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Clinical Studies |
Departments of Endocrinology (Y.J., F.R.) and Clinical Chemistry (M.F.), Leiden University Hospital, Leiden, The Netherlands
Address all correspondence and requests for reprints to: Dr. Ferdinand Roelfsema, Department of Endocrinology, Leiden University Hospital, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
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Abstract |
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Sixty patients with GHD (aged 20–70 yr) were randomized to one of the three dose groups. Group 1 used a dose of 0.6 IU/day for 12 weeks. Group 2 started at a dose of 0.6 IU for 4 weeks followed by 1.2 IU/day for 8 weeks. Group 3 used 0.6 IU for 4 weeks, followed by 1.2 IU/day for 4 weeks and 1.8 IU/day thereafter. IGF-I concentrations (nanomoles per L) were determined by RIA after extraction and purification on ODS-silica columns. The measurement of IGFBP-3 (milligrams per L) was performed by RIA.
The three groups were equal with regard to age, sex, and body mass index. At the start of the study, we found lower levels of both serum IGF-I and IGFBP-3 in childhood-onset GHD than in adult-onset GHD. Moreover, there was a gender difference; female GHD patients had lower serum IGF-I levels than male patients. Serum IGF-I levels were low in both childhood-onset and adult-onset GHD. Serum IGFBP-3 levels, however, were low in patients with childhood-onset GHD, but normal in patients with adult-onset GHD. After 12 weeks of treatment, IGF-I levels were low normal in the low dose group and normal in groups 2 and 3 of both adult-onset and childhood-onset GHD. In adult-onset GHD, serum IGFBP-3 increased to high normal levels in all groups, whereas it increased to low normal levels in childhood-onset GHD.
This study demonstrates differences in the biochemical characteristics of childhood-onset and adult-onset GHD. In patients with adult-onset GHD, serum IGFBP-3 levels are not significantly decreased and, therefore, cannot be used as a screening method for GHD or as a dose-finding parameter. GH therapy at doses of 0.6 and 1.2 IU/day in male and female patients, respectively, is, in general, able to increase serum IGF-I into the normal range after 12 weeks of treatment, without reaching supranormal levels of serum IGF-I. This dose could, therefore, be a starting dose in GH-deficient adults.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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3 IU/m2; 5 IU/day)
based on experience in children (5). However, these studies were
associated with a high incidence of side-effects (mainly salt and water
retention), which usually responded to a reduction in the dose (5). In
sequential studies using half this dose (0.035 IU/kg BW; 5
IU/m2; 2.5 IU/day), the number of side-effects decreased
significantly (6). Using lower doses in adults than in children is also
in agreement with the lower physiological GH production in adults than
in children. Moreover, the physiological GH production in adulthood
decreases with age (7, 8, 9, 10). In middle-aged women, the reported daily
production is about 47 µg/L·day (0.6 IU/day), whereas the mean
production in the adult male is 15 µg/L·day (0.2 IU/day) (11).
Assuming an availability of sc administered rhGH of 60%, the dose of
2.5 IU/day used is still high, especially in the adult male. A dose
between 0.6–1.8 IU/day should be more in agreement with the
physiological GH production in adults. We used doses calculated on the basis of estimations of physiological GH production. Sixty patients were randomized to 0.6, 1.2, or 1.8 IU rhGH/day. All three groups started at a rhGH dose of 0.6 IU/day for 4 weeks. Circulating concentrations of both insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were used to investigate the effect of 12 weeks of GH treatment with these three different doses.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thirty GH-deficient males and 30 GH-deficient females (mean age, 47 yr; range, 23–70 yr) were studied. A peak serum GH response less than 7 mU/L during insulin-induced hypoglycemia (ITT) confirmed GH deficiency (GHD). The cause of GHD in 7 of the 9 patients with a childhood-onset GHD was idiopathic or related to birth trauma (3 of them had been treated with GH before for 3–6 yr). The other 2 patients had craniopharyngioma and germinoma in childhood (both treated with GH for 5 and 2 yr, respectively).
