Until recently, the supply of growth hormone was so
limited that it was exclusively used to treat GH-deficient patients so that
short, slowly growing, GH-sufficient patients many of which failed to reach their
midparental target height could not be treated. With the advent of the
commercial application of recombinant DNA technology there is an unlimited
supply of growth hormone, so that medical indications, costs and ethics are the
only factors limiting the prescription of growth hormone. Multiple studies have
evaluated the effect of short term GH treatment in both GH-deficient and
GH-sufficient children, demonstrating that most of them had increases in growth
rate, SD-scores for height and predicted adult heights after 1-3 years of
therapy. Final height data are, however, only recently becoming available
particularly in many non GH-deficient short children treated with growth
hormone and results have been mixed and somewhat controversial. We will review
this data, as well as the recent reports on the effects of growth hormone
treatment on the bone mineral density and the bone markers of short children.
Growth Hormone Deficiency
Successful
treatment of growth hormone deficiency with human growth hormone was initially
reported by Raben in 1958 [1] and by 1964 it was clear that GH stimulated
linear growth in children with GH-deficiency. Studies from Britain, the United
States, Canada and Germany reported a significant negative relationship between
the linear growth response following GH therapy and chronological age, height,
bone age and weight [2]. The minimal effective dose of human growth hormone
extracted from the pituitary gland was found to be 0.03-0.06 IU/Kg/week by
Frasier et al. [3]; the same dose of
GH was found to be less effective in accelerating the growth velocity after
6-12 months of therapy, but Gertner et al.
[4] demonstrated how renewed catch-up growth could be obtained with increased
replacement doses of human growth hormone (from 0.1 U/Kg to 0.3 U/Kg three
times weekly). However, while the only source of human GH was cadaver
pituitaries, treatment efforts were limited by GH supply and treatment outcomes
in terms of adult height were not satisfactory with 50% of treated patients
failing to attain heights above the third percentile [5].
The
introduction of GH prepared by recombinant DNA techniques has allowed for
children to be treated with larger doses and in a continuous fashion until
final height. Near adult height was recently determined by Blethen et al. [6] in 121 GH-deficient children
who were prepubertal when they began treatment; GH was administered at a dose
of 0.3 mg/Kg/week initially three times weekly and then daily. Adult height as
a SD score was -0.7±1.2, significantly greater than the pretreatment height SD
score of -3.1±1.2, the predicted adult height SD score of -2.2±1.2 and the
height SD score at the start of puberty (-1.9±1.3). The etiology of
GH-deficiency and the presence or absence of spontaneous puberty did not affect
the outcome. Adult height in this study was positively dependent on height and
negatively dependent on age at the start of the study; statistically
significant variables included duration of treatment with GH, age, and height
at the start of GH and the growth rate during the first year of therapy.
So
as to assess the efficacy of GH therapy in GH-deficient children treated before
the age of 3 years, Rappaport and collaborators [7] treated 49 children with
isolated GH-deficiency or multiple pituitary hormone deficiency with daily
injections of 0.6 IU/Kg/week of GH. The mean height SD score had increased from
-3.6±1.0 to -0.9±1.2 after 4 years of treatment; during the fourth year the
mean height gain of 0.2 ±0.2 SD was significant and after 5 years a plateau was
reached with a height SD score -0.8±1.2 SD. Although this value remained below
normal for age indicating incomplete catch-up, only 16% of patients remained
below -2SD for chronological age. Similar results have been reported in other
studies, so that even in GH-deficient children diagnosed quite late in life
results are satisfactory. Cacciari et al.
[8] in GH-deficient children diagnosed at an age of 12.2±1.7 years reports a
significant improvement in height-SDS from a baseline of -2.2 to -1.3 after at
least 2 years of treatment with recombinant human growth hormone.
The
capacity of combined treatment with growth hormone and gonadotropin releasing
hormone analog (GnRH) to preserve the height potential of patients with GH
deficiency and early puberty was recently evaluated by Adan et al. [9] and Cassorla et al. [10]. The later found a greater
height gain in height prediction in patients treated with GH and GnRH than in
patients treated with GH and placebo after 3 years of therapy (mean of 14.0±1.6
vs 8.0 ±2.4 cm; p<0.05) suggesting that delaying epiphyseal fusion with GnRH
analog in pubertal GH-deficient children treated with GH increases height
prediction and may increase final height compared to treatment with GH alone.
Adan et al. concluded from their
study that combination treatment in patients with GH-deficiency and early
puberty leads to a normal adult height (-0.5±0.2SD), similar to predicted
height at the onset of therapy but lower than target height.
Growth
hormone influences not only skeletal growth and maturation but also bone
turnover and mineral deposition and several recent studies have suggested that
GH is probably also involved in the buildup and the maintenance of bone mass.
