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Original Studies |
Nemours Children’s Clinic and Research Programs (N.M.), Jacksonville, Florida 32207; Baystate Medical Center (E.O.R.), Springfield, Massachusetts 01199; Montefiore Medical Center (P.S.), Bronx, New York 10467; and Genentech, Inc. (K.M.A., J.B.), South San Francisco, California 94080
Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Division of Endocrinology, Nemours Children’s Clinic, 807 Nira Street, Jacksonville, Florida 32211. E-mail: nmauras{at}nemours.org
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Abstract |
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Of the 97 subjects enrolled, 45 were treated for 3 yr or more; 48 completed the study. Of the subjects who discontinued the study, the most common reason was satisfaction with their height, although others discontinued for adverse events or personal reasons. The frequency of patients who discontinued was the same in both groups. The primary efficacy analysis was the difference between dose groups for near-adult height, defined as the height attained at a bone age of 16 yr or more in males and 14 yr or more in girls; all subjects who qualified were included in the analysis. This difference was statistically significant at 4.6 cm by analysis of covariance (ANCOVA; P < 0.001; n = 75). For subjects who received at least 4 yr of rhGH treatment, the difference between dose groups at that time point was 5.7 cm (by ANCOVA, P = 0.024; n = 20). The mean height SD score at near-adult height was -0.7 ± 0.9 in the standard dose group and 0.0 ± 1.2 in the high dose group. At 36 months the cumulative change in height (centimeters) was 21.5 ± 5.3 cm (group I) vs. 25.1 ± 4.9 (group II; P < 0.001, by ANCOVA); the change in Bayley-Pinneau predicted adult height was 4.8 ± 4.2 cm (group I) vs. 8.4 ± 5.7 (group II; P = 0.032). Median plasma IGF-I concentrations at baseline were 427 µg/L (range, 204–649) in group I and 435 µg/L (range, 104–837) in group II; at 36 months they were 651 µg/L (range, 139-1079) in group I vs. 910 µg/L (range, 251-1843) in group II (P = NS). No difference in change in bone age was detected between groups at any interval. High dose rhGH was well tolerated, with a similar safety profile as standard dose treatment and no difference in hemoglobin A1c or glucose concentrations between groups.
In summary, compared to conventional treatment, high dose rhGH therapy in adolescents 1) increased near-adult height and height SD scores significantly, 2) did not increase the rate of skeletal maturation, and 3) appears to be well tolerated and safe. In conclusion, high dose rhGH therapy may have a beneficial effect in adolescent GH-deficient patients, particularly those who are most growth retarded at the start of puberty.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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During human puberty there is an approximate doubling of GH production rates (6), with peak production coinciding with peak height velocity (2). This increase in GH secretory rates is clearly mediated at least in part through sex steroid hormones, and in both testosterone-treated and estradiol-treated prepubertal children there is an augmentation of the GH production rates, mostly as an amplitude-modulated phenomenon, relatively independent of changes in pulse frequency (7, 8, 9). Nonaromatizable androgens such as oxandrolone (10) and dihydrotestosterone (11) have been shown to have no impact on GH production, whereas estrogen receptor blockade with tamoxifen decreases GH production in pubertal males (12). Taken in aggregate, these and other data suggest that estrogens are the main feedback regulator of the increased GH production observed in puberty.
The pubertal growth spurt accounts for approximately 17% of adult male height and 12% of adult female height (13); these differences are largely responsible for differences in the final height of adult men and women (14). Compared to normal adolescents, studies in children with GH deficiency (GHD) have shown that pubertal development may be impaired, with abnormalities in both the timing and the duration of puberty observed (15, 16, 17, 18, 19). Even though there is wide availability in western countries of recombinant human GH (rhGH), and there have been measurable increases in growth rate and final height documented in GH-treated GH-deficient children (20), delays in diagnosis are common, with many children not reaching their full genetic height potential despite GH treatment (20, 21). Strategies to increase final height in GH-deficient patients receiving GH therapy have hence included suppression of the hypothalamic-pituitary-gonadal axis with GnRH analogs. The latter has been relatively successful in increasing final height or predicted adult height in some studies, but not others (22, 23, 24, 25, 26, 27). The consequences of this approach however, as it pertains to bone accretion/bone density and the psychological impact of suppressing the timely course of puberty in an already short child have not been appropriately studied to date.