Fifty-one patients had adult-onset GHD (36 patients due to a pituitary adenoma, 3 patients due to trauma, 3 patients due to Sheehan’s syndrome, and 9 patients due to a tumor in the pituitary region). Three patients had isolated GHD. In addition to the GHD, 4 patients had LH/FSH deficiencies, 3 patients had LH/FSH and TSH deficiencies, 3 patients had LH/FSH and ACTH deficiencies, 33 patients had full anterior pituitary gland failure, and 14 patients had total pituitary gland failure. Patients were treated with conventional substitution when indicated.
Informed consent was obtained from all subjects, and the study was approved by the ethics committee of Leiden University Hospital.
Design of the study
All patients were treated with sc injections of rhGH (Genotropin, Pharmacia and Upjohn BV, Peptide Hormones, Uppsala, Sweden), given every evening for 12 weeks. At the start of the study they were randomized to one of the three dose groups: group 1 used 0.6 IU/day for 12 weeks, group 2 used 0.6 IU/day for 4 weeks followed by 1.2 IU/day for 8 weeks, and group 3 used 0.6 IU/day for 4 weeks, followed by 1.2 IU/day for 4 weeks and 1.8 IU/day thereafter. Blood was withdrawn at the start of the study and after 4, 8, and 12 weeks of rhGH therapy.
Assays
The total serum IGF-I concentration was determined by RIA (Incstar, Stillwater, MN) after extraction and purification on ODS-silica columns. The interassay coefficient of variation was less than 11%. The detection limit was 1.5 nmol/L. Age-related normal data were determined in the same laboratory. IGF-I was also expressed as a SD score from age-related normal levels. The measurement of serum IGFBP-3 was performed by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum samples were diluted 250 times. Standards were constituted from recombinant IGFBP-3, whereas [125I]IGFBP-3 served as tracer. The antiserum was polyclonal rabbit anti-IGFBP-3. The interassay coefficient of variation was below 6.8% at different levels. The limit of detection was 0.08 mg/L. No cross-reaction of IGF-I, IGFBP-1, and IGFBP-2 was detectable. Calculation of the IGFBP-3 SD score from IGFBP-3 to adjust for age and gender was performed using normative data, provided by Dr. J. van Doorn, Wilhelmina Kinderziekenhuis Utrecht (Utrecht, The Netherlands). The molar comparison of serum IGF-I to serum IGFBP-3 was determined with a molecular mass for IGFBP-3 of 28.5 kDa. Normative data were based on 54 healthy control subjects (aged 20–70 yr). SD scores for both IGF-I and IGFBP-3 lower than -4 or higher than +4 were set at -4 and +4, respectively.
GH was measured with a time-resolved immunofluorescent assay (Wallac, Turku, Finland), specific for the 22-kDa GH protein. Standards were human biosynthetic GH (Pharmacia) diluted in bovine calf serum and calibrated against the WHO First International Reference Preparation 80–505 (to convert micrograms per L to milliunits per L, multiply by 2.6). The detection limit of the assay was 0.03 mU/L (0.012 µg/L), and the intraassay coefficient of variation was less than 8.4%.
Statistical analysis
Statistical analysis was performed using SPSS for Windows (release 6.0, SPSS, Chicago, IL). Results are expressed as the mean ± SEM, unless specified otherwise. Student’s t test was used to compare levels between groups of patients. A paired t test was used to test for significant differences within a dose group in time. ANOVA and multiple ANOVA techniques were used to test for significant differences between the dose groups. Pearson’s correlation coefficient was used to calculate correlations. Differences were considered significant for P < 0.05.
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Results |
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In Table 1
, the characteristics of the patients in
the three groups are shown. The groups were equal with regard to age,
sex, height, weight, body mass index, and severity of GHD, estimated by
the maximum GH concentration measured during ITT. A significant inverse
correlation was found between the number of pituitary hormone
deficiencies and the maximum GH concentration during the
insulin-induced hypoglycemia (r = -0.54; P <
0.005). There was no correlation between the maximum plasma GH
concentration during ITT and circulating concentrations of IGF-I or
IGFBP-3.
