Endocrine Reviews 22 (4): 425-450
Copyright © 2001 by The Endocrine Society
Optimizing GH Therapy in Adults and Children
W. M. Drake,
S. J. Howell,
J. P. Monson and
S. M. Shalet
Departments of Endocrinology, St. Bartholomews Hospital, London
EC1A 7BE, United Kingdom; and Christie Hospital, Manchester, United
Kingdom
Correspondence: Address all correspondence and requests for reprints to: Dr. W. M. Drake, Department of Endocrinology, St. Bartholomews Hospital, West Smithfield, London EC1A 7BE, United Kingdom. E-mail:
w.m.drake{at}mds.qmw.ac.uk
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Abstract
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Until the advent of modern neuroradiological imaging techniques in
1989, a diagnosis of GH deficiency in adults carried little
significance other than as a marker of hypothalamo-pituitary disease.
The relatively recent recognition of a characteristic clinical syndrome
associated with failure of spontaneous GH secretion and the potential
reversal of many of its features with recombinant human GH has prompted
a closer examination of the physiological role of GH after linear
growth is complete. The safe clinical practice of GH replacement
demands a method of judging overall GH status, but there is no
biological marker in adults that is the equivalent of linear growth in
a child by which to judge the efficacy of GH replacement. Assessment of
optimal GH replacement is made difficult by the apparent diverse
actions of GH in health, concern about the avoidance of iatrogenic
acromegaly, and the growing realization that an individuals risk of
developing certain cancers may, at least in part, be influenced by
cumulative exposure to the chief mediator of GH action, IGF-I. As in
all areas of clinical practice, strategies and protocols vary between
centers, but most physicians experienced in the management of pituitary
disease agree that GH is most appropriately begun at low doses,
building up slowly to the final maintenance dose. This, in turn, is
best determined by a combination of clinical response and measurement
of serum IGF-I, avoiding supraphysiological levels of this GH-dependent
peptide. Numerous studies have helped define the optimum management of
GH replacement during childhood. The recent requirement to measure and
monitor GH status in adult life has called into question the
appropriateness of simplistic weight- and surface area-based dosing
regimens for the management of GH deficiency in childhood, with
reliance on linear growth as the sole marker of GH action. It is clear
that the monitoring of parameters other than linear growth to help
refine GH therapy should now be incorporated into childhood GH
treatment protocols. Further research will be required to define the
optimal management of the transition from pediatric to adult GH
replacement; this transition will only be possible once the benefits of
GH in mature adults are defined and accepted by pediatric and adult
endocrinologists alike.
I. Introduction
II. Physiology of GH Secretion and Action
A. Changes in GH and IGF-I levels with age
III. Pharmacokinetics of Administered GH
IV. Review of Pediatric Practice
A. Diagnosis of GHD and patient selection
B. GH treatment: dose and schedule
C. Puberty
D. Side effects of GH therapy
E. Predictors of response to therapy
V. Adult GH Replacement: Historical Perspective
VI. Rationale and Strategies for GH Replacement in Adults
VII. Tolerability
VIII. Clinical Response to GH Replacement
A. Body composition
B. Quality of life and well-being
C. Bone density and bone remodeling
D. Cardiovascular risk factors and cardiac structure and function
E. Conclusions
IX. Is Overtreatment Acceptable in the Asymptomatic Patient?
X. Biochemical Monitoring of GH Replacement
XI. Gender Differences in GH Responsiveness
XII. Adult GHD and Vascular Disease
A. GH replacement therapy and dyslipidemia
XIII. Alternative Mechanisms for Accelerated Vascular Disease
XIV. Transition from Pediatric to Adult Clinic
XV. Effects of Discontinuation of GH Treatment at Final Height
A. Body composition
B. Bone mineral density
XVI. Dosing Strategies for the Adolescent Patient
XVII. Influence of Adult GH Replacement Studies on Pediatric Practice:
Reevaluation of Pediatric Practice
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I. Introduction
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IT IS NOW more than a decade since the publication of the
earliest double-blind placebo-controlled studies of the use of
recombinant human GH (rhGH) in patients with adult-onset (AO) GH
deficiency (GHD) (1, 2, 3, 4, 5). In the intervening years,
increasing attention has been devoted to devising treatment protocols
that maximize the potential clinical benefit of treatment with GH,
while trying to minimize the risks that may result from prolonged
excessive GH exposure. In the original trials of GH replacement therapy
for adult hypopituitarism, GH dose was calculated on the basis of
weight and/or surface area (1, 2, 3, 4, 5). This was essentially
done as an extension of pediatric practice, as there was little or no
experience of GH therapy outside the pediatric setting at that time.
With time and shared clinical experience, it has become apparent that
such a dosing strategy was too simplistic and that the dose of GH needs
to be individually tailored for each patient (6, 7). In
retrospect, this was predictable, given that all other endocrine
replacement therapy needs to be carefully adjusted for each patient,
reflecting the wide variation in secretion and/or clearance rates, of
glucocorticoids, thyroid hormone, and gonadal steroids in healthy
subjects. Paradoxically, it is the increasing use of GH for the
treatment of AO hypopituitarism that has led to a more thorough
examination of the physiological role of GH after the completion of
linear growth. Inevitably, the recent experience in adult clinical
practice has prompted a critical reevaluation of the strategies used
for the management of GHD in childhood. This article will review the
current clinical practice of GH therapy for the attainment of final
height in children. It will then discuss methods of GH dosing in adults
with specific reference to our current state of knowledge about the
normal physiology of GH secretion and action after the completion of
linear growth. The issues that surround reassessment of GH status in
GHD children once final height has been achieved and the decision as to
whether to continue with GH therapy in this patient group will also be
reviewed. The article will conclude by examining, in the light of
recent clinical experience in GH dosing for adults, whether the time
has come for a closer examination of GH dosing strategies used in
pediatric clinical practice.
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II. Physiology of GH Secretion and Action
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In any discussion about optimizing GH dosing schedules, it is
important to remember that reproduction of normal physiological
patterns of GH secretion and action is limited by available modes and
routes of administration of exogenous GH. Hence, as with other forms of
endocrine replacement therapy (such as glucocorticoid replacement for
patients with primary or secondary adrenal failure), the aims of the
treating physician are limited to a maximization of clinical benefit
while minimizing the risks of excessive exposure.
GH is released from anterior pituitary somatotrope cells in a pulsatile
fashion, with surges of GH release punctuating long periods when GH
levels in plasma are very low and detectable only by sensitive
chemiluminescence assays (8) (Fig. 1B
). GH release, in turn, is stimulated
by GHRH and inhibited by somatostatin (SST), both of which are produced
by the hypothalamus (for review see Ref. 9). A separate
receptor exists, the GH secretagogue receptor (10), the
ligand for which (Ghrelin) has recently been cloned
(11). The details of the neuroendocrine mechanisms by
which these various inputs interact to regulate GH release, and in
particular the precise role of Ghrelin, are not fully elucidated, but
the simplest model postulates that a simultaneous drop in SST tone,
together with bursts of GHRH secretion, is responsible for the
generation of a GH pulse (12).

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Figure 1. Plasma time-curve for GH 1.2 IU given by injection
to an adult with GHD (a) compared with the physiological pattern of GH
secretion in a healthy middle-aged male (b). [Courtesy of Dr. Y.
Janssen, personal communication].
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GH is a 191-single polypeptide chain that exists in the circulation
partially bound to two separate GH binding proteins (GHBPs), one of
high (13) and one of lower affinity (14). The
higher affinity GHBP is the extracellular portion of the GH receptor,
two of which bind to different regions of the GH molecule, with
subsequent dimerization triggering GH-mediated cellular activation
(15). Although it is believed that levels of GHBP in the
circulation may be an indicator of the number and/or activity of GH
receptors, a major negative determinant of GH-BP levels in health is
abdominal obesity (16). This has obvious implications for
GH dose selection and monitoring, because the bioactivity of the same
dose of GH given to two people of equivalent age, sex, and gonadal
status will depend, at least in part, on their respective degrees of
visceral obesity.
The GH secretory pattern, hepatic GH receptors, and circulating GHBP
levels are closely interrelated. In the rat, linear growth is most
sensitive to pulsatile GH exposure and peak amplitude, whereas GHBP and
hepatic GH receptor levels are regulated separately by the level of
continuous GH baseline exposure (17). As in rats, baseline
GH levels are higher in females than males (18, 19, 20, 21),
although the magnitude is less apparent. Short-term comparisons of
continuous vs. pulsatile GH treatment in man have so far
revealed only minor differences in metabolic parameters (22, 23), but longer treatment in GH-deficient children shows
induction of GHBP after continuous, but not pulsatile, GH treatment
(24). It has been suggested that the GH pattern is
important for growth in man, since increasing the frequency of GH
therapy to daily injections improves its growth-promoting effect
(25, 26, 27), although in the short term once daily
subcutaneous injections stimulated growth equally well as continuous
subcutaneous infusion in GH-deficient children (24).
GH has some direct effects on peripheral tissues, most notably
epiphyseal chondrocytes (28), but the majority of its
actions are mediated through the peptide hormone insulin-like growth
factor-I (IGF-I), a member of the insulin-like gene family. Almost all
IGF-I in the circulation is bound to one of several IGF binding
proteins (IGFBPs), the most abundant of which is IGFBP-3. Together with
the acid-labile subunit (ALS), IGF-I and IGFBP-3 (levels of which are
all GH dependent) form a ternary complex of 150 kDa. This prolongs the
half-life of circulating IGF-I and ensures that levels in a given
individual remain stable throughout the day. However, the simplistic
use of serum IGF-I measurements as a precise marker of overall GH
status is flawed because of the many variables that affect both hepatic
and local tissue IGF-I production in response to a given GH stimulus.
Most strikingly, GH-mediated IGF-I production varies with gender.
Analysis of 24-h GH profiles in normal weight, middle-aged, healthy
volunteers shows that to maintain an equivalent serum IGF-I level, mean
daily production is approximately 3 times greater in women than in men,
due largely to an amplitude-specific divergence in the pulsatile mode
of GH secretion (29). Most circulating IGF-I is derived
from the liver, but it is also generated in nonhepatic tissues where it
appears to function in an autocrine/paracrine fashion
(30). IGF-I generation in response to a given GH stimulus
may be modulated by local tissue-specific factors, of which gonadal
steroids are an important example. Testosterone administration to
normal men and those with hypogonadotropic hypogonadism increases serum
IGF-I levels, while oral estrogen therapy improves the signs and
symptoms of acromegaly (31) and lowers serum IGF-I levels
in normal postmenopausal women (32). Furthermore,
estrogens have different effects on GH secretion and action depending
on the route of administration. Oral ethinyl estradiol attenuates IGF-I
production despite a 3-fold increase in mean 24-h GH, whereas
transdermal 17ß-estradiol does not alter overall GH secretion but
causes a slight increase in circulating IGF-I (33, 34).
Such changes are almost certainly physiologically important, on the
basis of changes in markers of connective and bone tissue activity that
parallel the changes in serum IGF-I levels (35).
As with other hormonal systems, GH, IGF-I, and the hypothalamic
peptides SST and GHRH form a complex feedback system at various levels.
For example, exogenous GH administration attenuates the size of
subsequent GHRH-mediated GH secretion, apparently independently of
circulating IGF-I levels (9, 36), and there is evidence
that hypothalamic GH receptor expression is suppressed by GH
(37). There are also data to suggest feedback regulation
of GH secretion by IGF-I (38).
A. Changes in GH and IGF-I levels with age
GH secretion continues throughout life (39, 40) and
this, together with the clinical features of adult GH deficiency and
the observed favorable effects of GH on hypopituitary patients, forms a
persuasive argument that GH may have important physiological functions
after the completion of linear growth. Rates of GH secretion increase
with the onset of sexual maturation, reaching approximately 23 times
their prepubertal levels by mid-late puberty (39, 40).