In 1991, Zamboni et al. [11] reported
that GH therapy for 6 months at a dose of 0.5 IU/Kg/ week administered
subcutaneously 6 times per week increased IGF-1 and osteocalcin levels, as well
as the bone mineral content of growth hormone deficient children, but not
reaching the values found in normal children of the same age. Saggese and
collaborators [12] in 1993 treated 26 GH-deficient children with growth hormone
(0.6 IU/Kg/week) for 12 months. Before therapy bone mineral density was reduced
for chronological, statural and bone ages, as were the levels of osteocalcin,
carboxyl-terminal propeptide of procollagen type I (PICP) and
1,25-dihydroxyvitamin D. During GH treatment, BMD significantly improved at 12
months, with a complete recovery in 46.2% of the children and an increase in
osteocalcin, PICP, intact serum parathyroid and 1,25-dihydroxyvitamin D.
Saggese
[13] further evaluated the effect of long term GH treatment on bone mass by
treating 32 GH-deficient children aged 7.2-16.3 years with GH for a mean of
48.2±13.2 months and measuring radial and lumbar BMD by dual energy x-ray
absorptiometry; results were corrected for bone age and lumbar BMD was
corrected for the estimated vertebral volumes. Before treatment patients showed
significantly reduced radial and lumbar BMD (-1.7±0.4 and -1.5±0.5 Z-score,
respectively) which increased significantly with therapy, so that in patients
treated for the longest time the BMD was 0.5 SD of age-matched mean levels.
They concluded that GH plays an important role in the attainment of peak bone
mass in children with GH-deficiency and suggested that GH treatment should be
continued until the attainment of peak bone mass irrespective of the height was
achieved.
Similar
findings were reported by Boot et al.
[14] after studying the effect of 2-3 years of GH-therapy in 40 GH-deficient
children; volumetric BMD, calculated to correct for bone size increased during
treatment, as did lean tissue mass and 1,25-dihydroxyvitamin D levels.
Osteocalcin, PICP and the cross-linked telopeptide of collagen I did nor differ
from normal at baseline, but increased after 6 months, while fat mass SDS
decreased during the first 6 months and remained stable thereafter.
Similar
results have been reported in GH-deficient adults, [15-17] with a reduction of
bone density at both distal and proximal sites, a decrease in osteocalcin and
procollagen III levels, a significant cardiac impairment supported by a
reduction of left ventricular mass index and left ventricular systolic function
and an increase in fat mass percentage, before therapy. Low dose GH-treatment
(70ug/Kg/week) normalized body composition, echocardiographic findings,
osteocalcin and procollagen III levels as well as proximal BMD, with an
increase although not to normal of distal BMD.
Turner’s Syndrome
Poor
growth velocity and short stature are hallmarks of Turner’s syndrome with final
heights of 140-143 cm reported in the European and North-american literature.
Conflicting reports on the GH secretion of patients with Turner’s syndrome have
been published. Several studies reported that a low GH response to provocative
tests and diminished GH secretion as determined by 24 hour overnight sampling
may contribute to the limited stature of these girls. While Zadik et al. [18] found an increase in the
integrated GH concentration (IC) with age and progression of puberty in normal
controls, he failed to find such an increase in girls with Turner’s syndrome so
that the IC-GH concentration was significantly lower in this group of patients,
but normalized with estrogen replacement. However, Van Es et al. [19] and we [20] found normal spontaneous GH levels in
prepubertal and pubertal age girls with Turner’s syndrome when compared with
controls. Decreased metabolic clearence of endogenous GH and specific
alterations in the pulsatile mode of growth hormone secretion have also been
reported in girls with Turner’s syndrome [21]. IGF-1 levels have been found to
be similar to those in bone age-matched, but lower than those in chronological
age-matched controls. GH-binding protein levels have been reported to be
elevated [22] and Zadik suggested a possible end organ resistance to IGF-1 in
these patients [18].
As
early as 1980 Rudman et al. [23]
reported a synergistic effect between oxandrolone and GH in stimulating growth
in Turner syndrome. Ross et al. [24]
in 1986 concluded that 0.15 U/Kg of GH three times weekly stimulated short term
growth in patients with Turner’s syndrome and that same year Raiti and
collaborators [25] and Rosenfeld et al.
[26] using pituitary derived and methionyl human growth hormone, respectively,
found similar growth promoting effects after 12 months of treatment. We [27]
found the growth velocity of 12 prepubertal girls with Turner’s syndrome to
increase from 3.5±0.4 cm/yr to 6.4±0.3 and 5.7±0.4 cm/yr following 12 and 24
months of growth hormone therapy at a dose of 0.5IU/Kg/week.
