Four Decades of Growth Hormone Therapy for Short Children: What Have We Achieved?
Harvey J. Guyda
Department of Pediatrics, McGill University, Montreal Childrens
Hospital-McGill University Health Center, Montréal,
Québec, Canada H3H 1P3
Address all correspondence and requests for reprints to: Dr. Harvey J. Guyda, Department of Pediatrics, McGill University, Montreal Childrens Hospital-McGill University Health Center, 2300 Tupper, Suite C-414, Montréal, Québec, Canada H3H 1P3. E-mail: harvey.guyda{at}muhc.mcgill.ca
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Introduction
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The therapeutic use of GH derived from human
cadaveric pituitaries was introduced in the late 1950s and early 1960s
(1). Initially, supplies were severely limited, and few patients
received treatment outside of research protocols. Although the
production of pituitary GH slowly increased over the first 2 decades,
supplies could not meet the demand to treat all patients believed to
have GH deficiency (GHD). Fortuitously, and too late for many patients
who had received pituitary-derived GH, the last 2 decades have seen the
dramatic increase in worldwide availability of biosynthetic GH. This
has resulted in improved treatment protocols for children with GHD as
well as the administration of GH for other non-GHD conditions in
childhood and adolescence: idiopathic short stature (ISS), intrauterine
growth retardation, chronic renal failure, and genetic disorders such
as Turner and Down syndromes (2, 3, 4). The adult population with
childhood-onset GHD as well as adult-onset GHD has begun to be
addressed, as has the use of GH in the elderly.
This commentary will focus on the patient populations for which the
majority of the supplies of GH have been used over the past 40 yr,
namely children and adolescents with short stature. Table 1
illustrates the current world-wide
distribution of GH use in almost 100,000 children. We will focus on the
attainment of final height, with consideration of psychosocial outcomes
when available. Where pertinent, comments with regard to the expanded
role of GH use in adult populations will be discussed.
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GH treatment of the GH-deficient child
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An evaluation of final height outcome for children with GHD
treated in childhood is confounded by several factors, including the
lack of a world-wide consensus on the definition of GHD, the lack of
uniform entry criteria, and the variable age of GH treatment onset,
dose of GH, spontaneous pubertal development, or sex steroid
introduction (5). Further, there are no parallel controlled studies to
assist in outcome evaluation. To interpret what follows, it seems
prudent to begin with a brief consideration of the criteria employed by
this author for the diagnosis of childhood GHD (5).
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The diagnosis of classical GHD
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The reported prevalence of idiopathic GHD (IGHD) per million of
total population varies from 1824/million in the United Kingdom,
Germany, and in France to 62/million in Sweden, and 287/million in the
United States (3). This high variability is related to differences in
diagnostic criteria, with inclusion for treatment of less severe forms
of IGHD, i.e. older age at diagnosis and higher median serum
GH level in provocation tests. The large majority of children with
short stature (<3rd percentile) and a growth velocity of less than 5
cm/yr (<10th to 25th percentile) have nonendocrine causes of their
growth failure. The minimal acceptable criteria for the diagnosis of
GHD should include a combination of auxological and biochemical
criteria for the most severe or complete forms of GHD. Children most
likely to have significant GHD and to benefit most from GH treatment
will be 1) of younger age, 2) significantly short (less than -3
SD score), 3) have significantly delayed skeletal
maturation (less than -2 SD score), and 4) be
growing slowly (<5th to 25th percentile for height velocity).
Recognizing that GH secretion is a continuous spectrum, most countries
have established criteria for the diagnosis of GHD based upon an
arbitrary peak serum GH response (usually >7 to 10 µg/L in
polyclonal RIAs) to at least two provocative GH stimulation tests (3, 5). The physiological assessment of GH secretion by frequent sampling
throughout the 24-h period is not more reliable, i.e.
encompassing both sensitivity and specificity, than standard
provocative GH stimulation tests. For this reason, most national
programs do not require physiological GH assessment (3). Several
researchers have shown a good correlation with combination use of serum
levels of insulin-like growth factor I (IGF-I) and IGF-binding
protein-3 relative to age- and sex-matched control values and GH
stimulation test results (6, 7, 8). As the criteria become less strict,
the inclusion into GH treatment programs of children who could be
considered to have normal GH secretion becomes increasingly likely,
until one arrives at the Australian model, in which GH secretion
assessment was not required (9). Finally, newer assay techniques, such
as enzyme-linked immunosorbent assay, immunoradiometric assay, and
ligand immunofunctional assay, in conjunction with a change in
GH standards employed in the assays, give serum GH levels that are more
than 2- to 3-fold lower than the normal GH level determined with older
polyclonal RIAs. This has confounded outcome assessment of patients
with classical GHD, who were usually diagnosed with the older RIAs.