Thereafter, GH secretion rates decline by approximately 14%, and the
half-life of GH shortens by 6% with each passing decade (39, 40). The reasons for this fall are not entirely clear, although
a reduction in responsiveness to injected GHRH and an increase in SST
have been documented in vivo in the rat (41, 42). In humans, repetitive administration of GHRH to elderly men
partially reverses the age-related decline in responsiveness to this
peptide (43), suggesting that failure of hypothalamic GHRH
release may, at least in part, underlie the age-related fall in
spontaneous GH secretion. Furthermore, concurrent with the suggestion
that SST is increased in older individuals, coadministration of
arginine enhances the GH-releasing activity of a GH-releasing
hexapeptide in healthy elderly, but not young, subjects
(44). These age-related changes in GH secretion are
largely paralleled by a decline in serum IGF-I levels in both men and
women (45). However, the positive relationship between
serum IGF-I and spontaneous 24-h GH secretion becomes less striking
with age (46). This may, in part, reflect increasing
obesity with advancing years. An inverse correlation has been
demonstrated between adiposity and plasma IGF-I levels (47, 48), although separation of this from the known effects of
obesity on GH secretion (40) is difficult.
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III. Pharmacokinetics of Administered GH
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rhGH is almost universally administered subcutaneously (Fig. 1A
).
Most studies report the time to reach peak level
(Cmax) is around 46 h after an injection, with
a length of disappearance of 2024 h (49, 50); these
figures correlate well with the kinetics of insulin absorption in
patients with diabetes (51). Studies comparing the
bioavailability of GH by continuous infusion and bolus injection show
significantly lower GH levels with subcutaneous administration compared
with intravenous, suggesting a degree of local subcutaneous degradation
(52, 53). The volume of injection may also be important.
Injection of 6 IU GH in three separate volumes on separate occasions to
normal individuals showed that the use of a larger volume resulted in a
higher Cmax and a greater area under the curve,
implying greater overall bioavailability (54).
It is apparent, therefore, that the GH/IGF-I system, like other
endocrine systems, is a dynamic one, the activity of which changes with
age, sexual maturation, body composition, and other factors. Clearly,
it is not possible to recreate normal physiology with a single
subcutaneous injection of GH, so the goal of treatment of GHD is
correction of the associated clinical syndrome. In children, failure of
linear growth is an almost universal presenting feature, whereas in
adults the diagnosis of GHD almost invariably is made in patients with
a background of known hypothalamo-pituitary disease.
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IV. Review of Pediatric Practice
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GH deficiency during childhood is associated with severe growth
retardation resulting in marked impairment of adult height. GH therapy
for GH-deficient children was first used in the 1950s with hormone
extracted from the pituitary glands of cadavers (55).
Because of the limited supply, suboptimal doses of pituitary GH were
administered initially in a standard fixed dose, independent of size,
two to three times weekly, and the response to therapy was modest.
Burns et al. (56) reported on the final height
of 55 GHD children treated before 1981. GH was administered at a dose
of either 10 IU twice weekly or 5 IU three times a week, irrespective
of weight or surface area. Treatment was begun between the ages of 9
and 14 yr in most of the children, and therefore a total weekly dose of
1520 IU represented a suboptimal GH dose by modern standards. The
smaller children, however, would have initially received a fairly high
dose relative to their size. At completion of growth, average height
was more than 2 SD below the population mean,
with stature in more than half the children failing to exceed the third
centile. The response to therapy did not differ between those treated
with two or three injections per week, despite a significant difference
in total dose received, suggesting that frequency of injections is
important. Other early final height studies also reported a modest
response to GH replacement, with adult heights not always significantly
greater than those observed in untreated individuals
(56, 57, 58, 59). In 1985, the first reports emerged of the link
between pituitary-derived GH therapy and Creutzfeldt-Jakob disease
(60), and human GH was promptly withdrawn. However, within
a year GH produced by recombinant DNA technology became available
(61). In addition to negating the risk of
Creutzfeldt-Jakob disease, synthetic GH also transformed the practice
of GH replacement by providing a potentially limitless supply of
therapy. This allowed the treatment of GHD children with higher, more
appropriate doses, and also enabled GH therapy to be offered to a much
wider range of patients. Subsequent studies have helped define which
patients benefit from GH therapy and the optimal dosing schedules.
A. Diagnosis of GHD and patient selection
In pediatric practice, the diagnosis of GH deficiency is usually
suspected on the grounds of auxological data, although a minority of
children are diagnosed because of known pituitary disease or after
radiotherapy involving the hypothalamo-pituitary region. Selection of
the patients most likely to derive clinical benefit from GH therapy
demands a sensitive and specific test that distinguishes GH-deficient
from normal subjects. A number of approaches have been used to confirm
GHD in childhood, including GH stimulation tests, 24-h GH profiles,
urinary GH, and measurements of IGFs and IGFBPs (62, 63, 64).
There is no single test, however, that can invariably distinguish
normal children from GH-deficient individuals, particularly those with
less severe degrees of GHD.
Provocative tests remain the standard method of confirming a
diagnosis of GHD in a child in whom the diagnosis is suspected on the
basis of auxological data, or a predisposing factor (64).
A number of different agents have been used including insulin,
arginine, glucagon, propranolol, clonidine, and
L-dopa (63). Physiological stimuli, such as
sleep, fasting, and exercise, have also been employed. The definition
of what constitutes a normal rise in serum GH concentration after
either physiological or pharmacological stimulation is largely
arbitrary. In early reports, a stimulated peak GH level of 5 ng/ml or
more was considered to be indicative of normal GH reserve. This
definition has gradually changed, influenced to some extent by the
increased availability of therapy after the advent of rhGH, such that a
level of between 7 and 10 ng/ml is now generally accepted as the
cutoff. IGF-I and IGFBP-3 levels have also been used as a measure of GH
status, and it has been suggested that the use of a combination of
tests improves diagnostic accuracy (62). However, there
remains no method of reliably separating all GH-deficient children from
GH-replete subjects, and this difficulty is reflected in the retest
data, which suggest that a substantial proportion of children treated
for GHD during childhood have entirely normal GH responses to standard
tests in adult life (65). In practice, the diagnosis of
GHD is based on careful clinical assessment, augmented by a number of
tests, which reflect GH status (63).
B. GH treatment: dose and schedule
There is good evidence that GH therapy should begin as soon as
possible to optimize long-term growth (66, 67, 68). Prompt
initiation of therapy is particularly important in young children in
whom fasting hypoglycemia may complicate GHD (69). While
there is broad agreement about the optimal timing of the start of
therapy, the selection of the appropriate GH treatment dose is less
clear.
There are several methods that may be employed for defining the optimal
replacement regimen in GH-deficient patients. Attempts can be made to
mimic normal physiology by administering GH at doses that approximate
to normal production rates, or by attempting to achieve serum levels of
GH or GH-dependent markers that are close to normal levels.
Alternatively, treatment may be selected on the basis of the reversal
of the biological endpoints of GHD, while minimizing any adverse
effects of therapy. In pediatric practice, the selection of optimal GH
doses and treatment schedules has rested almost entirely on the
response to therapy in terms of linear growth.
Some attempts have been made to define physiological GH requirements by
examining GH production in normal subjects, or by measuring biochemical
markers of GH status in treated patients. Studies in healthy children
have estimated daily endogenous GH production to be approximately 20
µg/kg/d (equivalent to 0.14 mg/kg/week) (70, 71), rising
to 35 µg/kg/d in late puberty (71), although
considerable interindividual variability exists (72, 73, 74, 75).
Extrapolating this to replacement doses is hampered by the different
pharmacodynamics of exogenous GH administered subcutaneously, but it
does provide an estimate of GH requirements. Few data exist regarding
the measurement of GH markers during replacement therapy in children.
Hibi et al. (76) measured plasma IGF-I, urinary
IGF-I, and urinary GH in a cohort of GH-deficient children and
suggested that a GH dose of 0.16 mg/kg/wk was close to a physiological
replacement dose. A more recent study has documented serum IGF-I and
IGFBP-3 levels within the normal range in a group of GHD children
receiving a mean GH dose of 0.17 mg/kg/wk. Furthermore, in a large
multicenter randomized US trial (n = 139), girls with Turner
syndrome received either 0.27 mg/kg/wk or 0.36 mg/kg/wk of GH in
combination with either low-dose estrogen or oral placebo, and only
1.4% had serum IGF-I levels greater than 2 SD
above the mean for age (77). In contrast, in a smaller
study of 31 patients, Tillman et al. (78)
reported two of 20 GHD and three of seven children with Turner syndrome
showed supraphysiological IGF-I levels during the first year of GH
treatment. As the measurement of IGF-I during childhood GH therapy
becomes commonplace, more information will become available regarding
IGF-I levels achieved with different GH doses. It is clearly important
that normative data should be accumulated across the childhood age
range.
The vast majority of clinicians have used the growth response to GH
therapy to define the optimal replacement dose. The endpoints used to
define the benefits of different doses have been both short-term growth
and growth velocity and, more importantly, final height. It was
recognized before the advent of rhGH that a dose-response relationship
exists between GH dose and growth rate (79, 80), and more
recent data have confirmed that GH dose influences the short-term
growth response to GH replacement (81, 82). In addition,
dose frequency has been shown to be an important factor in determining
the response to therapy. Changing from three times a week to a daily
subcutaneous injection results in an increased growth rate for a given
total GH dose (83, 84), although no further growth
advantage has been demonstrated with more frequent injections
(84, 85, 86). With the greater availability of rhGH, higher GH
doses have generally been used, and this has resulted in more favorable
final height data. Despite reasonable improvements in height
SD scores (the number of SD scores by
which an individuals height differs from the mean for his/her age and
sex) during treatment with pituitary-derived GH, average final height
in these children was only -2.3 SD scores
(87). The vast majority of patients treated with rhGH,
however, achieve a final height within the normal range, with an
average final height of -1.4 SD score (87).
In the last 5 yr a number of groups have published data from cohorts of
children treated with rhGH to final height (66, 68, 87, 88, 89, 90, 91, 92). Height gain in these studies, as assessed by the
difference between final height and predicted adult height or initial
height SD score, ranged between 0.8 SD and 2.4
SD, with average final height ranging between -2.1
SD and -0.7 SD. The criteria used to diagnose
GHD and therapeutic regimens employed varied between the studies and
probably account for much of the variation in the results.
These data confirm the benefits of treatment with a weekly dose of at
least 0.15 mg/kg but controversy remains concerning the additional
benefits of higher doses. Analysis of final height data suggests that a
dose between 0.17 and 0.3 mg/kg/wk is a reasonable replacement dose
(70). The most reliable data are taken from large
multicenter studies such as the Kabi International Growth Study (KIGS),
the National Co-operative Growth Study (NCGS), and the Genentech Growth
Study group (GGSG). Interpretation of data from these large cohorts of
patients is complicated by the fact that they were collected over a
number of years from many different centers, and there is therefore a
degree of variability in the treatment protocols employed. Thus, a
proportion of patients have received treatment that is now considered
suboptimal, and the responses to therapy need to be assessed with this
in mind. In addition, some of the differences observed in the response
to therapy may be due to differences in the study populations. Data
from the GGSG (66) suggest that treatment with 0.3
mg/kg/wk is associated with significantly greater improvements in final
height than those observed in patients enrolled into KIGS, who received
a lower average dose of 0.16 mg/kg/wk (88). The GGSG
cohort achieved a final height of -0.7 SD compared with
-1.5 in the KIGS group. However, the midparental height of the GGSG
cohort was significantly greater than that in the KIGS group, and,
after correcting for this, there was no difference in final height
achieved (88). In addition, data from the NCGS in a larger
cohort of GH-deficient children treated with 0.3 mg/kg/wk demonstrated
a more modest response (68) similar to that seen in the
KIGS patients (final height -1.4 SD). However, analysis of
a separate cohort of Swedish patients within KIGS treated with an
intermediate dose of 0.22 mg/kg/wk demonstrated complete normalization
of final height, indicating that higher doses may result in a better
response to therapy (88). Furthermore, a recent report
suggested a significant short-term growth advantage from a GH dose of
0.35 mg/kg/wk over that observed with 0.17 mg/kg/wk (93).
