, an increased resting metabolic rate, but no
change in PImax, PEmax, or in handgrip strength.
In an uncontrolled trial, Pape et al. [31] treated 7
underweight COPD patients, whose mean body
weight was 78% of ideal body weight (IBW), with
rhGH 0.15 IU/kg/day for 3 weeks. They reported
an increased nitrogen balance, a weight gain of 2.2
kg and a 27% increase of PImax.
In order to confirm a possible favorable effect
of rhGH, we conducted a randomized controlled
trial using the same dosage and duration [32]. Six-
teen underweight COPD patients were studied dur-
ing a 3-week inpatient rehabilitation program.
Their mean Forced Expiratory Volume in one sec-
ond (FEV
1
) was 39% of predicted and their mean
body weight was 77% of IBW. Daily, 8 patients re-
ceived injections of rhGH 0.15 IU/kg and 8 re-
ceived saline. Measures were performed at day 0,
after 3 weeks of treatment, and 2 months after the
end of treatment. After 3 weeks of treatment, lean
body mass increased more in the rhGH group
(+2.3 kg) than in the placebo group (+1.1. kg) and
this difference was still present two months later
(rhGH: + 1.9 kg; placebo: + 0.7 kg). However, PI-
max, PEmax and handgrip strength increased sim-
ilarly in the two groups. Peak oxygen uptake was
unchanged, whereas the 6 minute walking distance
decreased by 13% in the rhGH group and in-
creased by 10% in the placebo group. This unfa-
vorable effect could be due to changes in metabol-
ic rate. In the rhGH group, resting energy expendi-
ture increased by 8% at the end of treatment and
fell back to baseline two months later. This hyper-
metabolism induced by the administration of rhGH
increases the CO
2
load and may well explain the
adverse effect on exercise tolerance. In a prelimi-
nary report of a controlled trial, Casaburi et al.
[33] observed as well a gain of lean body mass
without functional improvement after 6 weeks of
rhGH in patients with severe COPD.
In summary, these studies show that rhGH in-
creases lean body mass but not muscular perfor-
mance in patients with COPD. It is possible that
rhGH favors production of non muscle proteins. It
is also interesting to note observations made in
competitive athletes: during high level training, the
administration of rhGH increases lean body mass,
but not the muscle size or strength. It appears that
intense physical training induces a maximal ana-
bolic effect through autocrine and paracrine effects
of muscle IGF-1, and that increasing circulating
IGF-1 through administration of rhGH provides no
further gain [34]. Finally, high dose rhGH induces
side effects like oedema, arthralgia, myalgia, hy-
perglycemia, and hypermetabolism. In view of its
high cost, rhGH does not represent a strategy of
choice to correct malnutrition in COPD.
Androgen hormones
Testosterone is the male sexual hormone pro-
duced by the testis (2.5-11 mg/day) and in small
amount by the ovary (0.25 mg/day). Besides its
virilizing action, testosterone has a marked anabol-
ic effect on skeletal muscle. Serum testosterone
levels decrease physiologically with advancing
age. However, patients with COPD often manifest
an abnormally low testosterone level due to sec-
ondary or less frequently to primary hypogo-
nadism. The contributing factors appear to be in-
creasing age, hypoxemia, and glucocorticosteroid
therapy [35-38]. The oral or parenteral administra-
tion of pure testosterone is inefficient because the
hormone is rapidly degraded. Different forms of
modified testosterone have been developed with a
markedly delayed catabolism. Further anabolic
steroid agents have also been synthesized with a
slightly lesser androgenic effect.
Schols et al. [39] reported the effects of 8
weeks of nutritional support and nandrolone in 217
COPD patients undergoing a rehabilitation pro-
gram. Patients were randomized either to a group
receiving nutritional support (N), to a group re-
ceiving nutritional support and nandrolone (N+A)
(every other week 50 mg in men, and 25 mg in
women), or to a group receiving a placebo (P).
Among the patients with nutritional depletion, fat-
free mass increased by 1.9 kg in groups N and
N+A, whereas it decreased by 0.6 kg in the group
P. Among nondepleted patients, fat-free mass in-
creased only in the N+A group (+1.4 kg). An in-
crease in PImax was observed in groups N and
N+A, however this change was small (<1 kPa) and
was not different between groups N and N+A. Fi-
nally, the 12 min walking distance increased simi-
larly in the three groups.
Martins-Ferreira et al. [40] studied 17 under-
weight COPD patients. The protocol lasted 6
months according to the following schedule: no
exercise during the first two months, inspiratory
muscle training during the following two months,
inspiratory muscle training and general exercise
329
APPETITE STIMULANTS AND ANABOLIC HORMONES
training during the last two months. The patients
were randomized either to a group receiving ana-
bolic steroids (A) (testosterone 250 mg once at
baseline and then stanozol 12 mg/day) or to a
group receiving a placebo (P). Lean body mass in-
creased by 2 kg in the group A and remained un-
changed in the group P. A similar increase of PI-
max was noted in the two groups, whereas the 6
min walking distance and the peak oxygen uptake
remained unchanged.
Finally, Casaburi et al. [41] assessed the rela-
tive effects of exercise training and of testosterone
supplementation in 40 COPD patients. The pa-
tients were randomized to 10 weeks of either
placebo (P), placebo and exercise (P+E), testos-
terone 100 mg/week (T), or testosterone 100
mg/week and exercise (T+E). Leg lean mass in-
creased by 3.4% with P+E, by 5.9% with T, and by
8.7% with T+E. Leg strength increased by 18%
with P+E, by 13% with T, and by 29% with T+E.
Strength training and testosterone supplementation
had additive effects on muscle mass and strength
in these patients. Thus, androgen hormones, in
particular testosterone, appear promising in COPD
patients who frequently manifest hypogonadism.
Several studies attest the safety of testosterone ad-
ministered at replacement doses.
In conclusion, the nutritional depletion devel-
oping in COPD appears to be multifactorial:
anorexia, inflammation, low anabolic hormones. It
is conceivable that therapy should combine differ-
ent anabolic stimuli like appetite stimulants, im-
munomodulation, anabolic hormones, nutritional
supplementation and exercise training, based on an
individualized prescription.
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