This is well exemplified by the report of extensive GH testing in the
evaluation of the short child by Carel et al. (10)
The use of magnetic resonance imaging has defined diagnostic markers in
a high percentage of children (up to 80%) previously labeled as IGHD.
The features of the Pituitary Stalk Interruption Syndrome (PSIS)
include lack of a visible or an interrupted pituitary stalk, anterior
pituitary hypoplasia, and lack of the normal posterior lobe hypersignal
in the sella turcica, with an ectopic hyper intense posterior pituitary
(11). In many patients with this finding, multiple anterior pituitary
hormone deficiencies may be found at diagnosis or later. More than half
of the patients with isolated GHD demonstrate findings of PSIS (11).
Isolated pituitary hypoplasia has been found in approximately 25% of
children with severe isolated GHD and, surprisingly, in 2533% of
children labeled as having ISS. This technique has not been used in the
majority of studies of final height attainment in short children
treated with GH reported to date.
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GHRH and GH-releasing peptides (GHRPs) in the evaluation of GH
secretory status in short children
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As normal GH secretion is dependent upon both GHRH stimulation and
somatostatin (SRIF) inhibition, we have recently addressed the utility
of controlling SRIF tone before the administration of a bolus of GHRH
as a diagnostic test (12). Our findings support the hypothesis that
control of endogenous SRIF tone can lead to an augmented and a more
reproducible peak serum GH response to a single bolus GHRH
administration in short children with normal GH secretion, as
determined with standard provocative GH tests. The combined GHRH-SRIF
test has been validated in a small number of GHD patients to determine
its reliability and specificity as a potential single test for the
assessment of GH secretion in the short child who may have normal GH
secretion (13).
The new generation of GH secretagogues, called GHRPs, stimulates GH
release when given by oral, intranasal, or parenteral route (1). The
coadministration of GHRP with GHRH provokes a synergistic effect on GH
release. In addition, several nonpeptide analogs that stimulate GH
release and may be given orally have been synthesized recently (1).
Children with classical GHD, and especially those with PSIS on magnetic
resonance imaging, will have a markedly diminished GH response to
GHRPs. This has been interpreted to indicate a chronic absence or
diminution of endogenous GHRH secretion. In children with so-called
neurosecretory dysfunction, a diagnostic category that this author does
not employ, the GH response to GHRP-6 was similar to that in normal
children and greater than that in children with idiopathic GHD. It
should also be noted that the reliability of GH stimulation tests, with
the use of GHRH or GHRPs in particular, can be improved if endogenous
SRIF tone is controlled by various agents, including pyridostigmine,
arginine, or pretreatment with SRIF analogs (12, 13).
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Reevaluation of GH secretion in adults treated with GH during
childhood: implications for GH therapy of adult patients with GHD
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There are several reports that document that the use of inadequate
diagnostic criteria for GHD in childhood may result in a significant
number of subjects having a normal GH result upon retesting after
discontinuation of GH therapy (14, 15, 16). The rate of normal retest may
exceed 50% of those children initially labeled as GHD. The Canadian
Growth Hormone Advisory Committee established strict diagnostic
criteria for the diagnosis of GHD in 1967. The diagnostic criteria
included clinical signs of GHD (short stature and growth velocity less
than -2 SD score below the mean for bone age) and peak GH
below 5 µg/L (before 1983) or below 8 µg/L (after 1983) after
insulin hypoglycemia, arginine, or combined
L-Dopa-propranolol testing on two separate occasions. The
Canadian Growth Hormone Advisory Committee established a follow-up
program in 1983 for routine retesting performed 13 yr after
termination of GH therapy. The data for 112 adults retested between
19831995 revealed a high true positive rate of 95% in childhood
onset due to organic causes and 91% in idiopathic GHD (Reyes, L.,
et al., unpublished). Only 7 of 112 had a peak GH more than
8 µg/L, and 13 of 112 patients had a peak GH more than 5 µg/L on
retest. The mean age at retest was 20.7 yr. As noted above, other
studies using less strict criteria may have retest normal rates as high
as 70% (10). These data have important implications for the diagnosis
of GHD in adults previously treated with GH during childhood.