A further increase in the dose to 0.7 mg/kg/wk conferred no additional
benefit, and this concurs with other studies that have examined the use
of higher GH doses (70, 94). In accordance with all these
data, recent internationally agreed guidelines for the treatment of GH
deficiency in childhood suggest a dose of 0.170.35 mg/kg/wk
(95).
Ultimately, the selection of the replacement dose is based on
interpretation of the available data, local availability of GH, and
also on financial grounds. Given the variability in GH production in
normal individuals, it is likely that GH requirements will vary from
patient to patient, and a more individual approach may eventually be
required. This would necessitate an accurate method for assessing and
monitoring the appropriateness of a given GH dose in each patient.
C. Puberty
GH production in normal individuals rises during puberty
(71). In addition, a positive correlation has been found
between total pubertal height gain and mean GH dose during puberty
(96). It has therefore been suggested that the dose of GH
replacement should be increased at the onset of puberty to mimic normal
physiology. Stanhope et al. (97), however,
demonstrated no increase in growth rate on increasing GH dose from 15
IU/m2/wk to 30 IU/m2/wk
during puberty in a small cohort of GH-deficient children, compared
with a control group who continued on 15
IU/m2/wk. Indeed, their data suggested that a
high GH dose accelerated the progression through puberty and may
therefore be detrimental to final height outcome. It should be noted,
however, that their conclusions were based on the short-term growth
response, and these children were not followed to final height. More
recently, Albertsson-Wikland et al. (98)
demonstrated no increase in total pubertal height gain in boys treated
with 0.42 mg/kg/wk compared with boys treated with 0.21 mg/kg/wk. In
addition, MacGillivray et al. (70) compared
data between several large studies of GH replacement employing
differing doses of GH. Pubertal height gain did not differ
significantly between the cohorts, suggesting no additional benefit
from a higher replacement dose during puberty (70). Thus,
while some centers still advocate an increase in GH dose at puberty,
many clinicians continue treatment at a similar dose (calculated per kg
or m2) throughout childhood.
The most likely explanation for the lack of a significant growth
advantage with an increased GH dose during puberty is that this is
associated with an advance in bone maturation. This will lead to
earlier fusion of the epiphyses and therefore shorten pubertal growth,
and it has thus been suggested that pharmacological delay of pubertal
development may improve the overall growth response to GH replacement.
Delaying the progression through puberty by the administration of GnRH
analogs has been standard practice for the treatment of precocious
puberty for a number of years. The main long-term goal of this therapy
is to prevent reductions in adult height, which will occur if puberty
is allowed to progress at an early age, because of the reduced time
available for linear growth. Improvements in final height have been
achieved with GnRH analog therapy in precocious puberty
(99, 100, 101), although some authors have suggested that the
addition of GH therapy may further improve growth. A few studies have
examined the effects of combined treatment with GH and GnRH analogs in
children with precocious puberty and normal GH levels (102, 103). In addition, there are a number of reports of combined
treatment in children with both GHD and early puberty (104, 105). The use of combined therapy has also been investigated in
short normal children (103, 106, 107, 108). The results of
these studies have been variable, with many showing little improvement
in growth velocity or final height. Nonetheless, it has been postulated
that GnRH analog therapy may augment the growth response to GH therapy
in GHD. A few studies have suggested improvements in final height
prognosis with a combination of GH and GnRH therapy
(109, 110, 111, 112). Some of these reports have been limited by the
use of final height predictions based on the short-term response to
therapy. The recent report from Mericq et al., however,
followed 21 GH-deficient subjects to near-final height defined as a
bone age of 14 yr in girls and 16 yr in boys (111).
Patients were randomly assigned to GH therapy plus LHRH analog of GH
alone. A significant gain in near-final height was demonstrated for
those receiving combination treatment compared with those treated with
GH alone (mean height SD score -1.3
vs. -2.7), with no alteration in body proportions. This was
achieved at the expense of significantly delaying puberty, with the
mean age at menarche in the girls treated with LHRH being 18.2 yr
compared with 15.9 yr in the GH-alone group. Thus, while these data are
promising in terms of potential height gain, the psychosocial
implications of pubertal delay need to be balanced against the growth
advantage that is potentially conferred by the addition of GnRH analogs
to GH therapy. In addition, the number of patients who have been
followed to final height remains small, and further data are required
before the addition of GnRH analog therapy can be routinely
recommended for use in GH-deficient children in the absence of
coexisting precocious puberty.
D. Side effects of GH therapy
There are a number of adverse effects that have been attributed to
GH replacement during childhood. The most comprehensive data are
available from large international surveillance studies that have been
specifically designed to monitor safety of treatment. Idiopathic
(benign) intracranial hypertension was first reported in 1992
(113), and a number of subsequent reports have confirmed
the relationship with GH therapy (114, 115, 116, 117, 118). Data from the
NCGS and KIGS databases have revealed 35 cases of idiopathic
intracranial hypertension from a total of more than 40,000 patients
receiving more than 109,000 yr of GH therapy (114, 117).
The condition improves after withdrawal of therapy, and GH can often be
restarted without a recurrence of the problem.
The question of the impact of GH therapy on tumor growth has often been
raised, particularly with reference to populations of children
previously treated for childhood malignancies. Because interpretation
of tumor recurrence data is complicated by biases introduced by the
selection of children for GH therapy, careful matching of control
populations is necessary. The available data do not suggest any
increase in the risk of tumor recurrence in the children after GH
treatment; both single-center studies (119) and
large-multicenter surveillance studies (114, 120) have
failed to show any increase in the incidence of de novo
malignancies during GH replacement. Fasting glucose levels have been
shown to rise after the commencement of GH therapy in children
(121), and there have been reports of the development of
diabetes mellitus during treatment (122). Data from the
NCGS (117) and KIGS have not suggested an increase in the
incidence of type 1 diabetes, but the KIGS database did demonstrate a
higher than expected incidence of type 2 diabetes in a heterogeneous
population including children treated with GH for short stature not due
to GHD (123). The incidence was, however, very small (34
cases per 100,000 yr of GH treatment), and it was postulated that the
higher rates may indicate an acceleration of the disorder in
predisposed individuals.
A number of other adverse events occur more commonly during GH therapy
in children. Slipped capital femoral epiphysis (117, 124),
gynecomastia (116), and juvenile osteochondritis
(114) have all been reported during treatment, although a
direct causal relationship with GH has not been established.
Interestingly, edema and carpal tunnel syndrome only occur only very
rarely in pediatric practice (117), although these are
commonly reported in adult-onset GH-deficient patients receiving GH
replacement (125). The reason for this discordance is not
clear.
E. Predictors of response to therapy
Several reports from large cohorts of GH-deficient children have
provided some information on factors that influence the growth response
to GH replacement (51, 66, 72, 73, 76, 82, 88, 89, 92, 108, 126). Analysis of the KIGS database suggested that first year
height velocity was negatively correlated with age and height
SD score and positively correlated with birth weight,
weight at beginning of therapy, GH dose, frequency of injection, target
height SD score, and degree of GHD, as judged by the peak
GH response to a stimulation test (81, 127). Analysis of
final height data demonstrated no effect of GH dose on adult height,
although the duration of GH therapy was a significant factor
(88). This underscores the need to begin GH therapy as
early as possible to attain the maximum final height, and also suggests
that, within the dose range used (10th90th centiles; 0.110.24
mg/kg/wk), variations in weekly GH dose has little effect on final
height. Data from the NCGS are consistent with these findings,
suggesting that the initial response to GH therapy may be predicted by
age, degree of GHD, weight adjusted for height, GH dose, injection
frequency, and midparental height (82). Final height was
dependent on pretreatment height and age, duration of treatment, sex,
and first year growth rate (66). Thus, knowledge of a
number of baseline parameters will help predict the response to
therapy. From these data, models have been developed that allow
reasonably accurate prediction of the first year growth velocity after
GH therapy. However, although a greater initial response to treatment
will be psychologically important to the patient and is likely also to
improve compliance, the final height achieved is generally considered
to be the most important goal of therapy. The model developed from the
KIGS database (127) has been extended to examine second,
third, and fourth year growth response and has demonstrated that first
year height velocity is the most important predictor of subsequent
growth. Extrapolation of these results would suggest that first year
height velocity is likely to be an important determinant of final
height; however, this has yet to be established, and at present these
models can predict only the initial growth after the institution of GH
replacement and not the overall response to therapy.
There are also a number of other markers that may help predict the
initial growth response. Markers of bone turnover are significantly
reduced in GH-deficient children and increase after GH replacement
(128). The increase in serum bone alkaline phosphatase
levels (a marker of bone formation) after 3 months of GH replacement
has been shown to correlate with improvements in the height
SD score in the first year of therapy. Serum leptin levels
also alter with GH status, predominately as a result of changes in fat
mass and distribution. Leptin levels reduce during GH replacement
(129), and changes in leptin concentration 1 and 3 months
after the beginning of GH therapy have been shown to correlate with
growth in the first year of treatment (130). These
observations of changes in bone alkaline phosphatase and serum leptin
indicate that metabolic markers are potential predictors of the
short-term growth response to GH therapy.
Standard GH replacement therapy in GH-deficient children thus consists
of daily injections of rhGH, usually administered at a weight-based
dose of between 0.17 and 0.3 mg/kg/wk. Treatment is initiated as soon
as possible once the diagnosis has been made and is continued until the
attainment of final height. This is usually defined as either a slowing
of growth to an annualized height velocity of less than 1 cm/yr or the
demonstration of fusion of the long bone epiphyses (131).
Improvements in linear growth have been almost the sole indication for
the use of GH in pediatric practice. There are some data, however,
concerning the use of GH in normally growing GH-deficient patients
after surgery for craniopharyngioma (132), which
demonstrated beneficial metabolic effects of treatment resulting in
advantageous changes in body composition and suggested that GH
replacement is indicated in these children despite their normal growth.
In addition, data from the use of GH therapy in children with
Prader-Willi syndrome have demonstrated beneficial effects of treatment
on body composition, muscle strength, and respiratory function
(133, 134, 135). These unusual situations highlight the
potential benefits of GH replacement in childhood other than linear
growth.
GH replacement has evolved since the pioneering work of the 1950s using
cadaveric pituitary-derived GH. Numerous studies have helped define the
optimal management of GH replacement during childhood. The recognition
of the importance of GHD during adult life has necessitated a more
detailed study of GHD and the impact of treatment, which has resulted
in a reevaluation of pediatric practice. The monitoring of parameters
other than linear growth to help refine GH therapy should now be
incorporated into childhood GH replacement. Further research will be
required to define the optimal management of the transition from
pediatric to adult GH replacement, and a smooth changeover will only be
accomplished once the benefits of GH after the completion of growth are
accepted by pediatric and adult endocrinologists alike.
 |
V. Adult GH Replacement: Historical Perspective
|
|---|
The earliest report of the beneficial effects of GH in the
treatment of adult hypopituitarism was in 1962, when increased vigor
and well being were reported by a 35-yr-old hypopituitary patient
treated with cadaveric GH (136). This was followed,
approximately 30 yr later, by a series of randomized,
placebo-controlled trials, in which it was convincingly demonstrated
that treatment of GHD adults with rhGH led to significant improvements
in body composition, well being, and serum lipoprotein levels
(1, 2, 3, 4, 5, 6). Almost coincident with these studies came the
first (137) of several reports (138, 139, 140) to
suggest that hypopituitarism is associated with decreased life
expectancy compared with age-matched healthy controls, despite adequate
replacement with glucocorticoids, thyroid hormone, and sex steroids.