As physiological data in puberty indicate that GH production is much higher during human puberty than at any other time, and the doses of GH have been traditionally kept constant on a milligram per kg basis, we designed this study to determine whether more than doubling the GH dose in GH-deficient patients in puberty would significantly increase their growth rates without undue advancement of bone age, thus improving adult height. A multicenter, randomized, two-dose study was performed until near-adult height was reached.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty centers in the U.S. participated in this multicenter
trial. The study protocol was approved by each local institutional
review board. Ninety-seven subjects (83 males and 14 females) with GHD
participated in this trial after obtaining informed written consent and
child’s assent. GHD was defined as peak GH levels of less than 10
ng/mL before original GH treatment by two standard stimulation tests.
Inclusion criteria demanded that all subjects had been treated with GH
for at least 6 months before the studies, and they had to be in
puberty, but with residual height potential. The males were aged 10–18
yr, with testis volume of 4 mL or more and bone age of 14 yr or
greater; the females were aged 8–16 yr, with Tanner breast stage of 2
or more and bone age of 12 yr or greater. The T4
level had to be within normal limits. ACTH- and gonadotropin-deficient
subjects were excluded from participation as well as those who had been
previously treated with sex steroids, had a history of malignancy
treated within the past year, had undergone spinal irradiation, or had
other causes of growth failure (systemic illnesses, skeletal
dysplasias, and chromosomal anomalies, including Turner’s syndrome).
The baseline clinical characteristics of the patients are summarized in
Table 1
. There were no significant
differences between the two treatment groups for any of the baseline
parameters.
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All patients were randomly assigned to continued treatment with GH (Nutropin, Genentech, Inc., South San Francisco, CA) at either 0.3 mg/kg·week (standard dose) or 0.7 mg/kg·week (high dose), sc, daily. Subjects were randomized to either the standard dose or the high dose arm in such a way as to maintain a balance with respect to sex, schedule of previous GH therapy (three times weekly or daily), bone age, chronological age, pubertal status (Tanner stage), previous 1-yr growth rate, height standardized by age and sex, and study center. Patients were seen as out-patients at 3-month intervals for up to 63 months, and physical exam and blood and urine tests were performed. Bone ages were determined every 6 months for the duration of the study.
Treatment with GH was discontinued at near-adult height, defined as a bone age of 16 yr or more for males and 14 yr or more for females and a growth rate less than 2 cm/yr for 1 yr. Adult height was defined as epiphyseal closure on hand-wrist bone age x-ray and no change (<1 cm) in height for 12 months. Dual emission x-ray absorptiometry (DEXA) scans (whole body and antero-posterior spine) for assessment of bone mineral density (BMD) were taken at or within 1 month of treatment discontinuation using either Hologic, Inc., 1000, 2000, or 4000 instruments (Hologic, Inc., Waltham, MA) or Lunar Corp. equipment (Lunar Corp., Madison, WI).
Sex steroid replacement therapy was allowed during the study in only four subjects; this was an institutional review board-approved amendment of the study. As the patients were in puberty at study entry, these subjects were considered to have developed hypogonadism and arrested puberty.