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The first patient was a 51-yr-old male (height, 182.5 cm; weight, 99 kg) with GHD due to trauma at 26 yr of age. He developed carpal tunnel syndrome after 5 weeks of rhGH treatment (4 weeks of 0.6 IU/day followed by 1 week of 1.2 IU/day). His serum IGF-I level at the start of treatment was 9.9 nmol/L (-1.6 SD score) and increased to 18.1 (0 SD score), 25.4 (+1.4 SD score), and 28.5 (+2.0 SD score) after 4, 8, and 12 weeks, respectively. Serum IGFBP-3 at the start of treatment was 1.8 (-0.1 SD score) and increased to 2.0 (+0.1), 2.3 (+1.5), and 2.4 (+1.7 SD score) after 4, 8, and 12 weeks, respectively. The second patient was a 55-yr-old male (height, 181.8 cm; weight, 99 kg) with a history of prolactinoma, which required pituitary surgery and radiotherapy. He developed fluid retention problems after 5 weeks of treatment (4 weeks of 0.6 IU/day followed by 1.2 IU/day). His serum IGF-I level at the start of treatment was 7.5 nmol/L (-2.1 SD score) and increased to 25.6 (1.4 SD score), 41.1 (>4 SD score), and 38.1 (+3.8 SD score) after 4, 8, and 12 weeks, respectively. Serum IGFBP-3 at the start of treatment was high, 2.7 (+2.9 SD score), and increased to 4.1 (>4 SD score), 4.2 (>4 SD score), and 4.6 (>4 SD score) after 4, 8, and 12 weeks, respectively. In both patients the dose was not increased after 8 weeks. The adverse events did not disappear, however, within the observation period of 12 weeks.
Childhood-onset vs. adult-onset GHD
In addition to the difference in clinical presentation between
childhood-onset and adult-onset GHD, a difference in biochemical
results, especially regarding serum IGFBP-3, was found (Fig. 1). Therefore, these groups were analyzed separately.
The baseline differences between these groups are presented in Table 2.
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Adult-onset GHD. Baseline circulating levels of IGF-I were low
in patients with adult-onset GHD (8.9 ± 0.5 nmol/L); 62% of the
patients had serum IGF-I levels below the fifth percentile. As shown in
Table 3a, no significant differences were found at the
start of the study in serum IGF-I and the IGF-I SD scores
among the three dose groups.
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Childhood-onset GHD. Patients with childhood-onset GHD had a
significantly lower serum IGF-I concentration (6.4 ± 0.9 nmol/L)
than patients with adult-onset GHD (8.9 ± 0.5 nmol/L;
P = 0.047; Table 2
). All patients with childhood-onset
GHD had serum IGF-I concentrations below the fifth percentile of normal
values. During rhGH therapy, serum IGF-I concentrations increased
significantly, reaching normal levels after 12 weeks of treatment
(Table 3b).
Serum IGFBP-3 concentrations
Adult-onset GHD. In Table 3a and Fig. 3, the
changes in serum IGFBP-3 during rhGH therapy are shown. At the start of
the study, both low serum IGFBP-3 levels (24% had serum IGFBP-3 levels
below the 5th percentile) as well as supranormal levels (16% had serum
IGFBP-3 levels above the 95th percentile) were found. Although no
differences were found in serum IGFBP-3 levels among the three groups
at the start of the study, groups 2 and 3 had a higher percentage of
patients under the 5th percentile of normal values (group 1, 6%; group
2, 29%; group 3, 35%). Four weeks of GH therapy at 0.6 IU/day
increased serum IGFBP-3 and IGFBP-3 SD scores significantly
(both P = 0.000). In groups 1 and 2, serum IGFBP-3 did
not significantly increase thereafter. In group 3, an additional
increase in serum IGFBP-3 was found between 4–12 weeks. However, no
significant differences in serum IGFBP-3 among the dose groups could be
found after 12 weeks of treatment. The mean serum IGFBP-3 concentration
after 12 weeks in all three groups was significantly higher than the
mean in healthy controls. Forty-six percent of the patients had
supranormal levels of serum IGFBP-3 (group 1, 41%; group 2, 50%;
group 3, 47%). Neither serum IGFBP-3 levels at baseline nor the
percent increase in IGFBP-3 during rhGH treatment was dependent on
gender.