Although it remains an intriguing possibility that the increased
visceral adiposity and abnormal cardiovascular risk profile associated
with adult GHD contribute to the demonstrable decreased life
expectancy, there are at present no solid data to support this
hypothesis or that treatment with rhGH improves mortality outcome in
adult hypopituitarism.
 |
VI. Rationale and Strategies for GH Replacement in Adults
|
|---|
In the absence of evidence that GH replacement therapy for adult
GHD is associated with an improvement in mortality outcome, it is the
development of symptoms of a characteristic clinical syndrome,
discussed in detail below, that is the most frequent trigger for
consideration of treatment of hypopituitary adults with rhGH. Unlike
other hormones used for the treatment of hypopituitarism, for which the
benefits of replacement therapy are universally accepted, there is
considerable national variation in the clinical indications for the
prescription of GH. This variation relates in part to financial
constraints, but it is also indicative of an area of clinical practice
in which the sudden availability of an unlimited supply of drugs has
necessitated a rapid evaluation of the indications for its use and,
hence, a strategy for its monitoring. Essentially three main approaches
to the practice of GH replacement have been used. One is that because
of its cost and the lack of evidence of its long-term efficacy in
improving cardiovascular risk and reducing mortality, GH replacement
should not be offered to hypopituitary patients A second approach,
adopted by some countries, is that all hypopituitary patients with GHD
require GH replacement, simply on the principle of complete hormone
replacement therapy. In most countries, however, a third approach is
adopted involving selection of patients for GH replacement. In the
United Kingdom and many other European countries, selection is made
largely on the basis of quality of life and/or bone mineral density
considerations, but alternative strategies could include selection of
patients with a particularly high cardiovascular risk profile.
The potential improvement of several of the adverse features of
the adult GHD syndrome with rhGH therapy means, in turn, that changes
in these parameters are used as clinical indicators of GH efficacy
during replacement therapy. During the double-blind placebo-controlled
trials of GH replacement, and in the immediate period after its license
for use in adults, it was thought, by analogy with pediatric practice,
that clinical monitoring would be sufficient and that markers such as
body composition would simply substitute for linear growth. However,
with time and shared clinical experience, it has become apparent that
individual responsiveness to GH is highly variable and that the dose
should be adjusted to suit each individual patient. This, in turn, is
accomplished using a combination of tolerability (i.e., the
occurrence of side effects), clinical response, and measurement of
biochemical indices of GH action. In the debate surrounding the
optimization of GH dosing schedules, supportive evidence comes from a
combination of placebo-controlled studies (both single- and
multicenter) and information collected through international
outcomes-based multicenter research databases, in which data are
recorded during longitudinal follow-up in a conventional clinical
setting. Although patient numbers may be limited in a single center, it
is often the case that those patients have been treated by a single
physician or group of physicians in an identical manner, such that it
becomes possible to draw conclusions about specific treatment
protocols. In contrast, dosing strategies vary between centers, but
large databases permit the identification of subtle trends regarding
individual susceptibility, together with early detection of important
safety issues that may not be possible from a single center or even a
single country.
 |
VII. Tolerability
|
|---|
rhGH has an identical amino acid sequence to endogenous GH
(61), such that side effects of GH replacement therapy are
almost exclusively due to excess dosing. In the early trials of GH
replacement, symptoms related to the antinatriuretic actions of GH,
such as edema, arthralgia, and myalgia, were common and necessitated
dose reductions in up to 40% of patients (2, 3). Side
effects were more common in elderly and obese patients
(141), both of whom would have received disproportionately
larger doses, in the early studies using weight-based dosing regimens,
than would be predicted from the physiological principles of GH
secretion outlined above. Side effects were significantly reduced by
beginning GH at smaller doses, building up to the (then) weight-based
target dose. Conversely, trials involving mostly lean and young adults
have been associated with fewer side effects (142).
However, even when GH doses are lowered because of adverse symptoms,
biochemical markers of GH action, such as serum IGF-I, remain elevated
in up to one-third of patients (143), suggesting that the
absence of classical symptoms of GH overtreatment is a relatively crude
method of judging excess GH exposure.
 |
VIII. Clinical Response to GH Replacement
|
|---|
In the absence of conclusive evidence that GH replacement reduces
cardiovascular mortality, it is the potential reversal of many of the
features of GHD, most notably abnormal body composition, impaired
quality of life, osteopenia with increased fracture risk, and cardiac
dysfunction, that leads to the initiation of treatment. It might
therefore be argued that each of these could be used as a marker of
efficacy during GH replacement. In discussing the merits of different
approaches to adult GH replacement therapy, it is important to note
that supportive evidence comes from both placebo-controlled and
open-label studies, each of which provide separate, but complementary,
information.
A. Body composition
GHD adults have increased android (abdominal and visceral) fat,
decreased lean body mass, and decreased total body water compared with
age-matched healthy controls (1, 2, 144). Several
double-blind, placebo-controlled studies, all slightly different in
design, have shown consistent, beneficial effects on all these
parameters with GH replacement therapy (1, 2, 3, 4, 5),
attributable to its known lipolytic (145), protein
synthetic (146), and antinatriuretic actions. A variety of
techniques are available for the assessment of body composition in
clinical trials of GH therapy in adult hypopituitarism, including
bioimpedance analysis (147), isotope dilution estimation
of total body water (TBW) (148), total body potassium
(TBK) estimation using a 40K counter
(149), dual energy x-ray absorptiometry
(150), anthropometry (151), and CT scanning
(152). Although some groups have used a four-compartment
model of body composition (144), most studies have
monitored changes in body composition on the basis of a two-compartment
model [fat mass (FM) and lean body mass (LBM)], each of which has
distinct physico-chemical properties. For example, estimates of LBM
from measurements of TBK rely on an assumption of 60 mmol potassium per
kg LBM (153). FM is then calculated by subtracting the
derived LBM from the total body weight. Isotopic dilution measurements
of TBW may be used to calculate LBM on the basis that water constitutes
73% of LBM (hence LBM = TBW/0.73). It is important to note that
such calculations are based on models of body composition in healthy,
GH-replete individuals and that extrapolation to GHD adults may not be
strictly valid. Further, although most techniques measure body fat with
accuracy and precision, some techniques, notably bioimpedance analysis
and dual energy x-ray absorptiometry, may overestimate LBM changes
(154). However, as can be seen from Table 1
, the qualitative effects of GH
replacement on body composition in adult GHD (both AO and CO) have been
strikingly similar in the trials listed, all of which were randomized,
double-blind, and placebo controlled. Some of the quantitative
differences between studies may, at least in part, be attributed to
different GH dosing regimens used and the discrepancies known to exist
between the various techniques available for the measurement of body
composition (154). Although many of the above techniques
are not routinely available outside supervised clinical trials, it
should be noted that the simple measurement of waist-hip ratio
correlates well with the reduction in visceral FM that occurs with GH
replacement and provides a sensitive and reproducible method of
monitoring certain aspects of altered body composition during GH
therapy (2).
Since the original demonstration, in placebo-controlled clinical
trials, that weight-based doses of GH replacement therapy favorably
modify various indices of body composition, a number of open-label
studies have examined the value of using such changes as the major
determinant of dosing during replacement therapy. Johannsson et
al. (158) randomized 60 patients to one of two dosing
regimens of GH: a high dose of 12 µg/kg/d or an individualized dose,
in which a low starting dose of GH was followed by individual dose
adjustments according to measurements of serum IGF-I and changes in
body composition, with relative weighting given to the more abnormal
parameter. Dose increments were generally made on account of a serum
IGF-I level below the age-related reference range, but in those
patients with a normal baseline serum IGF-I, dose adjustments were made
according to measurements of body composition. Improvements in body
composition were similar in the two groups but, in some individualized
dose patients, dose increments on account of persistently abnormal body
composition resulted in elevated serum IGF-I levels. This would suggest
that, in some hypopituitary patients, attributing the totality of
abnormal body composition solely to GHD may not be appropriate and that
increasing the dose of GH in an attempt to normalize body composition
may result in overtreatment, judged by biochemical markers of GH
action.
In a separate study (159), assessments of body composition
and measurements of biochemical markers of GH action (IGF-I, IGFBP-1,
and BP-3 and ALS) were monitored during 12 months of treatment with a
weight-based GH dosing regimen. Significant improvements in body
composition were observed. Although no individualized dosing was made
on the basis of the above measurements, dose reductions were necessary
in 7 of 20 patients because of side effects of fluid retention. Even
with these dose reductions, serum IGF-I remained elevated in seven
patients (35%), while ALS and IGFBP-3 were above the age-related
reference range in five (25%) and three (15%) patients, respectively
(159).
De Boer et al. (143) conducted a 12-month
placebo-controlled trial of GH replacement, randomizing 46
GHD male patients to one of four treatment protocols: placebo for 6
months followed by GH 2 IU/m2/d; or one of three
doses of GH for 12 months (1, 2, and 3 IU/m2/d).
Some reductions in dose were necessary due to unacceptable side effects
of GH excess, but the absence of such symptoms was a poor guide to
overtreatment, judged by serum IGF-I levels (Fig. 2
). Most of the patients treated with the
highest dose of GH had serum IGF-I levels outside the age-related
reference range. It should be noted that, in this study, the doses of
GH necessary to normalize serum IGF-I were also associated with
restoration of normal tissue hydration, emphasizing the potential use
of clinical markers of GH efficacy during GH dose titration.

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|
Figure 2. Measurement of IGF-I response in 46 men with
CO-GHD randomized to receive one of three starting doses of GH with
subsequent adjustment according to clinical characteristics. ,
Symptoms of GH excess. , No symptoms of GH excess. [Reproduced with
permission from H. de Boer et al.: J Clin
Endocrinol Metab 81:13711377, 1996 (143 ). © The
Endocrine Society.]
|
|
A more global assessment of the effect of GH on body composition and
the relationship to serum IGF-I comes from a recent international
report of 1,018 patients receiving GH replacement in 20 different
countries (160). Improvements in body composition, as
determined by the simple measurement of waist-hip ratio, were similar
in patients enrolled at the time of initiation of GH (GH
"naïve" patients) and non-naïve patients (those
already taking GH at enrollment into the database). However, mean GH
dose and mean serum IGF-I were significantly higher in
non-naïve patients, most of whom had previously been treated
with weight-based GH regimens, with subsequent adjustment of dose
during clinical follow up. Overtreatment with GH (defined as a serum
IGF-I greater than 2 SD scores above the mean) was seen in
both groups of patients, but was significantly more common in
non-naïve patients (23.3 vs. 15.9%). This might
suggest that the "extra" GH received by non-naïve patients
is not associated with a significant benefit in terms of improved body
composition, but is associated with a significantly greater incidence
of excess GH exposure, judged by elevated levels of serum IGF-I
(160).
B. Quality of life and well-being
Reduced quality of life and sense of vitality are well
recognized features of the adult GHD syndrome (161, 162).
Although this may in part relate to abnormal body composition and
impaired muscle strength, there is widespread agreement that the low
energy levels, social isolation, increased emotional stress, impaired
socio-economic performance, and greater difficulties forming
relationships evident in many hypopituitary patients are directly due
to GHD. In many countries, availability of GH is limited to
patients with severe GHD associated with one or a combination of these
symptoms, and their improvement is therefore an important clinical
parameter by which to judge the efficacy of GH replacement. The early
trials of GH replacement used a variety of generic methods to measure
and monitor well-being such as the Nottingham Health Profile (NHP)
(163) and the Psychological General Well-Being Schedule
(PGWBS) (164). The NHP questionnaire consists of a number
of specific questions, with yes/no responses, about energy levels,
sleep, relationships, emotional responses, physical mobility, and
pain. The Psychological General Well-Being Schedule (PGWBS) involves
the use of a rating (from 0, worst, to 5, best) for a series of
questions about affective categories such as anxiety, depression,
positive well-being, general health, and vitality.