Assays and x-rays
Blood was withdrawn for measurement of complete blood count, chemistry panel, and T4 and urinalysis was performed every 3 months for the first 36 months of the trial and yearly subsequently for the next 3 yr in those subjects still enrolled at that time. A 2-h glucose tolerance test was performed at baseline, 3 months, 12 months, and yearly thereafter for up to 72 months for the measurement of glucose, insulin, C peptide, and hemoglobin A1c (HbA1c) levels. All of these assays were run by standard automated analyzers at SmithKline Beecham (Dublin, CA). Serum testosterone concentrations (males) and estradiol concentrations (females) were measured every 6 months during the study by immunoassays at SmithKline Beecham. Plasma insulin-like growth factor I (IGF-I) concentrations and GH antibody titers were measured at 3-month intervals for the first 24 months and then at 6-month intervals for up to 72 months. IGF-I was assayed at Genentech, Inc., after acid-ethanol extraction as previously described (28). GH antibodies were measured by RIA at Genentech, Inc. Bone age determinations of the left hand and wrist were performed by Fels Institute (Yellow Springs, OH); the readers were blinded to the treatment arm. Predicted adult heights were estimated based on the Bayley-Pinneau table (29). DEXA scans were performed locally at each site and were read at a central location by Hologic, Inc.
Statistical analysis
Fisher’s exact test for proportions, the two-sample t test for between-group comparisons, and the paired t test for within-group changes were used for assessments of safety and efficacy. The significance level for all comparisons was 0.05; no adjustments were made for multiple testing. Log values were used when necessary because of skewed data.
The target primary measure of efficacy was adult height, however, there were a limited number of subjects who had reached adult height. Therefore, near-adult height was used as the primary efficacy variable. If bone age was missing at the last measured height, it was extrapolated from the previous bone age using the change in chronological age; this extrapolation was not used in any other analysis. The standard and high dose groups were compared for near-adult height using analysis of covariance (ANCOVA) with the protocol-defined covariates of sex, previous growth rate, schedule for previous GH therapy, baseline height, chronological age, bone age, and pubertal status (Tanner stage). An intent to treat analysis, including all enrolled subjects, was performed to support the primary analysis. In this analysis, the last measured height, obtained during treatment or at a posttreatment visit, was used for all subjects, including those in whom near-adult height was not achieved. BMD assessment was performed at study discontinuation only. To correct the spine BMD provided by DEXA for bone size, the bone mineral apparent density (BMAD) was calculated for the lumbar spine using the following equation: spine BMAD = bone mineral content (BMC) ÷ area3/2. Total body bone mineral content (BMC) was partially corrected for body size, calculated as BMC ÷ height (30, 31). Because of the limited amount of data collected, the analysis of these data is descriptive.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Near-adult height
Seventy-five subjects met the criterion for attaining near-adult height; of these, 41 required bone age to be extrapolated to the date of their last measured height to meet the criterion. Forty-two of the subjects who met the criteria for attaining near-adult height were in the standard dose and 33 were in the high dose group.
The standard and high dose groups were compared using ANCOVA using the covariates listed above. The use of sex steroid replacement therapy was a protocol-specified covariate; however, only four subjects received sex steroid therapy during the study, an inadequate number for use as a covariate. Based on ANCOVA, subjects in the high dose group were significantly taller at near-adult height than subjects in the standard dose group by an average of 4.6 cm (n = 75; P < 0.001; 95% confidence interval, 2.6–6.5 cm). The significant covariates were sex, baseline height, and bone age. The mean ± SD age at near-adult height was 17.2 ± 1.3 yr (range, 14.1–19.4 yr), with a mean bone age of 16.9 ± 0.9 yr (range, 14.2–18.2 yr). The mean duration of therapy was 3.0 ± 1.0 yr (range, 1.3–5.4 yr). There were no between-dose group differences at near-adult height in age, bone age, or duration of GH therapy. For subjects with near-adult height, the height SD score at last measured height was -0.7 ± 0.9 in the standard dose group and 0.0 ± 1.2 in the high dose group (P = 0.002). The change in height SD score was 0.6 ± 0.8 and 1.1 ± 1.0, respectively (P = 0.012).
Last measured height (intent to treat analysis)
In the intent to treat analysis, the last measured height was used for all subjects regardless of whether near-adult height was achieved. Using ANCOVA, subjects in the high dose group were taller at last measured height than those in the standard dose group by an average of 2.8 cm (n = 97; P = 0.036; 95% confidence interval, 0.2–5.3 cm). The significant covariates were sex, baseline height, age, and bone age. The mean ± SD age at last measured height was 17.0 ± 1.5 yr (range, 11.9–19.4 yr), with a mean bone age of 16.4 ± 1.3 yr (range, 12.3–18.2 yr). The mean duration of therapy was 2.7 ± 1.2 yr (range, 0–5.4 yr). There were no between-dose group differences in age or bone age at last measured height or duration of GH therapy.