The last decade has seen enhanced recognition of the adult syndrome of
GHD. Children with GHD cannot be assumed to become GHD adults and
should not continue on GH therapy into adult life without
reinvestigation. All children with severe GHD should be retested at
completion of linear growth to identify those with are truly GHD adults
who may benefit from replacement therapy (16). A recent workshop has
established a consensus on the diagnosis of adult GHD (17). The
recommendation is that severe adult GHD should be defined biochemically
in patients with evidence of hypothalamic-pituitary disease, subjects
who have received cranial irradiation, or patients with childhood onset
of GHD. Adult patients with hypothalamic-pituitary disease and one or
more additional pituitary hormone deficits require only one provocative
GH test. The insulin tolerance test is the longest established test and
has become the preferred test for the diagnosis of adult GHD. In
adults, a normal serum IGF-I level does not exclude the diagnosis of
GHD, and serum IGF-binding protein-3 has no diagnostic value in adults
(7, 17). All adults with documented severe GHD are considered to be
eligible for GH replacement. Initial reports have documented beneficial
effects in body composition and bone density, substrate metabolism,
physical performance, psychological well-being, and quality of life.
The effect on cardiovascular mortality remains to be determined. It is
recommended that adult GH therapy should start with a low dose
(0.150.30 mg/day) and should not exceed 1.0 mg/day. At present, the
best biochemical marker of GH action is serum IGF-I (18). Although
insufficient information is available at present, GH replacement is
most likely for life, raising the need for adequate
resources and facilities for long term monitoring. The major
restriction on the widespread use of GH in adult GHD is cost.
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Final height attainment in children diagnosed with GHD and treated
during childhood
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After 40 yr of experience with the use of GH to treat thousands of
children with GHD, the world experience concerning final height
attainment, particularly in a large series of patients, has been quite
limited until recently (19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32). The available data are summarized in
Tables 2
and 3
, which provide information on children
treated almost exclusively with either pituitary GH (19, 20, 21, 22) (Table 2
)
or recombinant GH (23, 24, 25, 26, 27, 28, 29, 30, 31, 32) (Table 3
). It is to be stressed that the
criteria used for the diagnosis of GHD varied considerably, and highly
variable assay methodology was used for the determination of GH values.
In addition, the therapeutic regimens used for GH doses and frequency
were quite disparate. Finally, the accuracy of the final height
measurement could not be assessed.
The limited published experience on the long term growth response after
treatment of GHD children with pituitary GH is summarized in Table 2
.
While an impressive mean gain of 1.9 SD score was achieved,
the patients still ended up quite short (-2.3 SD score)
due to the late onset of therapy associated with extreme short stature
(-4.2 SD score). GHD patients treated almost exclusively
with recombinant GH started with less height deficit and achieved
greater adult height than those treated with pituitary GH, with a mean
additional gain of 0.9 SD score (-1.4 vs. -2.3
SD score; range of final height, -0.1 to -2.1;
Table 3
). Although they did not achieve mean target height, the
majority of GHD patients treated with recombinant GH over the past
decade were within the normal adult range for height. These patients
received rGH at larger doses, more frequently, and usually for a longer
mean duration (6.2 vs. 5.6 yr). Patients who are younger and
who have the greatest deficit in height achieve the greatest total
height gain on GH therapy. The majority of studies show that patients
with spontaneous onset of puberty are shorter than those in whom
puberty is induced. The Kabi International Growth Study (27, 31)
demonstrated that midparental height is one of the major factors
influencing final height following GH treatment of children with
GHD.
One of the largest series reported the comprehensive outcome of all
children treated with GH in France over the last 24 yr (28). GH did not
restore normal growth to these children, most with apparent GH
deficiency (Table 3
). However, the diagnosis of GHD was uncertain in
many patients, especially those in whom puberty began at a normal age.
In Japan, as many as 30% of the patients previously labeled as IGHD
(Tanaka; Table 2
) most likely have idiopathic short stature (Tanaka,
T., unpublished observations). This has led to new stricter
criteria for GH therapy in Japan and a reduction in GH utilization
(Table 1
). In the Canadian follow-up study of 112 adults with GHD noted
above, final height was 162.6 ± 8.1 cm (-2.2 SD) in
boys and 153.1 ± 9.0 cm (-1.8 SD) in girls. This was
less than optimal, but superior to the outcome for Canadian GHD
patients treated before 1985 (19) (Table 2
).