The beneficial effect on height velocity
increment of adding estrogen to the GH therapy was small and even very low
estrogen doses were shown to induce breast development at an early age and to
accelerate bone maturation [22]. Recent studies have suggested that yearly
increments of the growth hormone dose results in a better growth response
during 4 years in girls with Turner’s syndrome, so that a stepwise GH-dosing
approach reduced the "waning" effect of the growth response after 4
years of treatment without undue bone maturation [28). Irrespective of the GH
dose used initiation of GH treatment at a younger age was shown to be
beneficial when expressed as cm gained or as final height prediction.
Several
recent studies have followed girls with Turner’s syndrome treated with growth
hormone for several years to final height. A final height of 150.4 ±5.5 cm,
8.4±4.5 cm taller than their mean projected adult height at enrollment in subjects
receiving GH alone and of 152.1±5.9 cm, 10.3±4.7 cm taller than their mean
adult projected height in patients receiving GH and oxandrolone, was reported
by Rosenfeld, et al. [29]. A similar
response has been noted by the Swedish group [30] with a net gain in height of
8.5 cm over the projected adult height and a mean final height of 154.2±6.6 cm
using 0.1IU/Kg/day of growth hormone and 0.05 mg/Kg/day of oxandrolone;
addition of 100 ng/Kg of ethinyl estradiol resulted in a net gain in height of
only 3 cm with an increment in bone age of 4.9±0.8 years after 4 years of
treatment.
However,
studies by Van den Broeck [31] and Dacou-Voutetakis et al. [32] starting treatment at a relatively advanced age (>10
years) resulted in a modest mean gain of 3 and 2.1 cm, with wide
inter-individual variation. Several authors have suggested that starting GH
therapy at an early age, as soon as the growth velocity starts decreasing and
girls with Turner’s syndrome start falling of their growth curves would be
beneficial, as a better final height may be attained and estrogen replacement
could be initiated earlier. However, Joss et
al. [33] found that starting growth promoting therapy early may not be
beneficial, as in many girls with a Turner-specific bone age below 9 years at
the onset of therapy the increase in height did not outweigh the advancement in
bone age.
As
to the bone mineral status of girls and adolescents with Turner syndrome, Ross et al. [34] in 1991 evaluated the bone
mineral content of the wrist and lumbar spine of seventy eight prepubertal
girls (4-13 years old) using both single and dual photon absorptiometry and
found them to have normal bone density for height age, but significantly
decreased bone density of the wrist for chronological age, bone age and BMI,
with an increased fracture rate of the wrist. Mora et al. [35] found radial bone mineral content values to be below
the 95% normal confidence interval in 44 of 49 untreated patients age 10.8±3.5
years. In 9 girls with Turner’s syndrome on growth hormone therapy for 3.2
years we [27] found normal bone mineral densities when compared to healthy
controls paired for height, bone age, weight and BMI (0.739 ±0.05 and
0.791±0.04 g/cm2 for femoral and lumbar spine BMD in Turner patients vs
0.750±0.05 and 0.699±0.02 g/cm2 in the controls).Similar results were reported
in growth hormone treated adolescents by Neely et al. [36] who concluded that Turner syndrome adolescents
receiving growth hormone were not osteopenic. Shaw et al. [37] recently concluded after following 18 girls aged 4-17
years over a period of 2.5 years that there is little evidence of reduced bone
mineral density in girls with Turner’s syndrome, regardless of whether they
were untreated or treated with growth hormone or estrogens.
Osteoporosis
is considered a common complication of Turner syndrome in the adult and the
exact cause of the decreased mineralization is unknown. It seems possible that
the lifelong estrogen deficiency characteristic of Turner syndrome might be the
cause of the osteopenia. Davies et al.
[38] found vertebral BMD in women with Turner syndrome to be similar to that of
other causes of primary amenorrhea and considered osteopenia not to be an
intrinsic feature specific to this disorder, but rather a result of extreme
estrogen deprivation. Mora et al.
[35] evaluated the effect of beginning estrogen replacement early in 16 girls
who were started on estrogens before the age of 11 years and found that
although still deficient compared to controls, early treated subjects had
better mineralization; they then followed 9 of these patients for 3.2 years
during replacement therapy and although their bone mineral content improved it
did not normalize
We
[39] studied 8 of our original patients who had been found to have normal bone
densities as prepubertal girls on growth hormone therapy, now as young adults
having reached their final height and on estrogen replacement for over 4 years;
despite the 6 year time and almost 19 cm height difference between the 2
studies their BMD had not changed and was decreased compared to both age and
gender or weight and pubertal status paired controls. They were also found to
have decreased serum concentrations of the bone formation marker PICP and
elevated levels of the bone resorption marker ICTP, so that they did not reach
their peak bone mass despite long term estrogen replacement. Controlled studies
using estrogen or placebo will be necessary to determine the exact role of
estrogens on the bone mineralization of these girls.