Change in height by duration of treatment
An additional analysis was performed for change in height by duration of treatment (by ANCOVA, using sex and baseline bone age as covariates). Subjects in the high dose group were taller than those in the standard dose group after 1 yr of therapy by an average of 1.6 cm (n = 90; P < 0.001). This difference increased with each subsequent year of treatment; after 2 yr the increase in stature was 2.4 cm (n = 72; P = 0.002); after 3 yr, it was 4.3 cm (n = 45; P < 0.001); and after 4 yr of therapy, subjects in the high dose group were taller than those in the standard dose group by an average of 5.7 cm (n = 20; P = 0.024).
Growth rate
The mean prestudy growth rate was 8.5 cm/yr in both groups for
subjects completing month 12 of the study. The mean month 0–12 growth
rate was 9.8 cm/yr in the high dose group (n = 44) compared with
8.2 cm/yr in the standard dose group (n = 43; P =
0.001 between groups). Improved mean growth rates were sustained in the
high dose group relative to the standard dose group in subjects
completing months 12–24 of the study, although this difference did not
attain statistical significance (n = 69; P =
0.063). The difference between treatment groups in growth rate was more
pronounced at months 24–36, reaching statistical significance despite
the reduced number of subjects (n = 41; difference, 1.7 cm/yr;
P = 0.038). Data for subjects completing 3 yr of
treatment (n = 41) are shown in Fig. 1.
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The mean height SD score was more than 1
SD below the mean in both treatment groups at baseline. The
mean change in height SD score was significantly greater in
the high dose group for months 0–12 (0.6 ± 0.3 vs.
0.4 ± 0.4; n = 45 in each group; P = 0.024
between groups). The difference between groups for the mean change from
baseline increased with continued therapy. As Fig. 2 illustrates, for subjects completing 3
yr of treatment, the mean change from baseline was 1.4 ± 0.8 in
the high dose group (n = 22) compared with 0.9 ± 0.7 in the
standard dose group (n = 22; P = 0.023 between
groups).
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The Bayley-Pinneau (B-P) PAH is based on height and bone age
measurements and is increasingly accurate as adult height is reached.
The standardized B-P PAH was similar in the two treatment groups at
baseline, at approximately 1 SD below the mean. After 3 yr,
standardized B-P PAH improved by 1.3 SD, or 8.4 cm, in the
high dose group (n = 20) compared with 0.8 SD, or 4.8
cm, in the standard dose group (n = 20; P < 0.032
between groups). The change from baseline to last PAH (or last measured
height) increased over time at a greater rate in the high dose group,
as shown in Fig. 3.
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In the standard dose group (n = 22), body weight was 41.5 ± 9.2 kg at baseline and 61.9 ± 10.3 at 36 months, whereas in the high dose group (n = 22) it was 41.0 ± 8.4 and 67.2 ± 15.0 at baseline and 36 months, respectively (by ANCOVA with covariate change in height, P = 0.21). Body mass index did not change significantly in either group (standard dose, 19.3 ± 3.6 kg/m2 at baseline vs. 22.0 ± 3.6 at 36 months; high dose, 18.7 ± 2.3 vs. 22.3 ± 3.2 at baseline and 36 months, respectively).
Bone age and Tanner pubertal stage
The change in bone age during each year of therapy is a measure of
the rate of skeletal maturation and is related to the tempo of pubertal
progression. As shown in Fig. 4, the
cumulative change in bone age was not statistically significantly
different between the two treatment groups at 1, 2, or 3 yr, with a
mean rate of advancement of approximately 1 yr/yr of treatment in both
groups. Similarly, the rate of advancement in puberty, as assessed by
Tanner pubertal stage for genitalia (males) or breasts (females), was
similar in the two dose groups (data not shown).