August et al. (29) analyzed pubertal growth and final height
in 194 female and 480 male subjects in the United States with a
diagnosis of idiopathic GHD, defined as a maximum stimulated GH level
of 10 µg/L or less and no evidence of an organic cause. The total
height gained during puberty was 22.4 ± 7.9 cm in males and
17.4 ± 6.3 cm in females. The percentage of adult height gained
during puberty was 13.3 ± 4.6% in males and 11.3 ± 4.0%
in females. These gains were similar to the results of two other
smaller studies of children with GHD and to growth characteristics of
normal children undergoing puberty. There was a significant negative
correlation between the age at onset of Tanner stage 2 and both the
total height and the percentage of adult height gained during puberty.
The near-adult height achieved (-1.3 SD score in
males and -1.6 SD score in females; Table 3
) did
not attain the target adult height SD score
(-0.4 to 0.5 SD score).
The Italian study by Cacciari et al. (32) is unusual in
comparison with the majority of studies reporting GH treatment of GHD,
due to the following: 1) the baseline height SD
score (-2.2) is less abnormal; 2) the duration of GH treatment (3.3
yr) is much less; 3) the mean age of onset of GH therapy (12.2 yr) is
older; and 4) the majority of patients were pubertal at this normal
age. This report illustrates the dilemma in the evaluation of outcomes
when the specific diagnosis of GHD is uncertain and the diagnosis of
so-called normal short stature is more likely. For this reason, these
data are not presented in Table 3
.
The social outcome of young adults treated with pituitary GH for
childhood GHD was not very satisfactory. Relative to the general
population, they tended to have lower educational status, higher
unemployment rate, and lower marriage rate (19). However, the
diagnostic etiology (e.g. cranial tumors), concurrent
medication dependency with risk of hypoglycemia, and the late
consequence of cranial irradiation confound studies of psychological
morbidity of childhood GHD. A more recent study has observed very
limited differences between GHD patients and same sex sibling controls
(33). Isolated GHD patients functioned marginally better than those
with multiple pituitary hormone deficiencies. These are very reassuring
findings that suggest that there is not significant psychological
morbidity associated with childhood GHD when optimal GH treatment is
provided.
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GH treatment and final height of the non-GH-deficient short
child
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Despite the paucity of published controlled data that clearly
indicate benefit, GH has become the most widely employed and most
controversial therapeutic agent in the non-GH-deficient short child
(3, 4, 5). The use of GH for the child with ISS and Turner syndrome
represents a significant proportion of total use, averaging from
2458% in the larger series (Table 1
). This section will review the
final height attainment with GH use in ISS and Turner syndrome.
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GH treatment benefits in idiopathic short stature
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There have been many short term studies that indicate that some
normal short children have acceleration of short-term growth velocity
with GH administration. Table 4
summarizes the most recent final height attainment data for 413 short
normal children treated with GH for many years (34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44). The majority
of patients were male, and the mean duration of GH treatment with
variable doses exceeded 5 yr. The overall mean final height gain over
predicted adult height was only 2.7 cm or +0.4 SD score.
One of the larger and more optimistic experiences with GH treatment of
ISS is the collaborative U.S. study sponsored by Genentech, Inc. (South San Francisco, CA) (43). This group has treated 121
patients with ISS not due to classical GHD for up to 9 yr. These
uncontrolled data suggest a more positive benefit in near-final height
attainment than all other studies have found. In their most recent
report of 80 of these short children (43), the difference from
predicted adult height was 5.9 cm for girls and 5.0 cm for boys.
Compared to 21 untreated historical controls with less than -2
SD, adult height was 9.2 cm greater for boys and 5.7 cm
greater for girls. These researchers concluded that GH treatment of
patients with marked short stature not associated with classical GHD
results in an increase in mean final height. The reasons for the marked
discrepancy between these data and the majority of other reports cited
above are unclear. It is possible that the initiation of GH treatment
at a younger age and the absence of undue bone maturation acceleration
may have been critical. As the drop-out rate in this study was 31%, an
intent-to-treat analysis would reduce the observed benefit.