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Eight of the nine patients had a serum IGFBP-3 level below the normal
range at the start of the study. In all patients, serum IGFBP-3 levels
increased significantly, although two of the nine patients (both using
1.2 IU rhGH/day) still had IGFBP-3 levels below the fifth percentile
after 12 weeks of treatment (Table 3b). Although the percent increase
in serum IGFBP-3 was larger, absolute levels were lower in patients
with childhood-onset GHD than in patients with adult-onset GHD after 12
weeks of rhGH treatment. Serum IGF-I/IGFBP-3 ratio
The mean molar ratio IGF-I to IGFBP-3 in 54 healthy controls was
0.26 ± 0.01. No influence of age or gender was found. In
adult-onset GHD patients, the ratio was significantly lower than that
in healthy controls (0.17 ± 0.01; P < 0.0005),
whereas in childhood-onset GHD patients, the ratio was not
significantly different from the normal value (0.33 ± 0.06;
P = 0.295; Table 2).
During GH therapy, the ratio increased significantly in all three dose groups of adult-onset GHD (P = 0.044, 0.002, and 0.000, respectively), reaching normal values in groups 2 and 3 (group 1, 0.20 ± 0.02; group 2, 0.24 ± 0.02; group 3, 0.24 ± 0.02). The molar ratio of IGF-I and IGFBP-3 did not change with rhGH in the patients with childhood-onset GHD (0.33 ± 0.04).
GH doses, IGF-I, and IGFBP-3
Adult-onset GHD. There was a significant correlation between serum concentrations of IGF-I and IGFBP-3 both at baseline and after 12 weeks of rhGH therapy (P = 0.038 and P < 0.0005, respectively). The percent increases in serum IGF-I and serum IGFBP-3 concentrations were significantly correlated (P = 0.048). The percent increase in serum IGF-I was correlated with the rhGH dose (P = 0.015), and a trend was found between the GH dose and the percent increase in serum IGFBP-3 (P = 0.053).
Childhood-onset GHD. There was a significant correlation between serum concentrations of IGF-I and IGFBP-3 at baseline, but not after 12 weeks of rhGH therapy (P = 0.001 and P = 0.403, respectively). The percent increase in serum IGF-I was significantly correlated with the percent increase in serum IGFBP-3 (P = 0.012). The percent increases in circulating levels of IGF-I and IGFBP-3 were not correlated with the rhGH dose (P = 0.466 and 0.607, respectively).
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Discussion |
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0.35 IU/m2·day; 0.06 IU/kg·week) was
insufficient to normalize serum IGF-I after 12 weeks of treatment, as
40% of this group still had serum IGF-I levels below the fifth
percentile, whereas doses of 1.2 (0.70 IU/m2·day;
0.128 IU/kg·week) and 1.8 IU/day (1.0 IU/m2·day;
0.178 IU/kg·week) normalized serum IGF-I levels in most female GHD
patients. As the male patients had higher serum IGF-I levels at the
start of the study, a dose of 0.6 IU (0.30 IU/m2·week;
0.05 IU/kg·week) rhGH /day was in almost all patients sufficient
to normalize serum IGF-I levels. With larger doses, the frequency of
supranormal levels (above 95th percentile) is high (45%).
The present study also examined 9 patients with childhood-onset GHD
(aged 23–57 yr; 7 men and 2 women). Within 12 weeks of treatment, all
nine and eight of nine patients reached normal levels of serum IGF-I
and IGFBP-3, respectively. The dose of rhGH in this study group was 0.6
or 1.2 IU/day (mean doses, 1.0 IU/day; 0.6 IU/m2·day;
0.11 IU/kg·week). Normalization of serum IGF-I was achieved with a
mean dose of 1.0 IU/day, which is comparable with the dose advised by
Wollmann et al. (12) but lower than the dose advised by
Møller et al. (13) and De Boer et al. (14, 15).
Wollmann et al. (12) examined 12 patients (9 men and 3
women) with childhood-onset GHD (20–36 yr of age) in a randomized
cross-over design with 3 treatment periods of 3 months each (0.125, 0,
25, and 0.5 IU/kg BW·week). They reported a normalization of serum
IGF-I and IGFBP-3 levels with the lowest dose investigated. Møller
et al. (13) examined 10 young (21–43 yr), mainly male,
adults with either childhood-onset or adult-onset GHD, receiving
various doses of rhGH (1, 2, or 4 IU/m2·day) during
consecutive 4-week periods. No difference in serum IGF-I could be found
with an age-matched control group when using a dose of 1 or 2
IU/m2·day. They concluded that a GH replacement dose of
1–2 IU/m2·day is adequate. De Boer et al.