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Plasma IGF-I concentrations increased to a greater extent in the
high dose group than in the standard dose group. Median values rose
from 508 to 681 µg/L in the high dose group at month 12 compared with
a change from 427 to 589 µg/L in the standard dose group and from 435
to 910 µg/L in the high dose group at month 36 compared with a change
from 427 to 651 µg/L in the standard dose group. However, the
differences between groups for the change from baseline, using log
values or standardized scores, were not statistically significant at 1,
2, or 3 yr. Table 2 shows the median data
in those subjects who had results available for 36 months. Mean IGF-I
SD scores were within the high normal range in both groups
during the study (see Fig. 5).
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Secondary efficacy measure: BMD (Table 3)
Thirty-four subjects dropped out of the study before the protocol amendment allowing for BMD measures to be obtained at discontinuation, and 63 discontinued after that date. Of these 63 subjects, 31 had BMD DEXA scans. The groups did not differ in mean total body or spine BMD (grams per cm2), nor did they differ when the comparison was made based on z-scores (for age and sex). There was also no difference between groups for spine BMAD or total body corrected BMC. None of the measures of BMD showed a relationship to treatment duration or the subject’s age. However, the average z-scores for the standard and high dose groups for total body (-0.9 and -0.8, respectively) and spine (-1.0 and -0.2) were lower than those in the general population.
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Overall, adverse events were reported in approximately equal percentages of subjects in the two treatment groups. There were no statistically significant differences in adverse events between treatment groups. Ten serious adverse events were reported during the study: four in the standard dose group and six in the high dose group (one subject in the high dose group reported two events). Of the serious adverse events, most were considered unrelated to GH therapy. One case of worsening scoliosis, which required surgery, was reported in each of the dose groups. These events were considered related to the rapid growth induced by GH and to the subject’s underlying condition. One case of hip pain in the high dose group was considered to possibly be related to the study drug. Six subjects discontinued the study because of adverse events: two subjects in the standard dose group because of scoliosis and thigh pain, respectively, and four subjects in the high dose group because of broadening of the nasal bridge, large shoe size, ankle swelling, and right hip pain. Cases of hyperglycemia, peripheral edema, and myalgia were only reported for subjects in the standard dose group. Two cases of mild hypoglycemia were reported in the high dose group. No cases of leukemia, slipped capital femoral epiphysis, or intracranial hypertension were reported during the study.
Other laboratories
Laboratory studies generally showed no significant differences
between groups. These assessments included frequent oral glucose
tolerance tests and HbA1c measurements. No
statistically significant differences were noted between the two dose
groups in glucose, insulin, and C peptide variables, except for a
greater increase in fasting insulin (P = 0.011) and C
peptide (P = 0.019) in the high dose vs.
standard dose group at 24 months. Median fasting and postprandial
insulin and C peptide levels increased in both dose groups at various
time points. Mean fasting and postprandial glucose levels were stable
throughout the study, although sporadic high individual values were
observed. Mean HbA1c increased slightly within
each dose group at 12 and 24 mo, returning to baseline values by 36 mo
(Table 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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An interesting and important finding of these studies is the normal pace of bone maturation, with bone ages advancing approximately 1 yr/chronological yr in both the standard and high dose groups. This was also accompanied by comparable pubertal development in both groups as observed on physical exam. Taken in aggregate, these data indicate that GH therapy, even in high doses, does not abnormally advance skeletal maturation or affect the tempo of puberty in GHD children.
This conclusion contrasts with that reported by Stanhope et
al. (32, 33), who studied 52 children with idiopathic isolated GHD
treated with GH before puberty; once children reached puberty they were
randomized to either GH at a standard dose of 15
IU/m2·wk (
0.2 mg/kg·wk) or a high dose of
30 IU/m2·wk (0.4 mg/kg·wk). Four-year
results showed no statistically significance difference in growth rates
between the two groups, but there appeared to be an acceleration of
pubertal maturation in boys on the higher dose regimen. As in our
study, no difference was observed in the rate of bone age maturation.