In those studies in which available untreated control children have
been studied, the final adult height attainment has usually been less
than predicted, thus adding potential additional benefit to the gain
over predicted height. For example, in the limited randomized
controlled trial by McCaughey (42), 8 girls treated at a GH dose of
1.0 IU/kg·week for a mean of 6.2 yr gained 3.5 cm over their
predicted height. However, they were 7.5 cm taller than the untreated
control group of 6 girls, and 6.0 cm taller than a nonconsent
group of 20 girls, similar findings to Hintz (43). In contrast, Kawai
et al. (45) found that 11 short girls treated with a dose of
0.5 IU/kg·week for an average of 5.4 yr had the same final height as
11 untreated controls.
Overall, the majority of the authors concluded that the effect of GH on
children with ISS was a moderate acceleration of growth, which may be
accompanied by similar acceleration of skeletal maturation. This
results in a mean final height that is just above the initial
prediction; without treatment, final height was just below prediction.
However, the mean final height SD score after GH treatment,
for an average of over 5 yr, in children with ISS indicated in Table 4
(-1.7 SD score) is nearly identical to the observed final
height with spontaneous growth in 229 children with ISS (-1.5
SD score for boys and -1.6 SD score for girls)
(46).
Conspicuous by its relative absence has been the downside or negative
outcome evaluation of GH treatment of short children. Only a few
reports describe the total number of patients that started on GH
treatment, the number of cases that did not continue for each year of
observation, or provide any discussion of the reasons for withdrawal.
There has never been a primary intent-to-treat analysis in this vast
published literature. In Australia (3), 34% of 1362 short children
(27% with classical GHD) and in the large study from France (28) 35%
of 2623 children with idiopathic or organic GHD who commenced GH
treatment for short stature did not complete 3 yr of therapy. More
significantly, 40 of 68 children (59%) with short stature and normal
GH secretion stopped receiving GH treatment early. Wit (44) reported
that a startling number of 935 of a cohort of 1258 (74%), who began GH
for ISS had dropped out. Based upon the high drop-out rates, it is very
likely that good outcomes are more likely to be reported than
unfavorable outcomes. A startling exception from Japan (47) has
described a dramatic loss of expected adult height in a small number of
short normal children treated with GH compared with an untreated
control group. A striking loss of 8 cm was observed, probably related
to age of onset of therapy in relation to age of pubertal onset and its
rate of progression.
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Regression to the mean in children with short stature
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As noted above, there is a very significant regression toward the
mean that takes place, and not all short children end up being short
adults. Studies have shown that patients with untreated ISS
spontaneously gained more than 1 SD in final height
compared to height at presentation, and patients presenting with
delayed puberty gained more than 2 SD as adults (48). The
majority achieved normal adult height, and only 10% did not achieve
their familial target height. In addition to these significant
observations, it has been reported that studies using historical or
nonrandomized controls overestimate treatment benefits by an average of
30% (49). Taken together, these critical studies may provide
assistance to physicians in the counseling of parents of the short
child. It is clear that uncontrolled data should not be used to claim
treatment benefits for gain in adult height.
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Is short stature a psychologically disabling disorder?
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GH treatment for short statured children with normal GH secretion
is sought by parents who believe that two things are true: first, that
GH will make children taller, and second, that being taller will
benefit the child. There has been a tendency to regard children who are
referred for evaluation of short stature as being disabled and to be
suffering from psychological dysfunction. Several researchers have
recently challenged the view that the provision of GH therapy for all
short children is justified to improve their psychological functioning,
even if final height is not altered significantly. A reevaluation of
the psychological status of both referred and population-based short
children has concluded that short stature does not appear to be
associated with clinically significant psychological morbidity
(reviewed in Ref. 4). The recently published guidelines and
recommendations of the drug and therapeutics committee of the Lawson
Wilkins Pediatric Endocrine Society (50) support a conservative
position. This committee concluded that GH has not been proven to be
effective in increasing final heights of children with growth disorders
other than growth failure due to GHD, including non-GH-deficient and
genetic short stature other than Turner syndrome. The American Academy
of Pediatrics (51) has recommended a similar cautionary approach.
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GH treatment benefits in Turner syndrome
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The material to be presented consists of three parts: 1) a review
of 16 published reports, 2) a report of the interim analysis of the
Canadian Randomized Trial of GH in Turner syndrome, and 3) a
preliminary report on an international meta analysis of final height in
Turner syndrome.