(14, 15) advised similar doses. They performed a study in 50 young GHD
males with childhood-onset GHD and used several parameters to estimate
the optimal dose: serum IGF-I, IGFBP-3, acid-labile subunit (ALS),
being free of clinical signs or symptoms suggestive of GH excess (15),
and lean tissue hydration by conductivity measurements (14).
Normalization of serum ALS required the highest rhGH dose (1.6–2.1
IU/m2·day) followed by normalization of serum IGFBP-3
(1.6–2.0 IU/m2·day), being free of side-effects
(1.5–1.9 IU/m2), and normalization of serum IGF-I
(1.2–1.6 IU/m2). Normalization of tissue hydration
required the lowest dose of rhGH (0.85–1.45 IU/m2·day).
However, the patients in this study were randomized to the dose groups.
Normalization of, for example, serum IGF-I with a dose of 2
IU/m2 does not exclude the possibility that this patient
would not have had normal serum IGF-I levels when using a dose of 1
IU/m2. In their study, mean serum IGF-I concentrations were
significantly lower than the age-related normal mean when using a dose
of 0.33 IU/m2, but normalization was achieved with a dose
of 0.66 IU/m2. The advised dose in this study is,
therefore, an overestimation of the dose required to normalize the
parameters.
Since the introduction of rhGH, several clinical trials have shown
beneficial effects of GH replacement therapy in GH-deficient adults
(1, 2, 3, 4). Initially, doses comparable with that used in children were
given (0.07 IU/kg BW; 3 IU/m2; 5 IU/day). These
studies, however, were associated with a high incidence of side-effects
(including salt and water retention). Later studies, therefore, used
half this dose, which decreased the incidence of side-effects and the
presence of supranormal levels of serum IGF-I (4, 6, 16). In
acromegaly, long term excessive GH levels are associated with an
increase in morbidity and mortality, mainly due to cardiovascular
disorders (17, 18). Avoiding supranormal levels of serum IGF-I by using
more physiological doses of rhGH is, therefore, important. With the
development of new, high sensitivity assays to measure the serum GH
concentration and by using intensified blood sampling over 24 h,
the physiological GH production in adults is lower than had been
thought for years and is dependent on age and gender (9, 11). In
middle-aged, normal weight women, the reported mean daily production is
47 ± 2 µg/L distribution volume·day (0.6 IU/day), whereas
the mean production in the male adult with normal weight is 15 ±
2 µg/L distribution volume·day (0.2 IU/day) (11). Assuming an
availability of sc administered rhGH of 60% (our unpublished data),
the mean physiological dose in middle-aged GHD patients should be
between 0.3–0.9 IU/day. Most studies used a GH dose based on body
weight or body surface. However, several investigators reported a
negative correlation between the physiological GH production and body
fat (8, 9). Therefore, using an rhGH dose based on weight is
contradictory. The doses used in this study were derived from the
physiological GH production (0.6–1.8 IU/day), independent of any body
composition parameter.
We noticed a difference in the biochemical parameters IGF-I and IGFBP-3 between childhood-onset GHD and adult-onset GHD. IGF-I is a protein synthesized in the hepatocytes, mediating many in vivo actions of GH. Serum IGF-I is GH dependent, with low levels in states of GH deficiency and high levels in GH excess (19, 20, 21). It is widely used to assess disease activity in acromegaly (19, 22, 23), and it is a good screening measurement of GHD in children (24). In this study, serum IGF-I was lower in patients with childhood-onset GHD than in patients with adult-onset GHD, which was also found by Johannsson et al. (25). In the present study all nine patients with childhood-onset GHD and 62% of the patients with adult-onset GHD had levels below the fifth percentile of normal values. In childhood-onset GHD, a comparable sensitivity level was reported by De Boer et al. (15), and in adult-onset GHD, both higher (Attanasio AF, Valk NK, Strasburger CJ, Birkett M, Matranga AMC, Lamberts SWJ, personal communication) and lower (26, 27) levels were reported. In the present study the sensitivity of the serum IGF-I concentration to diagnose GHD was higher than the sensitivity of the serum IGFBP-3 concentration in both adult-onset and childhood-onset GHD. IGFBP-3 is the most predominant binding protein of circulating IGF-I in postnatal life. IGFBP-3 is secreted by many normal cell types, including osteoblasts, endothelial cells, and fibroblasts (28). In the liver, IGFBP-3 is produced in nonparenchymal cells of the liver (29) and is thought to be GH dependent (30, 31). In the present study, however, the sensitivity of serum IGFBP-3 to diagnose adult-onset GHD was low: only 24% of the patients had a serum IGFBP-3 level below the fifth percentile of normal values for age and gender. On the contrary, in patients with childhood-onset GHD, the sensitivity of serum IGFBP-3 was higher (88%) than that in patients with adult-onset GHD, which could explain some contradictory results in the sensitivity of serum IGFBP-3 in diagnosing GHD. De Boer et al. (15) reported an IGFBP-3 sensitivity of 93% in GH-deficient adults of childhood onset, whereas Hoffman et al. (27) reported that only 28% of mainly adult-onset GHD patients had serum IGFBP-3 values below the normal range. The finding of low serum IGF-I with normal serum IGFBP-3 in patients with adult-onset GHD agrees with the in vitro study of Albiston et al. (32) that reported a smaller decrease in IGFBP-3 than in IGF-I messenger ribonucleic acid expression after hypophysectomy in adult rats.