Idiopathic Short Stature
This
is a group of children who are very short, are GH sufficient as determined by
provocative testing and are growing at a subnormal velocity for their age.
Several
studies have focused on possible disturbances in the neuroendocrine regulation
of episodic GH release of these children, but Veldhuis et al. [40] reported that the overall dynamics of GH secretion and
clearence in boys with idiopathic short stature (ISS) could not be
distinguished from physiological patterns observed in prepubertal boys of
normal height. One possible explanation for the growth failure of children with
ISS is a reduced peripheral responsiveness to GH; in a recent study [41] in 573
ISS children 90% had growth hormone binding protein (GHBP) below the age and
sex adjusted mean for controls and 20% had GHBP concentrations below the normal
range. Patients with ISS and low GHBP had lower standardized levels of
insulin-like growth factor 1 and higher mean 12 hour GH levels compared with
those with normal GHBP levels, suggesting partial GH insensitivity.
The
increasing availability of growth hormone has made it possible to conduct
clinical trials on a large variety of short children who are growing poorly and
are not GH deficient. As early as 1983 and 1987 Van Vliet et al. [42] and Gertner et al.
[43] demonstrated how human growth hormone administered at a dose comparable to
that used for the treatment of hypopituitarism increased the growth velocity of
some short children without growth hormone deficiency. A multicenter randomized
1 year trial of human recombinant GH treatment at a dose of 0.1 mg/Kg/three
times a week carried out in 1989 in 121 children with ISS reported a
significant increase in mean growth rate from 4.6±1.1 cm/yr to 7.5±1.2 cm/yr,
whereas the growth rate of untreated children did not change significantly;
they concluded that children who have significant short stature and slow growth
may benefit from a trial of growth hormone therapy [44]. However, that same
year Wit et al. [45] in a 2 year
study in which 30 short, slowly growing children with normal plasma growth
hormone response to standard provocation tests were randomly assigned to either
a treatment or a control group, concluded that although GH therapy appeared to
be safe and efficacious in increasing growth velocity, its efficacy in terms of
increasing final height remained uncertain as treatment resulted in an
unchanged height standard deviation score for bone age and ambiguous results on
final height prediction. In our experience in 32 prepubertal chidren with ISS
treated with GH hormone at a dose of 0.1 IU/Kg/day for 2 years the height
velocity increased from 3.8 ±0.9 cm/yr to 7.3±1.3 and 7.1±0.9 cm/yr at 12 and
24 months, while H-SD scores decreased from -2.4 ±0.4 to -1.8±0.5; predicted
adult height changed from 160.2±9.8 to 164.7.9 cm during this period [46].
Studies
evaluating the final height of children with ISS treated long term with GH have
yielded conflicting results. Loche et al.
[47] in 1994 reported on the effect of GH treatment (1.0 IU/Kg/week) for 4-10
years in 15 prepubertal non GH-deficient short children, concluding that GH
treatment did not increase their final height over target height. Hintz et al. [48] followed 80 ISS patients to
final height after treatment with 0.3 mg/kg/week of GH for 2-10 years and found
that their mean standard-deviation score for height increased from -2.7 to -1.4
with a mean difference between predicted adult height before therapy and
achieved final height of 5.0±5.1cm in males and 5.9±5.2 cm in females; they
concluded that the long term administration of growth hormone to children with
ISS can increase adult height to a level above the predicted adult height and
above the adult height of untreated historical controls. Similar findings were recently
reported by Buchlis et al. [49] who
found that the mean height gain of 6.8 cm in girls and 3 cm in boys, although
modest and variable provided significantly better height outcomes for the
majority of children with ISS.
Rekers-Mombarg
et al. [50] in a recent study found
increasing doses of GH for 4 years (3 IU/m2/day or 4.5 IU/m2/day equivalent to
0.2 and 0.3 mg/Kg/week) to increase the H-SD score for age by a mean of 2.5
(ISS standards) or 1.2 (British standards) but with an increase of bone age of
4.8 years during this period so that any effect on final height was expected to
be modest. Kawai et al. [51] even
suggested recently that there is a unfavorable effect of GH therapy on the
final height of boys with short stature not caused by GH deficiency, as puberty
begins earlier and the pubertal spurt is shortenned, so that the final height
of children treated for 4.2 years was 154.2±4.2 cm, while the final height of
untreated patients was 162.0±5.4 cm. Lesage et
al. [52] recently administered large GH doses (0.3 U/Kg/day) for 2 years to
10 prepubertal children before puberty and found it to promote sustained
acceleration of growth rate allowing near normalization of height. A
significant increase of insulin secretion induced by exogenous GH which continued
to progress during the 2 years of treatment was noted; this hyperinsulinemia
and relative insulin resistance was reversible after GH therapy was
discontinued and apparently had no effect on plasma lipid substrate.
