Recombinant Human Growth
Hormone Replacement Therapy in Adults
by Steven Grinspoon, M.D.
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
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 GH Replacement
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 1989;321:1797-1803.
- 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 1993;76:1344-1348.
- 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.