Even though we did not observe any deleterious effect of GH on the
tempo of puberty, it is possible that the higher doses used in the
present experimental paradigm (0.7 mg/kg·week) vs. the
high dose reported in the Stanhope study (0.4 mg/kg·week) may explain
the better outcome in terms of near-final height and growth performance
reported here.
During no other time in postnatal development are there higher IGF-I concentrations than those observed during puberty, with the upper end of normal range in 12- to 16-yr-old males close to 1000 ng/mL in most assays. However, one concern with the use of increased GH doses is the potential effect of increasing plasma IGF-I concentrations to supraphysiological concentrations (34, 35, 36). In the present studies there was substantial variation in plasma IGF-I concentrations in both groups, with the change in concentration from baseline ranging from -228 to 598 µg/L (median, 208) in the standard dose group vs. -277 to 1604 (median, 360) in the high dose group and no statistical difference between the groups. IGF-I levels above the normal range were observed in seven of the eight subjects in the high dose group at baseline. Even though the difference between groups was not statistically significant during treatment, the observation of overall higher levels in the high dose group requires careful follow-up of IGF-I concentrations in patients in whom these dose regimens are considered. Even though not customarily used by many in pediatric endocrine practice, the routine measurement of plasma IGF-I concentration during treatment with GH should help identify supraphysiological responses to GH, allowing for the GH dose to be adjusted more appropriately for each individual patient.
The effect of high dose vs. standard dose GH on total body and spine BMD was also assessed in patients at the end of therapy (n = 31). There was no difference in total body BMD or bone mineral content (corrected for height) or spine BMD, BMD z-score, or BMAD (corrected for bone size) between the two groups. However, the average z-scores for total body and spine BMD were lower than those of age- and sex-matched controls, congruent with the previous finding that young patients with GHD are at risk for reduced bone mass (37, 38).
The incidence of various adverse events was approximately equal in the two dose groups, with no significantly greater frequency of adverse effects clearly associated with the increased GH dose. Laboratory studies generally showed no significant differences between groups, and measurable titers to anti-GH antibodies were greatest at baseline and declined similarly in both dose groups during the study. There was no evidence of worse carbohydrate tolerance in the high dose group. Of the serious adverse events, most were considered unrelated to GH therapy. One case of worsening scoliosis, which required surgery, was reported in each of the dose groups.
In summary, a mean of 3 yr of high dose GH therapy to GHD adolescent children was associated with a statistically significant increase in near-adult height of 4.6 cm over that in children treated with standard doses of GH; in those treated for 4 yr, the increase was 5.7 cm. This was not associated with an undue advancement of skeletal maturation, alteration of the tempo of puberty, or greater frequency of adverse events. We conclude that high dose GH therapy, administered during a finite window of time, may be beneficial and safe in increasing the final adult height of youngsters with GHD who are in the midst of puberty. This may be particularly useful in those most growth retarded at the start of puberty. This strategy warrants careful monitoring of IGF-I concentrations and continued surveillance for adverse events.
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Footnotes |
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2 The investigators who participated in this study as part of the
Genentech, Inc., Cooperative Study Group are: Gilbert P.
August, M.D., at Children’s Hospital National Medical Center
(Washington, DC); Jennifer J. Bell, M.D., at Columbia Presbyterian
Medical Center (New York, NY); Thomas P. Foley, Jr., M.D., at
Children’s Hospital of Pittsburgh (Pittsburgh, PA); Ronald W. Gotlin,
M.D., at The Children’s Hospital (Denver, CO); Madeleine D. Harbison,
M.D., at New York Hospital-Cornell Medical Center (New York, NY);
Raymond L. Hintz, M.D., at Stanford University Medical Center (Palo
Alto, CA); Nancy J. Hopwood, M.D., at University of Michigan Medical
Center (Ann Arbor, MI); Margaret H. MacGillivray, M.D., at Children’s
Hospital of Buffalo (Buffalo, NY); Nelly Mauras, M.D., at Nemours
Children’s Clinic (Jacksonville, FL); Wayne V. Moore, M.D., Ph.D., at
Children’s Mercy Hospital (Kansas City, MO); Thomas Moshang, M.D., at
Children’s Hospital of Philadelphia (Philadelphia, PA); Katrina L.