In
an attempt to increase the final height of short non growth hormone deficient
children who enter into normally timed puberty several groups have administered
a GnRH analog to slow pubertal progression while attempting to increase the
growth velocity often decreased by the use of the analog with the simultaneous
use of growth hormone. While Saggese et
al. [53] found a beneficial effect of combined therapy on predicted final
height, both Balducci et al. [54] and
ourselves [55] have found no improvement in final height over predicted height
or over target height after 2-3 years of recombinant human growth hormone and
GnRH analog treatment. Longer studies in a larger population of patients and
with appropriate controls will be needed in order to clarify this issue.
There
is no clear way of predicting which children with ISS will respond to exogenous
GH therapy by increasing their growth velocity. Responses to therapy could not
be reliably predicted from baseline anthropometric variables, plasma insulin-
like growth factor 1 or growth hormone levels. Young children, with a greater
delay in bone age and a slower pretreatment growth rate may, however, respond
better to GH therapy.
The
effect of GH treatment on the bone mineral status of ISS children has to our
knowledge only been evaluated in 2 studies. Ogle et al. [56] in 1994 followed 11 short children without GH
deficiency treated with GH at a dose of 0.5±0.08 IU/Kg/week for 24 weeks. They
found mean L2-L4 BMD to be essentially unchanged at 8 weeks and to increase by
a mean of 0.03 g/cm2 at 24 weeks, while the expected increase in lumbar spine
BMD was 0.02 g/cm2 over 24 weeks. An increase rate of bone turnover was
suggested by the rise in hydroxyproline excretion (bone resorption) and the
trend towards an increase in alkaline phosphatase levels (bone formation). We,
[57] recently evaluated 14 prepubertal non growth hormone deficient short
children who were growing poorly and found them to increase their growth
velocity significantly from 3.9±1.1 to 8.1±1.9 cm/yr following 1 year of GH
treatment with and improvement in height-SDS from -2.2±0.5 to -1.8±0.5. Their
lumbar spine BMD was significantly reduced before therapy when compared to a
group of healthy controls paired for bone age and height (0.645 ±0.09 in ISS
patients vs 0.730±0.08 g/cm2 in controls) and increased after 1 year of therapy
reaching levels similar to those of the control group followed without therapy
for the same period (0.808±0.4 vs 0.760±0.08 g/cm2). Serum concentrations of
PICP, a bone formation marker, were similar to controls before therapy and
increased significantly during GH therapy, while serum levels of ICTP, a bone
resorption marker, were increased before therapy in children with ISS compared
to controls and increased further with treatment. We [57] concluded from this
study that short term GH treatment increases the growth velocity and the bone
mineral density of short, slowly growing non growth hormone children, but that
long term studies in a larger population were needed to determine the benefits
of this form of therapy on the final height and the peak bone mass of these
patients.
Uremia
Growth
retardation associated with chronic renal insufficiency (CRI) has been
identified for many years. The etiology of the growth retardation in children
with CRI is considered to be multifactorial with age at onset, primary renal
disease, fluid and electrolyte abnormalities, acidosis, renal osteodystrophy,
inadequate caloric intake and alterations of growth factors, all implicated
[58].
In
CRI endogenous GH levels are elevated as a result of reduced renal clearance;
despite elevated GH concentrations the IGF-1 secretory rate by the liver is
reduced possibly due to a reduction in the number of hepatic GH receptors, with
a reduction in the number of the GH binding protein levels (which represents
the extracelular domain of the GH receptor). Additionally, due to a reduced
clearance the insulin growth factor binding proteins (IGFBP’s) are elevated,
primarily IGFBP2 and IGFBP3, with a reduction of the available free IGF levels
[58].
Exogenous
growth hormone has been found to increase the IGF-1 levels to a greater extent
that it increases the IGFBP concentrations, thereby increasing the free IGF
levels and enhancing bone growth. Melhs and Ritz in 1983 [59] demonstrated how
recombinant human growth hormone improved the growth velocity of uremic rats
and initial studies by Koch et al.
[60] in 5 boys with CRI demonstrated how 1 year of growth hormone accelerated
the growth velocity with an improvement of height for age. In 1991 Fine et al. [61] reported that 9 boys with
growth retardation consequent to renal failure treated for 12-36 months with GH
prior to dialysis demonstrated a significant improvement in growth velocity
achieving a height-SD score of less than -2.0 or above the 5th percentile in
the growth curve; the mean calculated creatinine clearence did not decrease
significantly during the 36 months of therapy and there was no exacerbation of
the glucose intolerance of uremia following GH administration.
In
a placebo-controlled double blind, cross-over trial in which 6 months of
subcutaneous GH injections were either preceded or followed by 6 months of
placebo injection, Hokken-Koelega et al.
