Recombinant Human Growth
Hormone Replacement Therapy in Adults
by Steven Grinspoon, M.D.
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Acquired growth hormone (GH) deficiency
results from the destruction of normal pituitary and/or hypothalamic
tissue, usually from a tumor or secondary to surgical and/or
radiation therapy. Diagnostic criteria and clinical sequelae
of GH deficiency, although well established in children, are
currently areas of active investigation in the adult. It is
now apparent that acquired GH deficiency is associated with
significant changes in body composition, bone density, lipid
metabolism, cardiovascular function and physical performance.
In addition, new information is now available on the use of
low doses of recombinant human growth hormone (rhGH) to reverse
the sequelae of GH deficiency in adults.
The Growth Hormone Deficiency
Acquired GH deficiency is characterized
by weight gain, increased fat mass and decreased lean body mass.
In one recent study, total body fat was shown to be increased
by 7% in this population while lean body mass was decreased
to a similar degree (1). The increased fat mass is found in
a truncal distribution, thereby increasing the waist:hip ratio.
In addition, triglyceride levels are increased and HDL levels
decreased. The increased lipid levels may explain, in part,
the observation of increased vascular wall thickness, as measured
by carotid ultrasonography, in this population. These factors
all likely contribute to the increased incidence of cardiovascular
mortality seen in patients with GH deficiency (2).
Muscle mass and muscle strength
are diminished in GH-deficient patients. In the heart, these
changes are manifested by a reduced left ventricular mass, decreased
fractional shortening of cardiac myocytes, and decreased cardiac
output. Such abnormalities may contribute to the striking decline
in exercise capacity in this population. In one recent study,
exercise capacity, as assessed by cycle ergometry was decreased
by 20-25% compared to normal controls (3). Bone density is also
known to be reduced in the GH-deficient patient. In a recent
study, cortical bone density and spinal (trabecular) bone density
were 2.8 and 1.5 standard deviations below the mean for age
and sex matched controls (4).
Finally, patients with GH deficiency
appear to have impaired psychological well being and potentially
significant neuropsychiatric manifestations, such as lack of
concentration and memory impairment. Self rating questionnaires
consistently demonstrate reduced vitality, fatigue, social isolation
and depression (5). However, it is unknown whether this impairment
in psychological well being is associated specifically with
GH deficiency or is due to another factor associated with hypopituitarism.
Recombinant Human Growth Hormone
Recombinant human growth hormone
may become a novel therapeutic option for adults with acquired
GH deficiency. Recent studies indicate that many of the metabolic
and psychological abnormalities associated with GH deficiency
can be reversed with GH replacement, even at low doses which
are not associated with side effects.
GH therapy results in profound
changes in body composition: fat mass is reduced while lean
body mass increases. Growth hormone, at the relatively low dose
of 0.003 mg/kg was shown to normalize lean body mass over 6
months in 24 adults with GH deficiency (1). The improvement
in lean body mass is associated with increased protein synthesis,
muscle mass and muscle function. Total body fat mass also decreases
after 6 months of GH administration. The decline in fat mass
is most significant in visceral and trunk locations as compared
to the arms, neck and legs, suggesting that GH replacement therapy
will reverse the truncal redistribution of fat mass associated
with GH deficiency and impact on cardiovascular risk (6).
GH replacement in adults may have
a beneficial effect on lipids. In a recent study, it was reported
that short courses of GH reduced LDL cholesterol and this reduction
correlated with increased mRNA expression of the LDL receptor
in the liver (7). The potential benefit of this interaction
has yet to be investigated in longer term clinical trials, but
it must be noted that dramatic changes in serum lipid levels
are not consistently seen with GH administration.
The potential role of GH in the
maintenance of the skeleton has recently been investigated.
GH is known to stimulate osteoblast proliferation and thymidine
incorporation in vitro. Furthermore, GH stimulates systemic
and local production of Insulin Like Growth Factor I, another
known bone mitogen. In a recent study, GH replacement was shown
to increase significantly bone Gla-protein, a sensitive indicator
of osteoblast function (8). Less consistent changes in bone
density have been demonstrated with GH administration. However,
in a recent study using the sensitive techniques of quantitative
tomography and single photon absorptiometry, significant increases
of 5% and 4% were demonstrated in spinal and cortical bone density
over 12 months of therapy in GH-deficient adults (4). It thus
appears that GH administration may act to reverse the osteopenia
present in the GH-deficient patient.