A number of placebo-controlled studies have documented statistically
significant improvements in well-being, assessed by various methods,
after the initiation of GH replacement (3, 162, 165),
although such results have not been universally reported (5, 166). The reasons for such discrepancies are not entirely clear,
although it is interesting to note that many patients in the study of
Baum et al (166) did not achieve significant
increments in serum IGF-I levels, suggesting that compliance with GH
therapy may have been suboptimal. It is also important to note that
patients who participated in the early trials of GH therapy were
frequently the most severely disadvantaged in terms of psychological
distress (167) and therefore more likely to wish to
continue with GH replacement after a therapeutic trial
(168). Hence, because of these findings, caution should be
exercised in the interpretation of psychological well being data.
Since these placebo-controlled studies, a number of open-label studies
have examined the clinical utility of using well-being scores as a
marker of efficacy during GH replacement. In most cases, these studies
have used doses of GH that would now be considered inappropriately
high, and the proportion of patients with a serum IGF-I above the
age-related reference range was, in some cases, as high as 56%
(169). In one study (170), the effect of two
different GH dosing regimens (0.012 and 0.024 mg/kg/d) on well-being,
judged by NHP and PGWB scores, was investigated. Identical improvements
in well-being were observed in both groups, yet 45% of the patients in
the higher dose group had an elevated serum IGF-I compared with 24%
receiving the lower dose. In other words, the extra GH administered
resulted in no greater clinical benefit in terms of well-being, but was
associated with biochemical overtreatment in nearly twice as many
patients. In the same report, of those patients that chose to continue
GH therapy after the conclusion of the trial, 33% had a supranormal
serum IGF-I compared with 30% of those who elected to discontinue due
to a lack of improvement in well-being. If the dose of GH in the
"non-improvers" had been increased because of a poor clinical
response, it may have pushed serum IGF-I further into the acromegalic
range.
More recently, attempts have been made to use scoring systems for
psychosocial morbidity that are more specific to GHD. The adult GHD
assessment (AGHDA) score (171, 172, 173) provides a sensitive
and highly reproducible method of monitoring improvements in the
psychosocial consequences of GHD that may accompany GH replacement
therapy. The AGHDA questionnaire consists of 25 questions derived from
the symptoms most frequently reported by patients with adult-onset GHD.
A score of 25/25 represents the worst possible well-being score, while
scores of 4/25 or less have been recorded in a normal control
population (174). In those patients whose well-being
improves with GH, improvements in AGHDA scores occur within 3 months of
GH replacement therapy in the majority of patients and are maintained
at 6 and 12 months (175). Interestingly, improvements in
AGHDA scores may be seen in some patients treated with GH whose dose is
insufficient to have caused a significant increment in serum IGF-I,
suggesting that improvements in the psychological aspects of GHD may,
at least in part, be mediated directly by GH rather than via generation
of IGF-I (175). It is not known whether patients exposed
to excess GH (either in the context of acromegaly or by overtreatment
with GH in hypopituitarism) have AGHDA scores that are different from
control populations. However, an interesting comparison can be made
between hypopituitary patients treated initially on weight-based dosing
schedules, with subsequent dose adjustment during clinical follow-up
and patients initially started on low doses of GH with subsequent
careful dose titration on the basis of levels of serum IGF-I
(175). Maintenance doses of GH and serum IGF-I levels were
significantly higher in the patients initially treated with
weight-based dosing schedules, yet well-being, as judged by AGHDA
score, was no different.
C. Bone density and bone remodeling
It is thought that, in childhood, GH promotes longitudinal bone
growth by a combination of a direct effect on epiphyseal chondrocytes
(176) and by paracrine generation of IGF-I
(177). However, it is now widely accepted that GH also has
an important role to play in the achievement of peak bone mass after
the completion of linear growth and also in the maintenance of bone
mass through adult life. AO hypopituitary patients receiving
conventional endocrine replacement therapy are osteopenic compared with
age-matched healthy controls (178, 179), an observation
that is almost certainly clinically relevant given the increased
fracture rate evident in this patient group (180).
Furthermore, there are data to suggest that the severity of bone loss
is proportional to the biochemical severity of GHD (181).
The mechanisms for this disadvantage are not fully understood but are
likely to relate, at least in part, to reduced bone remodeling
activity. Activity of the bone remodeling unit (i.e., the
rate of bone turnover) may be assessed by measuring markers of the
activity of the two limbs of the bone remodeling unit. Osteoclasts
mediate bone resorption, and indices of their activity include
pyridinoline, deoxypyridinoline, and serum type I carboxy-terminal
cross-linked telopeptide. Markers of osteoblastic activity (bone
formation) include the bone-specific isoenzyme of alkaline
phosphatase (BSAP), osteocalcin, and carboxy-terminal propeptides of
type I collagen. GH stimulates proliferation and differentiation of
osteoblasts in vitro in humans (28) and in mice
(182) and further, surrogate, evidence for an
important effect of GHD in vivo is supported by the
observation of subnormal levels of osteocalcin and BSAP in adults with
GHD (142, 183).
Although osteopenia is an important factor in considering a trial of GH
replacement, few clinicians would regard it as the sole reason to begin
treatment. However, changes in BMD represent an important marker of
efficacy of GH therapy, and a review of the data in this regard is
appropriate. A number of placebo-controlled trials have examined the
effect of GH replacement on bone metabolism and BMD. From these studies
it is apparent that GH replacement is frequently associated with a
reduction in bone density in the short term (184, 185, 186),
probably as a result of an expansion of the bone remodeling space
(186). However, with more prolonged treatment increases of
bone density of 410% above baseline, measurements have been recorded
(185, 187). The study of Baum et al.
(187) is particularly noteworthy as the increments in BMD
were achieved with a dosing regimen of GH that specifically aimed to
avoid overtreatment by maintaining serum IGF-I levels within the
age-adjusted normal range. The timescale over which these changes occur
clearly preclude placebo-controlled studies of the long-term effects of
GH on BMD, but a number of open-label studies suggest that the
increments in BMD above baseline that are evident in placebo-controlled
trials continue with more prolonged GH replacement therapy over several
years (142, 188, 189).
An earlier indication of the efficacy of GH replacement on bone than
that evident by changes in BMD is provided by measurement of markers of
bone resorption and formation. Several placebo-controlled studies have
documented significant increases in markers of bone metabolism as early
as 4 months after beginning GH (190), possibly earlier
(189). From these and other reports it is clear that
individual response is highly variable and that measurement of markers
of bone metabolism have little use outside the setting of a clinical
trial. Furthermore, there is increasing evidence that the response to
GH in terms of BMD is, in part, gender dependent (189, 191). In men, prolonged GH replacement is associated with
sustained increments in BMD, whereas in women the benefits appear to be
limited to a stabilization of bone density. In both of these studies
serum IGF-I was maintained within the age-related reference range,
although the GH doses used were higher in women, further emphasizing
the need for individualized GH dosing.
Although, as stated earlier, osteopenia is seldom the sole reason to
initiate GH replacement for adult hypopituitarism, the timescale of the
effect of GH on BMD is such that a cautionary review of the potential
effects of overtreatment is appropriate, particularly as most of the
studies reviewed above used unphysiological, weight-based doses. GH
excess in the context of acromegaly is associated with elevated serum
levels of osteocalcin (192), changes that are similar to those seen in
many of the studies of GH replacement on bone and which are corrected
by successful surgical and/or medical treatment (192, 193). When not associated with hypogonadism, acromegaly is also
associated with increased bone mass and density, periosteal growth, and
bone widening (194). Hence, it seems prudent for patients with GHD and
low bone mass who are treated with GH to have their BMD monitored at
intervals during therapy, starting around 1218 months after the
beginning of GH therapy. Increments in BMD can be anticipated in most
patients, and maintaining serum IGF-I levels within the age-related
reference range is likely to avoid the potential adverse consequences
on bone of excess GH exposure.
D. Cardiovascular risk factors and cardiac structure and
function
The association of hypopituitarism with increased mortality has
directed attention to a possible role of GH in the regulation of
various cardiovascular risk factors. However, independent of this and
the possible role for GH replacement in favorably modifying an
individuals cardiovascular risk profile (see Section
XII.A), there is some evidence that GH improves cardiorespiratory
function and exercise performance in hypopituitary adults. This aspect
of GH replacement has not been the subject of such intensive research
as, for example, the effects of GH on body composition and quality of
life. Furthermore, it may be difficult to separate the direct effects
of GH therapy on exercise performance and cardiac dimensions and
function from secondary effects consequent upon changes in body
composition, cardiac afterload, and sodium and water balance associated
with GH therapy.
Nass et al. (195) demonstrated, in a placebo-controlled
trial, that GH therapy was associated with improvements in maximum
oxygen uptake and exercise capacity, in the absence of any significant
change in cardiac structure, as determined by transthoracic
echocardiography. More recently, Woodhouse et al. (196)
showed that GH replacement improved submaximal exercise performance and
was associated with an increase in type I skeletal muscle fiber size,
benefits that persisted after discontinuation of GH at the conclusion
of the study. No significant change was observed in quadriceps
strength, although improvements have been documented in muscle strength
in a separate, open-label study of longer duration
(197).
The relative contribution of a change in cardiac function to the
improved exercise capacity associated with GH therapy is difficult to
assess. Indeed, the role of GH in the regulation of cardiac structure
and function in adult life is far from clear. Several indices of
cardiac structure and function (exercise capacity, left ventricular
wall thickness, and fractional shortening) are abnormal in GHD adults
compared with age-matched healthy controls (198). This is most striking
in patients with childhood-onset GHD, in which there is
echocardiographic and radionuclide evidence of reduced cardiac output
and impaired diastolic function (142, 199). Evidence for
similar abnormalities of cardiac function in adult-onset GHD, however,
is rather conflicting. There is little doubt that the documented
abnormalities are less marked (198), although this may simply reflect
the duration of GHD at the time of study. GH replacement in
hypopituitary adults has been associated with an increase in LV wall
thickness, stroke volume, fractional shortening, and diastolic
function, as measured by prolonged isovolumic relaxation time
and early/atrial peak velocity ratio (E/A ratio) in open-label studies
of GH replacement (198, 200), but has not conclusively
been shown in placebo-controlled trials. Furthermore, in those open
studies, individual response to a uniform (weight-based) GH treatment
regimen was extremely variable. Although this aspect of GH replacement
certainly merits further investigation, the current literature does not
overwhelmingly support decreased cardiovascular performance and
exercise capacity as an indication for the clinical use of GH. If GH
does indeed improve cardiac function, the therapeutic window is likely
to be narrow, particularly with respect to the induction of left
ventricular hypertrophy (201). GH hypersecretion (in the
context of acromegaly) leads to a specific cardiomyopathy in which,
after an initial phase of cardiac hyperkinesis, myocardial hypertrophy
and diffuse interstitial fibrosis gradually lead to diastolic
dysfunction and, ultimately, congestive cardiac failure
(201). The detection of subtle signs of left ventricular
hypertrophy and impaired diastolic relaxation may be difficult using
standard transthoracic echocardiography, particularly outside the
setting of clinical trials, where interobserver variation of
measurements may be considerable. Treatment protocols that maintain
serum IGF-I levels in the age-related normal range are likely to avoid
the theoretical dangers of subtle GH excess on cardiac function.
E. Conclusions
It may be seen, from the above discussion, that clinical
monitoring is clearly an important part of the practice of GH
replacement (a characteristic clinical syndrome is, after all, the most
common indication for a trial of GH therapy). However, individual
response to treatment with GH is so variable that an apparent lack of
improvement in a single clinical parameter may prompt dose increments
that result in levels of IGF-I outside the age-adjusted normal range,
but which are not associated with symptoms of GH excess. The question
therefore arises as to whether long-term elevation of serum IGF-I is
acceptable in the context of the treatment of GHD and, further, whether
clinical efficacy is compromised by adopting strategies that
specifically aim to avoid this.
 |
IX. Is Overtreatment Acceptable in the Asymptomatic Patient?
|
|---|
The relatively recent advent of unlimited supplies of rhGH and its
use for the treatment of AO-GHD means that there are no long-term data
regarding the effects of an elevated level of serum IGF-I in
hypopituitarism. In the absence of such information, indirect evidence
must be extrapolated from clinical experience in the treatment of
acromegaly, a condition known to be associated with excess morbidity
and mortality (202), chiefly from cardiovascular causes
and presumed to be on account of the associated insulin resistance,
hypertension, and characteristic cardiomyopathy. The issue of insulin
resistance deserves particular mention in the light of the recent
report of an increased incidence of type II diabetes mellitus among
children treated with GH (123). It is not possible to
extrapolate directly such data to adult practice, on account of the
heterogeneity of the pediatric population reported (including, for
example, patients with Turner syndrome and chronic renal failure), but,
nevertheless, the argument for the avoidance of pharmacological doses
of GH would appear to be strengthened by such experience. Recent
reports, both from a single center and from an international study, of
the effect of more physiological doses of GH in hypopituitary adults,
are reassuring (160, 203).