[62] found 16 prepubertal uremic children to increase their growth velocity so
that the GH-induced height-velocity increase exceeded that of placebo by 2.9 cm
per 6 months without affecting bone maturation. IGF-1 and IGFBP3 levels
increased significantly, although the change in IGFBP3 concentrations was significantly
smaller than the GH-induced IGF-1 increase. Fructosamine, lipid and parathyroid
concentrations remained constant and renal function deterioration did not
accelerate. We [63], treated 13 prepubertal children prior to dialysis with 1
IU/Kg/week of GH for 2 years with an increase of their growth velocity from
4.3±2.1 to 9.1±2.0 cm/yr at 12 months and 8.6±1.8 cm/yr at 24 months of
treatment. Mean height-SDS improved from -3.5±1.0 to -2.6±1.3 and -2.0±1.0
during this period and mean serum creatinine and blood urea nitrogen levels
remained stable; however, 2 subjects had a significant deterioration of their
renal function at 6 and 9 months of GH requiring discontinuing treatment.
To
determine the usefulness of GH treatment among children with renal allografts,
Van Drop et al. [64] treated 9
children <16 years of age with poor growth with an improvement of growth
velocity from 1.9±1.1 to 7.2±1.8 cm/yr without acceleration of skeletal or
pubertal maturation. During treatment serum creatinine concentrations rose and
creatinine clearance decreased, but then remained stable; they concluded that
although GH treatment may be useful as adjunctive therapy for increasing growth
rates in selected children with renal allografts, creatinine concentrations
should be monitored closely during treatment in these children.
Hokken-Koelega
and collaborators [65] found GH therapy at a dose of 4 IU/m2 to induce and
maintain better catch-up growth during 2.5 years than a smaller dose of 2 IU/m2
without evidence of adverse effects and suggested that this higher dose may be
beneficial for children with severe growth retardation secondary to uremia.
Fine et al. [66] evaluated the impact
of a pause in GH treatment once target height (50th percentile for mid-parental
height) was reached and the impact of GH cessation after successful renal
transplant; he found that maintenance of height SDS was achieved in 27% and a
marked reduction in growth velocity, requiring reinstitution of GH therapy was
noted in 73% of uremic patients prior to transplant and that discontinuing GH
treatment at the time of transplantation did not result in substantive
post-transplantation "catch down" growth. In our experience [63]
discontinuing GH after 2 years of therapy in prepubertal children with uremia
prior to dialysis, resulted in a significant reduction of their growth velocity
and loss of height for age. Long term (>5 years) therapy with GH has
demonstrated that although the magnitude of improvement in growth velocity was
not sustained at the same level obtained during the initial years, continued
improvement in standardized height has been noted during long term treatment
[66].
As
to side effects, although no significant change in fasting or 2 hour
post-prandial glucose was noted with GH therapy, fasting and 2 hour
post-prandial insulin levels were significantly increased compared to baseline
at 24, 48 and 60 months following initiation of GH treatment, with a slight
increase in HbA1c but no clinical consequences.The risk of slipped femoral
epiphyses and avascular necrosis in children with uremia receiving GH remains
equivocal, so that it is advisable to obtain radiographs of the osseous
structures prior to initiating GH treatment and to repeat the radiographic
studies if clinical symptoms appear [58]. Several episodes of an acute rise in
the serum creatinine level shortly after initiation of GH and of an acute
rejection episode or allograft dysfunction during therapy have been reported,
but this incidence does not seem to be increased compared to that seen prior to
therapy.
Only 2 reports have evaluated the BMD of
children with CRI prior to transplantation, at baseline and during growth
hormone treatment. We [63,67] treated 13 prepubertal children for 2 years with
GH and found bone mineral content as well as bone mineral density in the lumbar
spine and in the femoral neck to be significantly reduced in our patients
compared to healthy controls paired for chronological age and similar to those
of a healthy control group paired for bone and height. Both these parameters
increased significantly during GH treatment so that at 12 months our patients
had values similar those seen in a healthy control population paired to our
patients for chronological age. While trabecular BMD did not change in a group
of untreated uremic controls during follow up, the percent of BMD change in
trabecular bone in our uremic patients during 24 months of therapy was very
significant (p< 0.001) and larger to that noted in a group of healthy
controls paired for bone age and height during 24 months of follow up.
Boot
et al. [68] also found baseline mean
lumbar spine and total body BMD of uremic patients not significantly different
from normal and these parameters did not change during GH treatment; height-SDS
and biochemical markers of both bone formation and bone resorption increased
significantly during GH treatment. However, their uremic patients treated with
GH had a tendency to increase lumbar spine BMD, with a tendency towards a
decrease in BMD in uremic untreated patients. It is difficult to compare the
results of both these studies, as our uremic patients were much shorter and
were growing slowlier than theirs and as different methods were used to
evaluate BMD; additionally bone densities in the study by Boot are compared to
healthy controls paired for chronological age and not controls paired for
height or bone age.
