The Treatment of Growth Hormone Deficiency in Adults
Bengt-Åke Bengtsson and
Gudmundur Johannsson
Research Center for Endocrinology and Metabolism
Sahlgrenska University Hospital Sahlgrenska, S-413 45
Göteborg, Sweden
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Introduction
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ADULT GH deficiency is recognized
as a specific clinical syndrome (1). Well-controlled clinical studies
have shown that GH deficiency in adults is associated with a cluster of
cardiovascular risk factors (2). These patients have an increased
amount of body fat with an abdominal preponderance (3, 4), an increased
prevalence of hypertension (5), impaired fibrinolysis (4), glucose
intolerance (6), insulin resistance (7), and premature atherosclerosis
(6). This cluster of cardiovascular risk factors associated with GH
deficiency might explain the doubling in cardiovascular mortality
observed in hypopituitary patients (8, 9). The quality of life is
impaired, and there are data suggesting an increased prevalence of
disability pensions among these patients (10, 11). In addition, these
patients have reduced bone mineral content and density with increased
prevalence of fractures (12, 13). Randomized placebo-controlled studies
indicate that GH replacement therapy can reverse several of these
biological changes (3, 14, 15, 16, 17, 18). Although these studies have been of
relatively short duration, replacement therapy with GH in adults has
now been approved by the regulatory authorities in Europe and the
United States. The long-term experience is, however, limited.
The optimum goal for GH replacement in adults is to improve and
normalize the aberrations associated with adult GH deficiency. One
cornerstone in releasing this objective is well-defined normative
values for the efficacy measurements that are used, particularly during
more prolonged GH treatment when dose adjustment may be needed because
of increasing age. No golden standard for the monitoring of GH
treatment is available, as a specific marker of its tissue effect is
lacking.
Previous treatment trials in adult patients with GH deficiency have
used doses of GH based on body weight or body surface area, adopted
essentially from the experience of treating GH-deficient children, and
have, therefore, ignored the presence of an individual responsiveness
to GH (19). Some of these trials have reported a high frequency of side
effects, mainly associated with fluid retention (3, 17). These side
effects were more prone to occur in older patients, and in patients
with a higher body mass index (20, 21), and may explain why trials
comprising young and mostly lean adults have reported few or no side
effects (14, 22).
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GH secretion in adults
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In healthy adults, it is known that fertile women have a higher GH
secretion than young men (23) and that GH secretion is inversely
associated with increasing age and adiposity (24, 25). These factors
should be considered during GH replacement. Instead, GH dose schedules
based on body weight or surface area results in higher daily doses of
GH in subjects with higher body weight and lower for most women
compared with men.
In middle-aged women, the reported daily production of GH is about 47
µg/L x 24 h, whereas the mean production in the adult male
is 15 µg/L x 24 h. Assuming an availability of sc
administered recombinant human GH of 60%, a dose between 0.30.6 mg
(0.61.8 IU) per day should be in agreement with the physiological GH
production in adults (26), which is markedly lower than the doses of GH
used in previous trials of GH replacement in adults.
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Individual responsiveness
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A highly variable response to GH treatment in adult GH deficiency
has recently been documented. The variability was, to some extent,
explained by differences in baseline body mass index (BMI), baseline
serum levels of the GH binding protein (GHBP), age, and gender. In
response to GH treatment, patients with a high BMI experienced a lower
reduction in body fat and patients with low baseline levels of GHBP and
younger patients displayed the most marked increase in lean body mass
and lean to fat ratio (19).
An inverse relationship between the baseline concentration of GHBP and
changes in body composition in response to GH treatment is in contrast
to previous experiences in children (27), where the baseline level of
GHBP correlates positively with the response to GH administration in
terms of growth velocity and insulin-like growth factor (IGF) I
increment. The observation is, however, in line with in
vitro experiments that demonstrate a dampening effect by GHBP on
the binding of GH to cells and on the GH-dependent IGF-I production
(28, 29).
A gender difference in the response to GH treatment has been observed.
The increase in fat-free mass, total body water, and decrease in body
fat is more marked in men than in women (19, 30). In addition, men
increase their lipoprotein (Lp) (a) levels more than women (31), and
women demonstrate a more marked increase in total bone mineral density
and a less pronounced increment in bone formation and bone resorptions
markers than men in response to the GH treatment (32). This gender
difference is most probably explained by differences in interaction
between GH and estrogens and androgens, respectively.
Adult GH deficiency is not a single clinical entity because the onset
may occur during childhood (CO) or in adult life (AO). GH deficiency
occurring in children is mainly idiopathic and is recognized as growth
failure. Appropriate therapy with GH, standardized over the past
decade, is discontinued when final height is reached. Somatic
development is unlikely to be complete at this stage. Thus, height,
body weight, BMI, lean body mass, and waist to hip ratio were found to
be higher in AO than in CO GH-deficient patients. Serum IGF-I
concentration was lower in CO than in AO GH-deficient patients (19, 33). Both groups displayed significant psychosocial distress, but the
deviation from normality was greater in AO patients (33). The apparent
differences in body composition at baseline between subjects with AO
and CO GH deficiency is probably explained by the lower body height in
CO (19). Other consequences of GH deficiency have been suggested to be
more pronounced in adults with CO, particularly in terms of heart
structure and function (34, 35), muscle mass (14, 36), and bone mass
(12, 37). This may be an effect of the immediate discontinuation of GH
treatment after the final height is reached (38). Whether this
per se makes the CO patients more or less responsiveness to
GH is not known (19).