Aside from the issue of avoiding iatrogenic biochemical acromegaly and
its theoretical complications, there are epidemiological data to
suggest that an individuals risk of developing carcinoma of the
prostate (in men) (204, 205) or breast (in women)
(206) may be influenced, at least in part, by their serum
IGF-I level, with values in the upper tertile being associated with a
higher incidence of developing malignant change in those organs. It is
important to note, however, that these studies were performed in
normal, GH-replete, adults and that it may not be appropriate to
extrapolate such findings to the practice of GH replacement in adult
hypopituitarism. Nonetheless, it seems prudent to avoid the use of GH
doses that are associated with supraphysiological serum IGF-I levels
until more data are available in this regard.
 |
X. Biochemical Monitoring of GH Replacement
|
|---|
Concern about the long-term consequences of iatrogenic
overtreatment with GH has caused attention to shift in recent years
toward the use of biochemical indices of GH action in the treatment of
AO-GHD. IGF-I, the tissue effector of many of the actions of GH,
circulates as a ternary complex of 150 kDa in association with IGFBP-3
and ALS. All three peptides are known to be GH dependent and, in theory
at least, may be considered as potential markers of GH efficacy. Of the
three, IGF-I is widely regarded as the most sensitive and
the most useful for the purposes of dose monitoring. In the
report of De Boer et al. (143), several
patients in the highest dose treatment group (3
IU/m2/d) reported side effects of GH excess.
Serum IGF-I was elevated above the age-adjusted normal range in a
number of these patients, but in far fewer were there supranormal
levels of IGFBP-3 and ALS. This would suggest that these latter two
peptides are less sensitive markers of GH action during GH replacement
than serum IGF-I. This is supported by the data of Drake et
al. (175) who treated 50 consecutive adult
hypopituitary patients with an identical dose titration regimen, with
dose adjustments every 4 wk on the basis of measurements of serum IGF-I
made every 2 wk. In addition, serum IGFBP-3 and ALS were measured in
one-third of these patients, but the results were found to be too
variable for routine clinical use (175) (Fig. 3
). In that study, "optimum" GH
replacement was arbitrarily defined as a serum IGF-I above the median
but below the upper limit of the age-related reference range. This was
done to allow those patients with severe GHD in association with a
low-normal serum IGF-I the maximum opportunity to benefit from GH
replacement. Maintenance GH doses, once the serum IGF-I was in the
target range, were higher, and the time taken to reach the target serum
IGF-I was longer in females than males (median daily dose 1.2 U
vs. 0.8, median time taken 9 wk vs. 4 wk,
respectively). Further, the mean increment in serum IGF-I from
baseline, once maintenance dose was achieved, was less in females than
males, despite the higher dose, confirming their overall decreased
susceptibility to GH. In spite of this smaller increment in IGF-I,
there was no gender difference in the extent of clinical improvement,
as determined by QoL AGHDA and measurement of waist-hip ratio.
Importantly, the extent of clinical improvement was similar to that
seen in the original trials that used weight-based dosing. Similar
findings were reported by Murray et al. (207)
whose regimen for GH therapy defined "optimum" GH replacement as
when symptomatic clinical improvement (judged by PGWB and QoL AGHDA)
coincided with a normal serum IGF-I. Together, these studies indicate
that the recent use of lower, more physiological doses of GH, in which
a major consideration is the avoidance of elevated serum levels of
IGF-I, is not associated with a loss of efficacy.

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|
Figure 3. Serum IGF-I (A), IGFBP-3 (B), and ALS (C)
vs. time in patients treated by dose titration. Adult GH
deficiency assessment (AGHDA) score (D) and waist-hip ratio (E) at
baseline and with GH therapy show no difference between males and
females, despite higher doses and longer time to reach maintenance dose
in females. [Reproduced with permission from W. M. Drake
et al. : J Clin Endocrinol Metab
83:39133919, 1998 (175 ). © The Endocrine Society.]
|
|
In spite of the above evidence, there remain some important concerns
with regard to the simplistic use of serum IGF-I levels as the sole
guide to the restoration of normal GH status during replacement
therapy. Serum IGF-I levels do not always reflect the true GH status of
an individual patient, as demonstrated by the fact that up to 30% of
patients with proven severe GHD have serum IGF-I levels in the lower
part of the age-adjusted normal range (208). Furthermore,
some patients with active, symptomatic acromegaly with mean GH levels
above the safe range (i.e., >5 mU/liter) (202)
exhibit normal serum IGF-I levels. The discrepancies observed in some
studies between GH status, as judged by indices of body composition,
compared with serum IGF-I levels, may be, in part, consequent upon the
method of administration of GH, as suggested by studies in rats
(209). It should also be noted that most blood samples for
serum IGF-I measurements are drawn in the early morning. Given that
there is a significant diurnal variation in serum IGF-I level with a
single subcutaneous nightly GH injection (with a peak in the morning
and a nadir at night) (210), it may be that such dosing
strategies are associated with a falsely high incidence of supranormal
levels of serum IGF-I.
It should also be noted that changes in serum IGF-I levels in response
to GH administration to hypopituitary adults persist long after the
effects on protein and lipid metabolism (211). Changes in
serum IGF-I correlate poorly with changes in leucine and glycerol
kinetics, suggesting that restoration of a normal circulating IGF-I
does not necessarily imply normalization of normal body composition
(212).
 |
XI. Gender Differences in GH Responsiveness
|
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A compelling argument for the use of individualized, as opposed to
simplistic weight- and/or surface area-based GH dosing, is the marked
difference in GH doses that are required to achieve an equivalent
clinical and biochemical response in men and women. The reasons for
this discrepancy are not entirely clear, although attenuation of GH
action by estrogen is an obvious candidate. In healthy
postmenopausal women, administration of estrogen decreases serum IGF-I
levels, despite an increase in pituitary GH secretion, and attenuates
IGF-I production during an IGF-I generation test (33, 34).
Further, oral estrogen administration partially ameliorates the
symptoms and signs of acromegaly (31) and, when GH excess
is reversed by surgical adenomectomy, the subsequent accumulation of
fat mass is more marked in men than women (213). This
would imply that estrogen has a modulatory effect on the lipolytic
effect of GH, resulting in less marked accumulation of fat when the GH
excess is corrected. Clearly, such findings, in healthy and acromegalic
individuals, cannot be directly extrapolated to exogenous GH
administration to patients with GHD. However, in a placebo-controlled
trial, an identical (weight-based) GH dose administered to GHD men and
women resulted in a greater reduction in fat mass and serum lipoprotein
levels in men compared with women, effects that were accompanied by a
statistically greater increase in serum IGF-I levels
(214). Recent, open-label studies also support the view
that hypopituitary female patients require higher maintenance GH doses
than males for a given clinical and biochemical response
(175, 215).
The route of estrogen administration has received considerable
attention as a possible determinant of maintenance GH dose in
hypopituitary women. In healthy, postmenopausal women, transdermal
estrogen does not modulate hepatic IGF-I production to the same extent
as oral estrogen, although a similar effect may be observed when the
number of estrogen patches is increased (33). In an
open-label study examining GH doses required to maintain serum IGF-I in
the upper part of the reference range, Cook et al.
(215) demonstrated that women taking oral estrogen
required approximately twice as much GH as women taking transdermal
estrogen, whose maintenance dose was similar to men. Although other,
larger studies have not demonstrated a significant difference in
maintenance GH dose on the basis of estrogen usage (160, 175), those studies did not specifically examine the use of
transdermal estrogen as a variable. The findings of Cook et
al. (215) clearly have important implications in
terms of the cost of maintenance GH dosing and merit further
investigation.
 |
XII. Adult GHD and Vascular Disease
|
|---|
Attempts to unravel the possible mechanisms by which GHD may
contribute to the increased mortality of hypopituitarism are severely
hampered by the lack of a true control population, i.e.,
patients with anterior pituitary failure but normal GH reserve. This is
because of the predictable way in which hypopituitarism develops, with
GHD characteristically antedating failure of gonadotropin secretion and
deficiencies in TSH and ACTH reserve. Hence, while it would be logical
to compare mortality outcome between patients with hypopituitarism and
GHD to those who are hypopituitary but GH replete, the clinical reality
is that such patients do not exist. In the absence of a satisfactory
control population, observational studies of various surrogate markers
of cardiovascular morbidity and their improvement with GH replacement
provide some evidence for an etiological role for GH in the increased
cardiovascular risk that may be prevalent in hypopituitary patients.
These markers include dyslipidemia (156, 216),
hyperfibrinogenemia (217), elevated levels of plasminogen
activator inhibitor (217), and increased abdominal fat
distribution (218). Further surrogate evidence for
increased vascular morbidity in hypopituitarism comes from measurements
of the structure of and flow in peripheral arteries. Arterial
intima-media thickness is a well-validated indicator of early atheroma
in epidemiological studies, and observations of easily accessible
arteries such as the carotid and femoral correlate well with disease
elsewhere such as in the epicardial coronary arteries. The percentage
of peripheral arteries containing atheromatous plaques and the number
of plaques contained within those arteries are both greater in
hypopituitary patients compared with age- and sex-matched controls
(219). Measurements of brachial artery and large arterial
compliance suggest a reduction in large vessel distensibility
(220, 221), but population studies examining whether this
translates into significant changes in blood pressure are difficult to
interpret on account of the greater medical attention afforded to
hypopituitary patients compared with healthy volunteers. GH has both
vasodilatory (222) and antinatriuretic (223)
actions: hence, the effects of GHD on systemic blood pressure are
likely to be complex.
A. GH replacement therapy and dyslipidemia
The effect of GH replacement on lipid metabolism has been studied
in several placebo-controlled trials (2, 5, 156, 218). The
results of these studies were strikingly similar, with significant
decreases observed in serum total cholesterol. Reductions in
low-density lipoprotein cholesterol and/or an increase in high-density
lipoprotein cholesterol were also observed, although these did not
reach significance in all studies. GH replacement appears to have
little effect on plasma triglycerides or ApoA levels. Changes in
Lp(a) levels, known to be an independent risk factor for
vascular disease, high-density lipoprotein cholesterol, and
triglycerides have been inconsistent, vary considerably with the
assay methodology (224), and may depend, at least in part,
on the patients apoE phenotype (225).
Although these abnormalities and their improvement with GH replacement
are frequently cited as evidence that GHD is associated with increased
mortality, it is important to note that many of these studies used
weight-based dosing regimens that would now be regarded as excessive
(0.25 IU/kg/wk, 12/5 µg/kg/d, with the exception of one study
(2) in which twice this dose was used). Such concerns
apply equally to other surrogate markers of increased cardiovascular
morbidity such as hyperfibrinogenemia (217) and elevated
levels of plasminogen activator inhibitor (217). In a
recent open-label study of the effects on lipid profiles of GH
replacement delivered by dose titration to maintain serum IGF-I above
the median but within the age-adjusted normal range, statistically
significant reductions in total cholesterol and LDL-cholesterol were
evident (203). However, the changes were lower than those
observed in the original placebo-controlled trials, and the greatest
benefit was seen in patients with the highest values at baseline. Abs
et al. (160) reported that, since the advent of
dose titration, the use of more physiological doses of GH has been
associated with only modest improvements in lipid profiles in males and
little change in females. These reports emphasize that it is not
possible to extrapolate data from studies utilizing pharmacological
doses of GH to modern clinical practice in which lower, more
"physiological" doses are used; and that it is far from clear
whether GH replacement invariably improves the cardiovascular risk
profile of patients with GHD.
 |
XIII. Alternative Mechanisms for Accelerated Vascular Disease
|
|---|
Aside from GHD, unphysiological hormonal replacement is another
possible cause of accelerated atherogenesis. Many features of
glucocorticoid (GC) excess (glucose intolerance, central obesity,
hyperinsulinemia, and raised triglycerides) are similar to those of
hypopituitarism with GHD and known to be associated with increased
vascular disease (226, 227). GC monitoring regimens vary
significantly between centers, but measurements of circulating cortisol
in patients taking hydrocortisone generally suggest excess GC exposure
during the day and underreplacement at night (228, 229).