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Review of 16 published reports
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Donaldson published an excellent analysis of 10 reports of final
height in 481 girls with Turner syndrome from the recent world
literature (52), and several additional studies have appeared
subsequently (53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68) (Table 5
). None of
the studied included a control group, but several were randomized to
different treatment regimens. There was considerable variation in the
treatment protocols as to dose and age of onset of GH therapy and in
the use of estrogens or anabolic steroids (oxandrolone). The mean age
of onset for GH therapy varied from 1015 yr with doses from 0.52.1
IU/kg·week. Estrogens were added from a bone age of more than 11 yr
to a chronological age of 19 yr at doses of 50500 ng/kg·day.
Oxandrolone was used at least in some subjects in five studies at mean
ages of 9.313.2 yr, at a dose of 0.050.1 mg/kg·day. Two reports
from National Cooperative Growth Study (NCGS) are illustrative
of the different outcomes that may be found within the same treatment
protocol. In the largest published study, Plotnick et al.
(63) reported a final height of 148.3 cm in the entire NCGS
database of 622 girls, whereas in a much smaller study, Rosenfeld
et al. (62) reported a final height of 150.4 in the subjects
treated with GH alone (n = 17) and 152.1 in the GH plus
oxandrolone group (n = 43).
The world survey summarized in Table 5
indicates that mean final height
in 2217 girls with Turner syndrome treated with GH is 150.0 cm, which
is 5.7 cm above the projected adult height. There was considerable
individual variability in all studies. Some girls were very short
despite GH therapy, with minimum final height varying between
131.5145 cm in 5 studies. It can be concluded that girls with Turner
syndrome as a diagnostic group do benefit in final adult height with GH
treatment. However, all studies showed a poor outcome in some girls. In
assessing the relevant factors, which may contribute to the optimal
benefit, many researchers have concluded that there are three major
variables to be considered: 1) age of onset of GH treatment, with
younger age being better; 2) GH dose, with larger doses for longer
periods being more efficacious; and 3) age of onset of sex steroid
substitution, with most favorable results ensuing when estrogen
administration was delayed until growth was nearly completed. It is
critical that appropriate controlled studies assess which of these
variables are most critical and, more importantly, best for the
patient. The need has been stated for large national and international
cooperative efforts to perform proper randomized controlled trials and
meta analyses (49).
 |
Canadian randomized trial of GH in Turner syndrome
|
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In 1985, a randomized controlled trial of GH treatment to final
height in Turner syndrome was initiated in Canada (69). One hundred and
fifty-four girls with cytogenetic diagnosis of Turner syndrome, aged
713 yr, were randomly assigned with stratification for height
relative to age at entry to receive no treatment (C) or human GH (hGH;
Humatrope, Eli Lilly Canada, Toronto,
Canada; 0.05 mg/kg, six times weekly). Ethinyl
estradiol (2.5 µg daily) was started at age 13 yr and was
increased to 5.0 µg daily at age 14 yr, and 20 µg on days 124 of
each month at age 15 yr, with medroxyprogesterone acetate (10 mg) added
on days 1524 of each month. Subjects returned for follow-up every 3
months to final height as defined by growth rate less than 2 cm/yr and
bone age of 14 yr or more. Ninety-two girls (59.7%) had karyotype
45,XO. Sixty-nine girls have achieved final height (29 controls and 40
hGH treated), 45 withdrew from the study (32 controls and 13 hGH
treated), and 40 remain in the study (17 controls and 23 hGH treated).
The final height attained was 141.4 ± 4.7 cm (mean ± 1
SD) in controls and 146.2 ± 6.5 cm in the hGH group
(69). Height gains from baseline were 17.0 ± 4.7 (controls) and
24.6 ± 7.8 (hGH) cm. Gains in height SD score (Lyon,
69a) from baseline were 0.3 ± 0.4 (controls) and 1.5 ± 0.5
(hGH). The mean hGH effect estimated by analysis of covariance was
6.5 ± 1.1 cm (mean ± 1 SE) for final height
(P < 0.001), 7.9 ± 1.7 cm for height from
baseline, and 1.2 ± 0.1 for height SD score
(Lyon) from baseline (P < 0.001). The frequency
distribution of height SD score (Lyon, 69a) from
baseline is shown in Table
6.