As
to the effect of renal transplantation on the BMD of uremic children, Feber and
collaborators [69] reported a significant decrease of BMD during the first 6
months after surgery, despite normal graft function and improvement in growth;
all these patients were receiving a combination of immunosuppressive therapy
which may have contributed to these changes. In conclusion, longer studies in a
much larger number of patients will be necessary to clarify the effects of GH
on the bone mineral status of children with CRI.
Intrauterine Growth
Retardation
In
approximately one fifth of significantly short children, postnatal growth
failure is believed to be related to intrauterine growth retardation (IUGR). GH
has been detected in the fetal circulation by 10 weeks of gestation, rises
significantly by midgestation and decreases subsequently by term birth. This GH
secretion is pulsatile and is under hypothalamic control through GHRH and
somatostatin secretion. The intense GH secretion towards mid-gestation is
thought to be related to an earlier responsiveness to GHRH compared to
GH-inhibiting factors; the gradual decrease in fetal GH secretion towards birth
may be due to inhibition by circulating IGF-1. During the first postnatal days
hypersomatotropinemia is seen with a hyperresponse to GHRH and increased
circulating levels of IGF-1; this intense activity of the somatotropic axis is
probably one of the mechanisms driving the postnatal catch-up growth that
occurs in most these patients. Approximately 85-90% of term newborns with a
birth weight or length below -2 SDS display sufficient catch-up growth to
attain a height above -2SDS by 2 years of age [70].
The
prevalence of GH insufficiency seems to be increased in children with IUGR.
This insufficiency may consist of classical GH deficiency or of subtle
abnormalities in GH secretion as reported by Boguszewski et al. [71] in 106 patients who were found to secrete less GH than
healthy children of short stature born with a height and weight appropriate for
gestational age. They appear to have low normal circulating IGF-1, suggesting
an altered sensitivity to the growth-promoting actions of IGF’s and their
binding proteins.
As
early as 1971 and 1972, Tanner et all
[72] and Grunt et al. [73] treated
some IUGR patients with human growth hormone with disappointing results
possibly due to the low frequency of administration. Foley et al. [74] in 1974 using growth hormone substitution doses found
GH to be an effective therapeutic agent in some young patients who have
intrauterine growth retardation. In 1979 we [75] reported on our experience
treating 19 prepubertal patients with IUGR. Growth rates were 4.8±1.4 cm/yr
before therapy, 7.6±2.3 and 5.9±1.4 cm/yr in the first and second year of
treatment. Height-SD scores increased from -4.5±1.1 to -3.9±1.6 (p< 0.05)
compared to a control group of untreated IUGR children who were -4.4±1.2
height-SDS before and -4.2±1.3 after follow up (NS).
Attempts
to treat this group of patients with higher doses of growth hormone began once
recombinant human growth hormone became available. In 1994 Chatelain et al. [76] reported on their experience
treating 95 short prepubertal children with non-GH deficient IUGR in a double
blind, controlled study comparing the effects of placebo or two doses of GH
(0.4 or 1.2 IU/Kg/week). A significant GH dose-dependent growth acceleration
was noted with a mean height gain of 0.66±0.07 SD in the low dose group and of
1.25±0.07 in the subjects receiving the high dose, but with a faster bone
maturation progression in this latter group (30.2 ±1.5 months over 24 months of
treatment). High dose GH administration over two years was reported to be
effective by de Zegher and collaborators [77] with a near doubling of growth
velocity and weight gain and a mean height increment of more than 2 SDS; the
GH-induced catch-up was associated with elevated serum concentrations of
insulin, insulin-like growth factor 1 and insulin-like growth factor binding
protein.
In
a metanalysis of four independent European randomized, controlled, multicenter
studies in 244 patients treated for 2 years with GH, de Zegher et al. [78] conclude that GH
administration is a promising therapy for normalizing short stature and low
weight after insufficient catch-up growth in children born small for
gestational age. In 1998 Boguszewski [79] reported on the findings of the
Nordic multicenter trial which demonstrated that within 3 years of GH given at
a dose of 0.2 IU/kg/day the target height of IUGR patients can be achieved and
de Zegher [80] very recently concluded after a 6 year follow up of his patients
that most patients can be brought to the normal centiles for age after 2-3
years of GH therapy and that a good percentage of them will then follow this
percentile into puberty; for the subjects falling of the curve a second
treatment course would be suggested. It remains to be seen if the final height
of these patients improves as follow up continues during their pubertal
development and growth spurt. Results from France in 70 IUGR children treated
with lower GH dosages (0.4±0.1 U/Kg/week) for 4.6±2.5 years showed a very
limited effect on final height [81].