Further, metabolism of cortisol to inactive cortisone is GH dependent
(230, 231), such that administered hydrocortisone may
remain metabolically active for longer in GHD subjects. The long-term
effects of prolonged overnight hypoadrenalism on atherogenesis are
unknown.
There is evidence that subclinical primary hypothyroidism is associated
with accelerated atherogenesis (232). This risk, although
somewhat attenuated, may extend to individuals with compensated
hypothyroidism associated with dyslipidemia. Biochemical assessment of
thyroid function in hypopituitarism is restricted to measurement of
circulating T4 and T3,
levels of which may vary by at least 2-fold in healthy subjects. It is
therefore difficult to be certain that subtle underreplacement with
thyroid hormone is not an etiological factor for premature vascular
disease in hypopituitarism. Conversely, given the recent demonstration
of increased cardiovascular morbidity associated with a low TSH
(233), it is equally difficult to be sure that marginal
overreplacement is not contributing to increased cardiovascular
mortality.
In summary, it is now accepted that AO-onset hypopituitarism is
associated with reduced longevity. The relative contribution of
premature vascular disease to this increased mortality has not been
consistent, but there is a substantial body of indirect evidence that
hypopituitary patients have an unfavorable cardiovascular risk profile.
The extent to which GH replacement corrects this adverse risk profile
is not clear, because many studies have used pharmacological rather
than physiological doses of GH. Data from a large, multinational
outcome-based research database suggest that fasting lipid profiles are
significantly improved by the lower doses of GH now considered to be
more appropriate for replacement, although the effects are less
dramatic than those observed in the early placebo-controlled trials
(160). It will require several more years of large-scale
surveillance to determine the net effect of GH on cardiovascular
morbidity and mortality in hypopituitarism.
 |
XIV. Transition from Pediatric to Adult Clinic
|
|---|
The completion of linear growth has, traditionally, been the
logical endpoint at which to discontinue GH therapy for GHD children.
Indeed, for many patients, particularly those with isolated GHD, this
is likely to have been predicted by the childs physician at the start
of treatment. However, in the light of the above discussion on the
effects of GH in adult hypopituitarism, the practice of discontinuation
of GH at final height requires careful reevaluation. Adults and
children with GHD have traditionally been managed by physicians in
separate departments, and the clinical research performed by those
departments has, in general, focused on different clinical endpoints.
This means that there is a paucity of data on which to base management
decisions in young adults who have completed their linear growth. As
discussed earlier, GH secretion rates decline rapidly once puberty is
complete and continue to decline steadily thereafter (39).
Hence, the diagnostic criteria for severe GHD in adults (<3
µg/liter, 9 mU/liter during a provocative test) (234)
may not be appropriate for an individual who has just completed linear
growth. The definition of severe GHD in this age group has yet to be
defined, but it is likely to be more closely allied to the
pediatric range (<510 µg/liter, <1530 mU/liter)
(235).
Observational discontinuation studies provide some surrogate evidence
as to the effects of GH discontinuation at the completion of linear
growth. Such studies require cautious interpretation, because of the
fact that a substantial proportion of patients treated with GH
replacement in childhood show evidence of normal GH status by the time
final height is achieved (236, 237, 238, 239, 240). This observation
makes retesting mandatory before re-starting GH can be considered. The
guidelines from a consensus meeting on the diagnosis of GHD in adults
(7) suggested that in patients with isolated idiopathic
GHD, two biochemical tests of GH status are required, while a single
provocative test is sufficient in patients with multiple pituitary
hormone deficits. The issue is further clouded by the fact that, until
fairly recently, supplies of GH were limited, such that some of the
older publications in which GHD adolescents have been compared with
age-matched healthy controls may have included patients treated with
suboptimal GH dosing regimens due to the lack of availability of
pituitary-derived GH.
 |
XV. Effects of Discontinuation of GH Treatment at Final Height
|
|---|
It is not sufficient merely to cite evidence from the adult
literature as an argument for continuing treatment with GH in GHD
adolescents after the completion of linear growth. Several
observations, such as lower IGF-I levels, lower lean body mass, reduced
height, less reduction in quality of life assessment, and less marked
derangement of serum lipoprotein levels in CO-GHD, suggest that the CO-
and AO-GHD states should be considered as two separate entities
(156). Given that the logic for continuation of GH into
adult life lies in the prevention of the adult GHD syndrome, a brief
review of the evidence that withdrawal of GH therapy in this patient
group is associated with adverse pathophysiological changes is
necessary before possible dosing strategies can be discussed.
A. Body composition
There is some evidence, in GHD young adults, that withdrawal of GH
therapy is associated with adverse changes in body composition.
Rutherford et al. (241) reported a
statistically significant decrease in muscle strength and an increase
in fat mass in adolescent patients with CO-GHD 1 yr after cessation of
GH. Similar changes in fat mass were subsequently reported by Colle and
Auzerie (242) and, although, both studies were
small (eight and six patients, respectively), analysis of nine separate
studies that have examined this question does suggest that withdrawal
of GH at the completion of final height is associated with the
development of abnormal body composition (243). In a
recent report of the effects of discontinuation of GH at final height
(244), adverse changes in body composition within 12
months of withdrawal of GH were documented, in patients subsequently
shown to be GHD on retesting at the conclusion of the study. However,
interpretation of these data is made difficult because IGF-I levels in
those patients subsequently shown to have persisting GHD were
approximately 50% greater than those with normal GH reserve on
retesting. In other words, such data may relate more closely to the
effects of the reversal of GH excess than to the discontinuation of
more physiological doses of GH.
In a recent study, Vahl et al. (245) randomized
patients either to continue with a weight-based GH dose or placebo for
12 months after the completion of linear growth. At the end of this
time, all patients continued GH. Statistically significant increases in
body fat were noted in the placebo-treated patients, changes that were,
in large part, reversed when GH was recommenced. Interestingly, despite
these changes in body composition, no significant differences were
noted in insulin sensitivity between the two groups (246).
These findings provide important, complementary evidence to
observational discontinuation studies, but must be interpreted with a
degree of caution. The (weight-based) doses of GH used in the study
were closer to those employed in pediatric than adult practice, despite
the fact that several of the patients were in their mid-20s. Serum
IGF-I levels were elevated in several patients at the start of the
study and remained elevated in many of those randomized to continue GH.
Studies in similar patients, utilizing lower, more physiological, doses
of GH, are needed.
B. Bone mineral density
As discussed earlier, there is clear evidence that GH is important
for the maintenance of BMD in adults, and it is likely to be important
in accruing bone mass early in life (179, 247). Most bone
mass is acquired during late adolescence or young adulthood and,
together with subsequent age-related loss, determines an individuals
fracture risk later in life. Patients with CO-GHD are relatively
osteopenic compared with age-matched healthy controls (179, 247). This is true both for patients with isolated GHD and those
with multiple pituitary hormone deficiencies (247),
supporting a role for GH in the attainment of peak bone mass. After
cessation of GH therapy in young men with AO-GHD, far from significant
bone loss, BMD continues to increase for at least the next 18 months
(248), although it remains unknown whether this increase
in bone mass is suboptimal in the absence of GH replacement. However,
the confounding issue of the adequacy of GH treatment may be
particularly important in this area, as BMD is significantly higher in
younger patients treated with rhGH compared with patients treated
initially with cadaveric GH (249). Although it is
generally accepted that GHD in childhood is associated with a failure
to reach peak bone mass, there are no data at present from controlled
trials to justify a recommendation of continuation with GH therapy at
final height. However, it is clear that BMD should be assessed in these
patients and, indeed, continuation of GH therapy until the achievement
of peak bone mass has been advocated (249).
In summary, there is some evidence that withdrawal of GH therapy on
completion of linear growth in GHD adolescents may be associated with
impaired somatic development and adverse changes in body composition.
To date, there is little evidence that such patients are significantly
disadvantaged in terms of quality of life and well-being, insulin
sensitivity, or surrogate markers of cardiovascular risk. In the
absence of such data to justify widespread continuation of GH into
adult life and the paucity of evidence of the consequences of delaying
reintroduction of therapy, a number of potential strategies exist. One
approach is to continue GH therapy in a seamless manner into adult life
with only a brief cessation of therapy to allow reassessment of GH
status. A second strategy, given that the greatest short-term benefit
of GH replacement in adult life is improved quality of life and that
psychological benefit is proportional to the degree of pretreatment
morbidity, is to offer GH replacement only to those patients who, on
withdrawal of GH at final height, are most disadvantaged in terms of
QoL. A proportion of GH-deficient patients report entirely normal QoL
while off treatment, and this is more common in CO disease
(156). Hence, a period of time off treatment would allow
an assessment of whether GH therapy is likely to be symptomatically
beneficial. A policy of seamless transition from childhood to adulthood
would not permit the identification of such patients. Furthermore, the
prospect of life-long therapy with GH may not be particularly appealing
to an adolescent patient who has completed treatment to final height.
Compliance with further therapy is likely to be greatly enhanced
if the patient is allowed to experience a significant period of
symptomatic GHD before beginning replacement in adult life. A third
strategy for the management of GH during transition to adult life is to
continue with GH for a few years after the completion of growth
to facilitate the development of peak bone mass, after which therapy
could be discontinued.
 |
XVI. Dosing Strategies for the Adolescent Patient
|
|---|
In addition to the timing of GH therapy during transition from
childhood to adult life, a question remains regarding the most
appropriate dose to employ. The doses of GH used toward the end of
linear growth are approximately 36 times the average dose used in
adult GH replacement. This is in keeping with the decline in normal GH
secretion after the completion of puberty. A number of different
approaches may be taken to dosing in such patients, and the most
appropriate method will depend, at least in part, on the timing of the
recommencement of GH after retesting. If GH therapy were stopped for a
number of years after the attainment of final height, restarting
treatment at a low dose and gradually titrating up according to the
IGF-I response (i.e., the increasingly standard practice in
adults) would probably be most appropriate. However, if a seamless
transition of GH therapy into adult life is used, various, alternate,
options exist. A low-dose titration regimen could be instituted as soon
as the decision has been made to continue treatment. However, it is
likely that the dose required to normalize serum IGF-I levels in the
period immediately after the completion of linear growth will be closer
to the pediatric than adult dose, and building up to an appropriate
maintenance dose may take some time. It may therefore be more
appropriate initially to continue treatment at the pediatric dose and
gradually titrate down according to serum IGF-I levels. A further
potential approach would be to continue GH at the higher pediatric dose
until the completion of somatic development to allow maximal accrual of
bone and muscle mass before transition to adult replacement levels.