Improvements in exercise capacity
and cardiac function have been demonstrated among GH-deficient
patients receiving GH replacement in several recent studies.
Such patients show increased oxygen uptake and power output
during cycle ergometry associated with increased skeletal muscle
mass and improved cardiac function. Echocardiography has shown
that left ventricular mass index, fractional shortening and
fiber shortening velocity all improve after 6 months of low
dose GH therapy (8).
Side Effects Associated with Low-Dose
The dose of rhGH is an important
consideration in the therapy of acquired GH-deficiency. Large,
pharmacological doses of GH are often associated with the clinical
sequelae of GH excess, including fluid retention and hypertension.
However, increasingly smaller, physiological, doses of rhGH
are currently being used for replacement in GH- deficient patients
without such sequelae. At a dose of 0.03 mg/kg/week, Bengtsson
et al. demonstrated only minor side effects including fluid
retention and mild arthralgias in the majority of patients but
did report carpal tunnel syndrome in one patient (6). In all
cases, further reduction of the GH dosage resulted in amelioration
of side effects. In another recent study in which a smaller
dose of GH was used, 0.01 mg/kg was administered three times
per week without any reported side effects (8). It remains unknown,
however, whether chronic administration of GH at doses which
keep IGF-I levels within the normal range will also improve
key metabolic variables.
Growth hormone deficiency is an
important cause of excess morbidity and even mortality. Evidence
from a number of smaller studies indicates that GH replacement
will improve body composition, lipid metabolism, bone density,
cardiovascular function and psychological well being. Important
issues remaining are the precise clinical definition of partial
vs. complete GH deficiency in such patients and clarifying the
best tests to make this diagnosis. In addition, it is unclear
whether some of the observed beneficial effects reflect pharmacological
GH therapy rather than physiologic GH replacement. Nevertheless,
it is apparent that small doses, unassociated with sequelae
of GH excess, may suffice to achieve the desired metabolic results.
Definitive recommendations on dosage and the long term effects
of GH therapy, particularly on cardiovascular morbidity and
mortality, will be determined by the prospective studies now
underway at the MGH and other centers around the country.
- Salomon F, Cuneo RC, Hesp R
et al. The Effects of Treatment with Recombinant Human Growth
Hormone on Body Composition and Metabolism in Adults with
Growth Hormone Deficiency. New England Journal of Medicine
- Bengtsson BA. The Consequences
of Growth Hormone Deficiency in Adults. Acta Endocrinologica
1993;128 (Suppl 2):2-5.
- Cuneo RC, Salomon F, Wiles CM
et al. Growth Hormone Treatment in Growth Hormone Deficient
Adults. II. Effects on Exercise Performance. Journal of Applied
- O'Halloran DJ, Tsatsoulis A,
Whitehouse RW et al. Increased Bone Density after Recombinant
Human Growth Hormone (GH) Therapy in Adults with Isolated
GH Deficiency. Journal of Clinical Endocrinology and Metabolism
- McGauley GA, Cuneo RC, Salomon
F et al. Psychological Well-Being Before and After Growth
Hormone Treatment in Adults with Growth Hormone Deficiency.
Hormone Research 1990;33 (suppl 4):52-54.
- Bengtsson BA, Eden S, Lonn L
et al. Treatment of Adults with Growth Hormone (GH) Deficiency
with Recombinant Human GH. Journal of Clinical Endocrinology
and Metabolism 1993;76;309-317.
- Johnston DG, Bengtsson BA. Workshop
Report: the Effects of Growth Hormone and Growth Hormone Deficiency
on Lipids and the Cardiovascular System. Acta Endocrinologica
1993;128 (Suppl 2): 69-70.
- Amato G, Carella C, Fazio S
et al. Body Composition, Bone Metabolism, and Heart Structure
and Function in Growth Hormone (GH)-Deficient Adults Before
and After GH Replacement Therapy at Low Doses. Journal of
Clinical Endocrinology and Metabolism 1993;77:1671-1676.
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