In this randomized controlled study to final height, hGH treatment
significantly increased the mean final stature of girls with Turner
syndrome. For intent to treat analysis, long term follow-up of all
randomized subjects is planned. Determining the magnitude of the hGH
treatment effect on final height, the impact of age at hGH initiation,
the effects on psychological functioning, and the hGH-sex steroid
regimens for optimal growth await further analysis.
 |
Preliminary report on the international meta analysis of final
height in Turner syndrome
|
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The project goal is to understand the reasons for variability in
adult height outcomes after GH supplementation in Turner syndrome. All
published authors of studies of this topic have been contacted and
asked to submit information about patient selection criteria, patient
characteristics (karyotype, parental height, baseline height, and bone
age), GH treatment (dose), and cotreatments (androgens, estrogens, and
pubertal induction). The database currently contains 505 patients from
17 different study groups. The meta analysis of these data is expected
to be available in 2000 (Taback, S., M. Kramer, and H. J. Guyda,
in preparation). This analysis will supplement, but cannot replace, the
need for randomization to different treatment plans in the evaluation
of treatments.
The focus of attention in the use of GH in girls with Turner syndrome
has been on adult height, with few reports on psychosocial functioning
related to the use of either GH and/or estrogen therapy. The Canadian
CDCT trial included psychological assessments before, during, and at
the end of GH and/or estrogen therapy. The analysis is awaiting
conclusion of this study. Lagrou et al. (70) recently
reported that perception of short stature, acceptance of therapy, and
psychosocial functioning are different according to age, but no
consistent changes in these parameters occurred in relation to 2 yr
of GH therapy in 31 girls with Turner syndrome.
Additional studies are warranted to assess the psychosocial impact of
GH therapy in girls with Turner syndrome.
 |
GH treatment of children born with intrauterine growth retardation
(IUGR) or small for gestation age (SGA)
|
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In approximately 1520% of strikingly short children, postnatal
growth failure is related to decreased prenatal growth velocity or
IUGR, resulting in infants who are SGA. The literature has been
inconsistent on the birth size definition, using low birth weight
and/or birth length (less than -2 SD) as criteria. Most
studies indicate that it is the low birth length that is most critical
in the 1520% of SGA infants who end up with persistent short stature
during childhood and adulthood (71, 72). De Zegher et al.
(73) have reviewed all prior studies in which GH has been administered
to SGA children, including a meta analysis of four studies in Europe.
Short term studies of 25 yr have revealed variable results, but
generally, younger SGA children receiving higher doses appear to
benefit most over the short term (74). However, this is often at the
expense of an acceleration of bone maturation and earlier puberty,
which limit the anticipated adult height gain. Few data are available
on final height. Ranke et al. (71) have summarized the data
for 720 SGA patients treated with GH in the Kabi International Growth
Study database. At the time of assessment for this GH study, the
patients had failed to show catch-up growth after age 2 yr. An
unusually high number of cases (50%) were considered to be GH
deficient by their criteria. Treatment with GH at a dose of 0.5
IU/kg·week began at 9. 2 yr for SGA (n = 593) and at 7.0 yr for
Russell Silver syndrome (n = 127). Sixteen SGA patients have
gained 1.0 SD score (-2.7 vs. -1.7)
in final height after 4.3 yr of GH treatment at a median dose of 0.76
IU/kg·week, with onset at a median age of 12.7 yr (Table 7
). The researchers concluded on the basis of this
small sample that GH treatment is effective in increasing final height
above the predicted height and in achieving the target height.
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Table 7. Approximate height attainment attributed to GH
treatment in various diagnostic categories of short
stature
|
|
In contrast, Coutant et al. (72) reported that GH in a
relatively low dose of 0.4 IU/kg·week, beginning at age 10 yr,
had a limited effect on final height, which was not different
from that in an untreated group (-2.0 vs. -2.2
SD score), despite a treatment gain of 0.6
SD or 3.4 cm. Other studies (75) have shown
that untreated SGA patients achieve a final adult height in the range
of -1.5 to -2.0 SD score. It has been noted
that midparental height may be low in the SGA population, ranging from
-1.0 to -1 .4 SD score (71, 72, 73, 74, 75). Thus, it would
appear that GH administration may normalize height during childhood if
administered early (before age 5 yr), but that it does not provide
significant adult height gain in this patient group.
 |
Predictors of height velocity response to GH
|
---|
A number of studies are in progress to evaluate the effects of
treatment with GH on growth and final height in children with short
stature. Few are prospectively designed with randomized controls (49).