There are no current data that indicate the correct approach to adopt
although current studies are addressing this issue. Regardless of the
strategy adopted, robust age-related reference ranges for GH-dependent
serum markers are mandatory.
 |
XVII. Influence of Adult GH Replacement Studies on Pediatric
Practice: Reevaluation of Pediatric Practice
|
|---|
It may be considered a disadvantage of adult GH replacement that
there is no easily definable clinical endpoint of treatment, such as
linear growth, against which therapy can be titrated. However, the
absence of an easily measurable effect of treatment has necessitated a
far more detailed study of GH replacement that has widened our
knowledge of the regulation and actions of GH in adult life. This has
also been assisted by the much wider scope for clinical studies in
adults compared with children. Placebo-controlled studies are extremely
difficult to perform in pediatric practice, particularly when there is
only a finite window of opportunity for growth to occur. In addition,
assessment of some parameters such as BMD and quality of life in
children is problematic. Thus, the extension of GH therapy to adults
has provided new information that has prompted a reassessment of
pediatric practice and raised a number of important questions.
The results of retesting patients treated for GHD during
childhood have demonstrated that a significant proportion have normal
GH responses to provocative tests after the completion of linear growth
(65, 236). It has been suggested that this may indicate
that GHD can be temporary, but no convincing evidence for this theory
has been produced. A more likely explanation is that a significant
proportion of children diagnosed as GH deficient in childhood actually
have normal GH reserve. While the proportion of individuals
inappropriately labeled GH deficient will vary between different
cohorts (groups with more organic GH deficiency are likely to have
fewer patients with normal GH reserve) (236), on retesting
it is likely that all large groups of GH-deficient children will
contain some GH-replete patients. This has implications for the
interpretation of data from studies of childhood GH replacement. The
peak GH response to provocative tests negatively correlates with final
height in GH-treated children, suggesting that GH-replete subjects will
not respond as well to GH replacement as severely GH-deficient
patients. This is supported by the observation that GH treatment of
children with idiopathic short stature, Turner syndrome, or skeletal
dysplasia (all of whom have normal GH secretion), does not result in
the same magnitude of growth response as treatment of severely
GH-deficient children. Thus, the presence of GH-replete subjects in a
cohort of GH-deficient children will dilute the observed response to GH
therapy, and studies of GH replacement may therefore be underestimating
the benefit of treatment if they contain a significant proportion of
normal individuals. In addition, data from treatment of children with
idiopathic short stature and Turners syndrome suggest that larger
doses of GH are required to enhance growth of GH-replete children.
Clinicians need to be aware of these possible flaws in previous studies
and of the potential problems with diagnosis of GHD in childhood.
Studies of the treatment of GH-deficient adults have demonstrated the
wide range of actions of GH and have indicated the potential
abnormalities associated with GHD and the changes that occur with GH
replacement. This has confirmed that the benefits of GH replacement
during childhood extend beyond linear growth and suggest that the
assessment of parameters other than height may be useful. The efficacy
of GH therapy in childhood has, however, been almost entirely evaluated
by changes in linear growth. Decisions regarding the selection of
patients for GH therapy, the dosing schedules used, and the duration of
treatment are based, to a great extent, on auxological criteria, and
achievement of a maximal final height is the ultimate (and in some
cases the only) goal of therapy. Indeed, a recent commentary on the use
of GH for short children over the last four decades focused almost
entirely on linear growth (87).
There is, however, a flaw in concentrating only on linear growth when
considering the optimal treatment of GH-deficient children. Studies
in non-GHD children given GH therapy for idiopathic short stature or
Turner syndrome have demonstrated that pharmacological GH treatment
results in increased growth velocity and an improvement in final height
in GH-replete individuals if enough GH is given and treatment is
initiated at an early enough age. This is, of course, no surprise given
the increased linear growth observed in children with pituitary
gigantism. Thus, excessive replacement of GH-deficient patients may
confer a minor growth advantage over physiologically replaced
individuals. Complete reliance on growth parameters to monitor therapy
is therefore likely to result in overtreatment of some patients. It
could be argued that it is more important to maximize the final height
of a GH-deficient child than to attempt to achieve near-physiological
GH replacement. This is contrary, however, to standard practice in
other areas of endocrinology in which physiological replacement of a
deficient hormone is usually considered the ideal of therapy. With
modern treatment protocols, the majority of GH-deficient subjects
will reach a height within the normal range, and it must be questioned,
therefore, whether supraphysiological treatment can be justified on
clinical or financial grounds.
Finally, the reliance on final height as the ultimate goal of
therapy ignores the fact that moderate short stature per
se does not confer any physical disadvantage on patients.
Rather, it is assumed that short stature has a deleterious effect on
psychosocial functioning, for which there is some evidence (250, 251). More recent reports, however, have failed to confirm this
(252, 253, 254, 255) and have suggested that the original studies
were flawed by referral bias, as short children with academic or
behavioral problems were more likely to be referred to clinics and were
therefore more likely to participate in studies than children with
short stature who did not have such difficulties (256).
Studies of nonreferred populations have failed to show any psychosocial
disadvantage in normal short children (257), suggesting
that social and behavioral problems may have been inappropriately
attributed to short stature. Thus, while there is evidence of
psychosocial disadvantage among GH-deficient patients, the extent to
which this can be attributed to short stature per se, and
therefore the extent to which improvements in final height will be
beneficial, is doubtful.
There are very few data concerning the impact of GH status on
parameters other than growth, such as body composition, BMD, and lipids
during childhood. This relates, in part, to the paucity of normative
data for comparison in younger subjects, and the difficulties presented
by the impact of linear growth and pubertal development on BMD and body
composition measurements, particularly in GH-deficient patients in whom
poor growth and delay in pubertal development may be apparent. A few
studies, however, have demonstrated reduced BMD in GH-deficient
children compared with age- and sex-matched normal controls, with
improvements after the initiation of GH replacement (249, 258, 259). Despite this, studies in young adults have demonstrated
low bone mass after GH replacement in childhood (179, 247, 260, 261). This is likely to be a result of periods of untreated GHD
either before the start of childhood treatment or between the
completion of childhood therapy and the assessment of bone mass,
although the possibility of suboptimal childhood GH replacement also
exists.
Changes in body composition are well recognized effects of GH
replacement during childhood, although this has rarely been formally
assessed. An increase in lean body mass with an associated reduction in
fat mass has been demonstrated following commencement of GH therapy
(129, 258). After discontinuation of therapy at the
completion of linear growth, unfavorable changes in body composition
occur within the first 12 months (244). Similarly,
beneficial effects on lipid profiles have been observed during
childhood GH therapy (258), with adverse changes occurring
after the completion of treatment in adolescence (242).
Measurement of some of these parameters during childhood will assist in
defining an individuals response to therapy. This will be of
particular importance at the end of linear growth and may be helpful in
deciding the optimal management strategy during the transition to
adulthood.
Studies of GH replacement in adult life have also provided information
regarding the correct replacement dose for GH-deficient patients.
Symptoms of GH excess are relatively more common during the treatment
of adults (262), particularly in the initial studies of
adult GH replacement in which patients were commonly given
supraphysiological doses. In addition, with potentially life-long
treatment, some concern exists about the health risks, and extra
financial burden, of mild overtreatment. This has been emphasized by
recent reports linking circulating IGF-I levels in the upper part of
the normal range with breast and prostate cancer in normal individuals
(204, 205, 206). As a result, efforts have been made to ensure
that GH is administered in a physiological fashion, and methods for
optimally monitoring therapy have been investigated (143, 263, 264). In adults, measurement of serum IGF-I appears to be the
most reliable way of assessing the appropriateness of GH dose, and
this, in combination with clinical evaluation, forms the basis for the
monitoring of therapy (7).
In pediatric practice, the dose of GH is usually calculated
according to weight or surface area, and the appropriateness of this
dose is not monitored biochemically. This does not allow for any
interindividual variability in GH sensitivity or residual GH secretion.
Unfortunately, there are few data regarding IGF-I levels in children
treated with GH; a pathologically low level while on treatment implies
poor compliance or suboptimal dosage (78), but the fear
that many children might only achieve an increase in growth velocity at
the expense of a pathologically elevated IGF-I level has not been born
out in practice (77, 78), although more data
are required. Thus, it is likely that some children treated with GH are
receiving supraphysiological doses. Because of the relatively short
duration of treatment during childhood compared with that potentially
used in adult practice, concerns regarding side effects of mild
overtreatment are less. There are no data, however, that confirm the
long-term safety of mild GH excess during childhood. In addition, the
financial restraints imposed on most practices would argue for using
the lowest efficacious dose possible. Thus, it would seem reasonable to
aim for physiological replacement as an ideal goal of therapy.
Extrapolation from adult practice would suggest that maintaining the
IGF-I within the normal range is the most reliable way of achieving
this, and monitoring of IGF-I levels during treatment would provide a
relatively simple method of individualizing GH replacement. However,
there is likely to be some reluctance to rely entirely on the IGF-I
level as the indicator of optimal treatment dose in patients who have
responded well to GH replacement in terms of growth but demonstrate a
high level of IGF-I. There are no data at present that indicate whether
reducing the dose to that which will maintain the IGF-I within the
normal range would have any deleterious effect on growth. For the time
being, linear growth remains the main goal of childhood GH treatment.
The usefulness of knowing the IGF-I level in terms of titrating the GH
dose remains to be proven in pediatric practice.
Finally, the demonstration of the benefits of GH in adult life
suggest that, instead of being a treatment that is confined to
childhood, GH replacement should be considered potentially as
life-long. The management of the transition between pediatric and adult
GH replacement remains a challenge. Preparation for the possibility of
treatment in adult life should begin during childhood with discussions
of the possible need for continuation of therapy after the completion
of linear growth. The most appropriate management of the transition
period will depend, to a great extent, on the patients reaction to
the possibility of the continuation of treatment, and this in turn will
depend on the information provided by the pediatrician during childhood
therapy. A patient who has been assured that GH injections need only be
continued until the completion of linear growth is less likely to be
receptive to the idea of continuing therapy into adult life than the
patient who has been adequately prepared. Thus, the acceptance of
treatment during adulthood will be determined, to some extent, by
the acceptance of the benefits of adult GH replacement by
pediatricians. This will require recognition that there is more to GH
replacement than growth itself.
 |
Footnotes
|
|---|
Abbreviations: AGHDA, adult GH deficiency assessment; ALS,
acid-labile subunit; AO, adult onset; BMD, bone mineral density; BSAP,
bone-specific isoenzyme of alkaline phosphatase; CO, childhood onset;
FM, fat mass; GC, glucocorticoid; GGSG, Genentech Growth Study Group;
GHBP, GH binding protein; GHD, GH deficiency; IGFBP, IGF binding
protein; KIGS, Kabi International Growth Study; LBM, lean body mass;
NCGS, National Co-operative Growth Study; NHP, Nottingham Health
Profile; PGWB, Psychological General Well-Being Schedule; QoL, quality
of life; rhGH, recombinant human GH; SST, somatostatin; TBK, total body
potassium; TBW, total body water.
 |
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W. M. Drake, P. V. Carroll, K. T. Maher, K. A. Metcalfe, C. Camacho-Hubner, N. J. Shaw, D. B. Dunger, T. D. Cheetham, M. O. Savage, and J. P. Monson
The Effect of Cessation of Growth Hormone (GH) Therapy on Bone Mineral Accretion in GH-Deficient Adolescents at the Completion of Linear Growth
J. Clin. Endocrinol. Metab.,
April 1, 2003;
88(4):
1658 - 1663.
[Abstract]
[Full Text]
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Y. Song, S. Kato, and J. C. Fleet
Vitamin D Receptor (VDR) Knockout Mice Reveal VDR-Independent Regulation of Intestinal Calcium Absorption and ECaC2 and Calbindin D9k mRNA
J. Nutr.,
February 1, 2003;
133(2):
374 - 380.
[Abstract]
[Full Text]
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D. C. O'Sullivan, T. A. M. Szestak, and J. M. Pell
Regulation of IGF-I mRNA by GH: putative functions for class 1 and 2 message
Am J Physiol Endocrinol Metab,
August 1, 2002;
283(2):
E251 - E258.
[Abstract]
[Full Text]
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M. E. Molitch
Diagnosis of GH Deficiency in Adults--How Good Do the Criteria Need to Be?
J. Clin. Endocrinol. Metab.,
February 1, 2002;
87(2):
473 - 476.
[Full Text]
[PDF]
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