Parker, M.D., at University of Alabama School of Medicine (Birmingham,
AL); Leslie P. Plotnick, M.D., at Johns Hopkins Hospital (Baltimore,
MD); Edward O. Reiter, M.D., at Baystate Medical Center (Springfield,
MA); Alan D. Rogol, M.D., Ph.D., at University of Virginia Health
Sciences Center (Charlottesville, VA); William E. Russell, M.D., at
Vanderbilt University Medical Center (Nashville, TN); Paul Saenger,
M.D., at Montefiore Hospital (Bronx, NY); Dennis M. Styne, M.D., at
University of California (Davis, CA); Thomas A. Wilson, M.D., at State
University of New York Health Sciences Center (Stony Brook, NY); and
David T. Wyatt, M.D., at MACC Fund Research Center (Milwaukee,
WI).
Received May 4, 2000.
Revised July 3, 2000.
Accepted July 5, 2000.
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E. W. Leschek, S. R. Rose, J. A. Yanovski, J. F. Troendle, C. A. Quigley, J. J. Chipman, B. J. Crowe, J. L. Ross, F. G. Cassorla, W. F. Blum, et al. Effect of Growth Hormone Treatment on Adult Height in Peripubertal Children with Idiopathic Short Stature: A Randomized, Double-Blind, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3140 - 3148. [Abstract] [Full Text] [PDF]
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L. E. Underwood, K. M. Attie, and J. Baptista Growth Hormone (GH) Dose-Response in Young Adults with Childhood-Onset GH Deficiency: A Two-Year, Multicenter, Multiple-Dose, Placebo-Controlled Study J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5273 - 5280. [Abstract] [Full Text] [PDF]
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W. Xu, A. Janss, and T. Moshang Adult Height and Adult Sitting Height in Childhood Medulloblastoma Survivors J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4677 - 4681. [Abstract] [Full Text] [PDF]
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M. B. Ranke, A. Lindberg, D. D. Martin, B. Bakker, P. Wilton, K. Albertsson-Wikland, C. T. Cowell, D. A. Price, and E. O. Reiter The Mathematical Model for Total Pubertal Growth in Idiopathic Growth Hormone (GH) Deficiency Suggests a Moderate Role of GH Dose J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4748 - 4753. [Abstract] [Full Text] [PDF]
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M. Tauber, B. Berro, V. Delagnes, N. Lounis, B. Jouret, C. Pienkowski, I. Oliver, and P. Rochiccioli Can Some Growth Hormone (GH)-Deficient Children Benefit from Combined Therapy with Gonadotropin-Releasing Hormone Analogs and GH? Results of a Retrospective Study J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1179 - 1183. [Abstract] [Full Text] [PDF]
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 J.-C. Carel, E. Ecosse, J. Coste, S. Loche, M. Maghnie, and M. Cappa Growth hormone in growth hormone deficiency BMJ, November 2, 2002; 325(7371): 1037 - 1037. [Full Text]
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V. Mericq, H. Gajardo, M. Eggers, A. Avila, and F. Cassorla Effects of Treatment with GH Alone or in Combination with LHRH Analog on Bone Mineral Density in Pubertal GH-Deficient Patients J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 84 - 89. [Abstract] [Full Text] [PDF]
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P. Cohen, G. M. Bright, A. D. Rogol, A.-M. Kappelgaard, and R. G. Rosenfeld Effects of Dose and Gender on the Growth and Growth Factor Response to GH in GH-Deficient Children: Implications for Efficacy and Safety J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 90 - 98. [Abstract] [Full Text] [PDF]
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E. O. Reiter, S. L. Blethen, J. Baptista, and L. Price Early Initiation of Growth Hormone Treatment Allows Age-Appropriate Estrogen Use in Turner's Syndrome J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1936 - 1941. [Abstract] [Full Text]
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