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Markers of GH action
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There is no optimal marker for long-term physiological replacement
dose of GH. It is unlikely that GH treatment can be adequately
monitored by clinical means alone. Hence, various GH-dependent
biochemical markers have been suggested, such as IGF-I. IGFs circulate
bound to specific binding proteins [IGF binding proteins (IFGBPs)],
which regulate their bioavailability and bioactivity. To date, six such
IGFBPs have been characterized. IGFBP-3 circulates in highest
concentrations and binds to 90% of circulating IGFs to form 150-kDa
ternary complexes with an acid-labile subunit (ALS) (39). Both IGFBP-3
and ALS levels are GH dependent. In a study of adult men in the age
range of 2040 yr with CO GH deficiency, the minimal dose of GH
required for normalization of serum IGF-I concentration was 0.22
mg/m2·day and 0.33 mg/m2·day for ALS and
IGFBP-3. In patients receiving 0.67 mg/m2·day, mean serum
IGF-I concentration rose to abnormally high levels, whereas at this
dose mean serum IGFBP-3 and ALS concentrations were not different from
normal. The lower sensitivity of IGFBP-3 and ALS to GH doses in the
high range was also apparent during long-term treatment (40). A dose of
0.2, 0.4, or 0.6 mg per day was used in 51 AO GH-deficient patients. In
female patients, a dose of 0.2 mg/day was insufficient to normalize
serum IGF-I after 12 weeks of treatment, whereas doses of 0.4 and 0.6
mg/day were able to normalize serum IGF-I levels in most female
GH-deficient patients. In the male patients, a dose of 0.2 IU/day was
in almost all patients sufficient to normalize serum IGF-I levels
(41).
Serum IGF-I may, however, be clinically inadequate in reflecting the GH
status of the individual patient because a substantial number of
patients with severe GH deficiency have normal serum IGF-I
concentrations (42, 43). It should also be recognized that GH delivered
by a more continuous pattern increases serum IGF-I concentration more
than a pulsatile secretion of GH (44), whereas the pulsatile pattern
may in some respects produce a more marked tissue response (45). The
usefulness of serum IGF-I is further complicated by the fact that there
is a diurnal variation during daily sc evening injections of GH,
irrespective of whether the patients have been treated for a short or
long period of time. A serum sample obtained in the morning from a
GH-deficient subject given GH in the evening would overestimate the
true 24-h integrated serum concentrations of IGF-I by about 1417%
(46). During more prolonged treatment over 2 yr, increased sensitivity
to GH was seen, as the concentration of IGF-I remained unchanged during
simultaneous 20% dose reduction of GH (20).
Changes in body composition have been a remarkable consistent finding
in all treatment trials with GH in adult GH deficiency. Assessing body
composition could, therefore, be a tool for optimizing the replacement
dose and to monitor the long-term treatment effects. Bioelectric
impedance analysis is a simple technique to assess body water. By
applying this method in young adult males with GH deficiency it was
found that an average dose of GH of 0.37 mg/m2·day
resulted in a rapid normalization of whole body resistance. Doses equal
to or higher than 0.67 mg/m2·day resulted in abnormally
low resistance, suggesting overhydration (47).
An incongruity between the normalization of serum IGF-I concentration
and body composition has been observed. In a 2-yr study, no
relationship was found between the changes in serum IGF-I concentration
and the changes in body composition (20). Moreover, in that study the
initial dose of GH was based on the patients body weight, but after
dose adjustment due to side effects and serum levels of IGF-I above the
age and sex adjusted reference values there was no relationship between
the dose of GH and body weight, indicating the importance of factors
other than body weight for the daily dose of GH.
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Individualized dose titration
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In a study of 60 adult GH-deficient patients an individualized
dose schedule was used with a low starting dose (0.17 mg or 0.33 mg per
day), independent of body weight. The dose was titrated according to
clinical response, age- and sex-adjusted reference values for serum
IGF-I, and according to age-, sex-, and body weight-adjusted reference
values for body composition. Within a year, the average GH dose
was 0.45 mg per day. Compared to a matched group receiving an
established GH dose according to body weight (12
µg/kg·day), similar mean response to GH in terms of changes in
body composition, glucose homeostasis, Lp(a) and blood pressure was
obtained in both treatment groups, with significantly fewer side
effects in the group receiving the individualized dose schedule. By
using the individualized dose schedule for GH treatment, it was found
that women were given more GH per kg of body weight than men and older
patients less GH per kg of body weight (48). This is well in accordance
with our knowledge about individual responsiveness to GH and
physiological GH secretion in healthy adults.