Side
effects with the high dose use of GH include an increase in insulin levels
without negative effects on fasting glucose levels or glycosylated hemoglobin.
As insulin resistance has been reported in small for gestational age children,
fasting insulin and glycosylated hemoglobin concentrations need to carefully
monitored during and after GH treatment in this group of patients. Although
high dose GH induces an acceleration of bone maturation, a gain in height-SD
scores for bone age has also been shown. As to predictors of the growth
response to GH in this group of children low baseline IGF-1 and IGFBP3 levels,
low integrated GH concentrations and slow growth velocities before therapy
appear to be useful in predicting response to GH [82,83].
To
our knowledge there is no information available in the literature as to the effects
of GH on the bone mineral density and on bone markers of children with
intrauterine growth retardation.
Other Entities
Renal
hypophosphatemic rickets is characterized by growth failure with
disproportionate short stature, owing mainly to bowing of the lower limbs
associated with skeletal deformities and reduced bone mineralization. Although
combined treatment with high doses of inorganic oral phosphate salts and the
more biologically active form of vitamin D have resulted in a rise of serum
phosphate concentrations and in the healing of rickets, it does not always
promote linear growth so that many children do not grow appropriately.
GH
administration stimulates renal phosphate reabsorption and 1,25(OH)2D
production, but data on the therapeutic effects of GH in patients with
hypophosphatemic rickets are still limited. In 1990 we [84] demonstrated how 14
months of recombinant human growth hormone therapy resulted in an increase of
the growth velocity, predicted adult height and serum phosphate levels of a
prepubertal boy with hypophosphatemic rickets already on vitamin D and
phosphate salts. These results were then confirmed by Wilson et al. [85] who treated 9 children with
GH alone for 4 weeks and with combined therapy for 24 weeks.
Saggese
et al. [86] in 1995 reported on their
experience in treating 12 prepubertal children with hypophosphatemic rickets, 6
of whom received 0.6 IU/Kg/ week of GH combined with conventional treatment ,
while the remaining 6 received conventional therapy alone; both were followed
for 3 years. Height SD-scores, growth velocity SD-scores, predicted adult
height, serum values of phosphate, bone alkaline phosphatase isoenzyme,
osteocalcin, propeptides of type I and type III procollagen, intact parathyroid
hormone, 1,25-dihydroxyvitamin D and TmP/GRF, as well as radial bone density
improved significantly only in patients treated with GH and conventional
therapy, without any side effects. They concluded that long term GH
administration may benefit growth, phosphate retention and bone density in this
group of patients, but long term follow up will be needed to determine if final
height and bone mass are improved by this form of therapy.
Not
all short children with hypophosphatemic rickets seem to benefit from GH
treatment. Cameron et al. [87] very
recently reported treating 5 prepubertal children who were well controlled on
oral phosphate and calcitriol, with GH at a dose of 0.03 mg/Kg/day. After 12
months of therapy no significant biochemical or radiological benefits were
observed, without an increase in the growth velocity SD score and no
significant decreases in mean height SD or growth velocity SD scores were noted
when GH therapy was ceased.
Osteogenesis
imperfecta is a heritable disorder of connective tissue with bone fragility as
its main feature. Severe growth deficiency is always present in type II and is
frequently seen in moderate type IV and mild type I osteogenesis imperfecta.
The growth hormone and somatomedin axis was evaluated by Marini and
collaborators [88] in nine children with osteogenesis imperfecta, demonstrating
a decreased GH responsiveness to growth hormone releasing hormone and a blunted
somatomedin response to exogenous GH; mean 24-hour GH values and mean peak growth
hormone response to provocative agents were within the normal range.
Antoniazzi
et al. [89] treated 7 prepubertal
children with osteogenesis imperfecta with 0.6 IU/Kg/week of GH for 12 months.
Linear growth velocity in treated patients increased significantly from
3.57±0.55 to 6.04±0.69 cm/year, while bone age did not advance faster than
chronological age. Serum levels of osteocalcin and of the carboxyterminal
propeptide of type I procollagen were significantly reduced before therapy and
rose after 12 months of GH. Before therapy patients with osteogenesis
imperfecta had lower anteroposterior, lateral, and calculated true bone density
than the normal population of the same sex compared for both age and height,
and after GH bone density increased significantly in all these areas; fracture
risk was not increased in these patients. Again, long term studies, in a larger
population of patients and in a controlled environment will be needed before GH
treatment can be recommended for the treatment of children with osteogenesis
imperfecta.
Abbreviations
GH = Growth Hormone
BMD = Bone mineral density
ISS = Idiopathic short stature
IUGR = Intrauterine growth retardation
CRI = Chronic renal insufficiency
PICP = Carboxy-terminal propeptide of type 1
collagen
ICTP = Carboxy-terminal cross linked
telopeptide
of type 1 collagen
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