In some studies, auxological or biochemical predictors of height
velocity response to GH have been sought to potentially select those
children most likely to respond to an invasive, expensive, and
potentially harmful intervention (18). Initial height SD
score, age, and maximum GH response to provocative tests are important
predictors of response for patients with GHD. The dose of GH, the
difference between height SD score of an individual child
and midparental height SD score, and pretreatment growth
velocity are the best independent discriminant analysis for predicting
responsiveness to the initial 6 months of GH therapy in short children
with normal GH responses to provocative tests. Various biochemical
parameters have not proven to be widely useful, although serum IGF-I is
the best indicator of effective GH action (18). In the majority of
these publications, only short term growth responses were available and
a long term benefit or gain in final height could not be assessed.
However, it may be useful to conduct a properly controlled study to
determine whether any of these suggested factors are indeed valuable
predictors for those few children who may show a clear benefit with GH
therapy (49).
 |
GH treatment risks
|
---|
The careful monitoring of any child receiving such a potent
therapeutic agent as GH is mandatory. Several potential risks have been
delineated with the use of both pituitary-derived and biosynthetic GH,
including pseudotumor cerebri, slipped capital epiphysis, fluid
retention, and carpal tunnel syndrome (1, 76, 77). From 19631985,
about 8000 patients in the United States received National Hormone and
Pituitary Program GH. Of these, 22 may have developed Creutzfeldt-Jakob
disease (NIDDK Office of Communication, June 22, 1999). In children
without known risk factors, there is not an enhanced risk of leukemia
or increased mitogenesis in brain neoplasms (77). The inherent risk of
each of these potential complications is probably very small. However,
the use of increased doses of GH in children with nonendocrine short
stature (0.35 mg/kg·week or > 1.0 IU/kg·week), which are
twice those required to promote growth acceleration in most patients
with classical GHD, has the potential to increase the usual risk
factors. However, when recombinant GH is administered for an approved
indication at an approved dosage, it has been remarkably safe to date
(76, 77).
 |
The use of GH to increase adult height: has the outcome achieved
expectations?
|
---|
Children with short stature who begin GH treatment have the
expectation of achieving normal adult height (usually above the
population mean) and not just target height, with all of the benefits
that they or their families expect from this attainment. Unfortunately,
this expectation has not been matched with the outcome; the majority of
patients with classical GHD, children with ISS, or girls with Turner
syndrome treated with GH have not achieved normal adult height if the
median is used (Table 7
). However, individual patients have shown
dramatic responses and have surpassed target height expectations. In
the patients with GHD, an earlier age of onset of GH therapy, with
daily administration of GH at doses of 0.51.0 IU/kg·week, can be
expected to achieve a final height in the target range, with normal
psychosocial functioning.
In the past 2 decades, there has been expanded administration of GH to
short children with normal GH secretion. Some of the reasons include
the following: the discontinuation of the use of pituitary-derived GH
in most industrialized countries in 1985; the timely availability of
biosynthetic GH (often described as unlimited, with no acknowledgment
of the cost to society); the wish of parents to have taller children to
optimize their future success (the ideology of "heightism"); the
proliferation of manufacturers of GH who wish to have an expanded
market beyond the traditional use for classic GHD; and the creation of
a climate of uncertainty about ones ability to precisely make an
accurate diagnosis of GHD, with the introduction of imprecise
terminology, such as GH inadequacy, GH insufficiency, GH
unresponsiveness, partial GHD, and, more recently, partial GH
insensitivity. The outcome of this increased use has been the promotion
of certain legitimacy to the providers of GH for the "normal short
child." In this controversy, there has been inadequate debate about
the reported lack of demonstrated long term benefit in terms of either
growth or psychological status and the potential for negative impact
that an unfulfilled expectation may have on a short child and his or
her family. Most published literature does not support the view that a
significant benefit will arise in the majority of idiopathic short
children who have normal GH secretion by historical standard criteria.
Indeed, one may echo a recent editorial title by Prof. Brook (79):
"Growth hormone: panacea or punishment for short stature?" In
contrast, the current data do suggest that some, but not all, patients
with Turner syndrome will benefit in final height after the
administration of GH, although much less than patients with GHD and
with considerable variability. The challenge for the next millennium
will be to develop methodology that will identify those short children,
including those with Turner syndrome, who will most likely benefit from
the administration of GH over a prolonged period of time. It is to be
hoped that the next decade of GH research will provide additional
insight to make this a truly cost-effective and globally available
treatment for the majority of patients treated with GH.
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Table 6. Distribution of final height attainment in Canadian
randomized controlled clinical trial of GH treatment of girls with
Turner syndrome
|
|
Received August 16, 1999.
Revised August 19, 1999.
 |
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