The previously noted incongruity between the normalization of serum
IGF-I concentration and body composition was also obvious in this trial
(48). Consequently, individualized GH doses enabled one third of the
patients to normalize both their serum IGF-I and body composition, but
overtreatment was also observed. This demonstrates the large variance
and lack of precision of an individual measurement used to monitor GH
replacement. Although several disadvantages, the normalization of serum
IGF-I concentration is probably the most useful marker of GH treatment
(40) and may better reflect overtreatment than other serum markers and
the measurement of body composition.
It has been suggested that lower doses/levels of IGF-I stimulate bone
formation more markedly than bone resorption (49). Furthermore, IGF-I
may be more potent in enhancing the formation of collagen type I and
less effective when it comes to stimulating bone resorption than GH
(50). It has, therefore, been suggested that lower doses of GH may
generate a more marked anabolic action on bone than higher doses of GH
(51). The results of measurements of serum osteocalcin and total body
bone mineral content in the trial comparing individualized GH doses
with higher doses based on body weight (48) indicate, however, that the
anabolic action on bone is no less with higher doses of GH than with
lower doses. Different baseline bone mineral density z-scores should,
however, be considered when studying the response to GH treatment in
terms of bone mineral content and bone mineral density (32).
The increased Lp(a) concentration in response to GH might be an effect
of overly high doses of GH (31, 52). However, although a lower,
individualized and probably more physiologic amount of GH is
administered, the increment in Lp(a) is similar to that in patients
with higher doses of GH (48). This suggests that the more continuous
bell-shaped pattern of GH during sc administration might be of more
importance to the increment in Lp(a) than the total amount of GH
administered (53). We know little about the importance of the time of
GH exposure in terms of responsiveness during more prolonged GH
treatment, but these aspects are important when it comes to the aim of
achieving a physiologic GH replacement.
The results of a large, long-term study (2050 months) (54) confirm
the findings of previous, shorter investigations showing that GH
replacement therapy can significantly improve many aspects of quality
of life in adults with GH deficiency (10, 17, 55). In addition, the
improvements in quality of life that occur shortly after the initiation
of GH therapy are sustained in the longer term. Indeed, it seems that
some aspects of quality of life continue to improve during long-term
therapy. Furthermore, in a retrospective analysis, almost 60% of the
patients receiving GH for 1268 months felt that their quality of life
was still improving. An important finding is that almost one third of
patients who experience beneficial effects of GH therapy state that
such effects have become noticeable only after GH had been administered
for at least 6 months. This finding has clear implications for clinical
practice: it indicates that, once the decision has been taken to
initiate GH therapy in an adult with GH deficiency, the therapy should
be continued for a minimum of 6 months, and ideally, for longer before
judgments are made regarding its efficacy in improving quality of life
and psychological well-being.
In the absence of an optimal marker for physiological replacement
therapy of GH in adults the importance of clinical judgment is
increased. To avoid side effects in the initial phase of treatment, the
value of closely monitoring clinical effects, particular in terms of
increased extracellular fluid volume becomes evident. This is because
normalization of serum levels of IGF-I does not exclude the possibility
that the GH dose is too high in an individual patient (40).
Furthermore, as stated previously, the delay until the patient clearly
experiences benefits of the treatment may be long. The patient should
be carefully informed of this and that should be considered during the
more prolonged GH replacement therapy in adults.
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Safety
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Concern has been expressed about the potential risk of development
of neoplasia during GH replacement therapy. This is based in part on
the increased risk of neoplasia in acromegalic patient. However,
experience from a long-term surveillance study in pediatric patients
(56, 57) does not show any increased risk of new or recurrent
neoplasia. However, it should be borne in mind, that in contrast to the
situation in children, GH deficiency in adults is predominantly
secondary to pituitary and peripituitary tumors and their associated
therapy.
An increased left ventricular wall thickness was observed after
42 months of GH treatment in a small number of patients. These patients
received overly high doses of GH, at least during the initial phase of
treatment (58). This indicates that the therapeutic window with GH in
terms of heart structure and function is probably not as wide as has
been thought, particularly during long-term replacement, as changes in
the myocardium may progress with prolonged GH administration. However,
direct extrapolation of data from acromegalic patients to GH-deficient
patients with GH therapy seems inappropriate, as the production rate of
GH in acromegaly by far exceeds the ordinary GH replacement dose.
Further long-term monitoring of GH-deficient adults receiving GH
substitution therapy is clearly needed.
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Summary
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In analogy with other hormonal replacement therapy GH treatment
should be commenced with a low starting dose, independent of body
weight or body surface area. Hormonal replacement should mimic the
normal physiology to minimize the risk of side effects in the life-long
replacement of adults. We should, therefore, consider individual
responsiveness and also be aware of the difference between pattern of
GH under normal condition and during sc administration. The safety and
monitoring of GH replacement therapy in adults have been addressed in
the Growth Hormone Research Society Consensus Guidelines for
Diagnosis and Treatment of Adults with GH Deficiency from the Port
Stephens Workshop, April 1997 (59). Besides finding better and more
accurate biochemical markers for choosing correct GH replacement dose,
future research should address the long-term benefits and safety with
GH replacement in adults, with special emphasize on incipient risks in
terms of cardiovascular disease (31, 58) and of neoplasia, in
particular.
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