The underlying mechanism for the difference in biochemical parameters between GHD acquired at childhood or that acquired as an adult is not clear. With stepwise multiple regression analysis we found serum IGF-I to be dependent on the estimated years and severity of GHD, but not on the GHD group (childhood vs. adult onset) or age of the patient (data not shown). The severity of GHD was estimated with the maximum GH value during ITT. Serum IGFBP-3 was dependent first on the age of onset of GHD (adult or childhood onset) and secondly on the estimated number of years of GHD, but not on the severity of GHD. We might speculate on the factors contributing to the observed differences between these two groups of patients, such as sensitivity of IGFBP-3 synthesis to the circulating GH concentration, synthetic capacity, and/or metabolic degradation. We have no evidence that the GH receptor in childhood-onset GHD is less sensitive to GH, as we did not find a lower percent increase in serum IGFBP-3 (and IGF-I) during rhGH therapy in this group compared with the adult-onset group. However, lower organ mass and, thus, synthetic capacity in childhood-onset GHD are plausible, but if organ mass as such is the most important factor in the synthesis of GH-dependent proteins, one would also expect a parallel decrease in serum IGF-I in childhood-onset GHD, which is not the case. Finally, it is possible, that the metabolism of IGFBP-3 by proteolytic enzymes is different in these two patient groups, but direct evidence for this is lacking.
In healthy controls, GH secretion is subject to exquisite metabolic regulation, including rapid negative feedback regulation by serum IGF-I. Van den Berg et al. (11) reported higher GH production in healthy women than healthy men, but similar serum IGF-I concentrations. Assuming comparable free IGF-I, they speculated that GH is biologically less active in women, that IGF-I clearance is higher in women than in men, and/or that the feedback sensitivity of the hypothalamo-pituitary axis to the suppressive effects of IGF-I is relatively attenuated in women compared with men. Lieberman et al. (33) studied the effect of a supraphysiological rhGH dose in healthy elderly women (60–69 yr) with and without oral estrogen replacement therapy. They reported a higher incremental response in women without estrogen replacement therapy and concluded that orally administered estrogen inhibits the IGF-I response to GH. In the present study, female patients with adult-onset GHD had lower serum IGF-I levels at the start of the study than male patients, despite similar maximal GH levels during ITT. These gender differences in serum IGF-I were still present after 12 weeks of rhGH therapy. This finding supports the hypothesis that GH is less biologically active in women, possibly due to the oral estrogen therapy that was used by most women, and/or that the IGF-I clearance is higher in this group. The hypothesis of a difference in feedback sensitivity of the hypothalamo-pituitary axis can be rejected based on the results of the present study.
The molar ratio of IGF-I to IGFBP-3 is thought to reflect free, biologically active IGF-I (34). In active acromegaly, this ratio is increased, and in the elderly, it is decreased. We found a decreased ratio in the patients with adult-onset GHD, which was also reported by Jørgensen et al. (35). GH treatment increased the molar ratio significantly to normal values, confirming the results of Jørgensen et al. (35). This observation suggests an increase in free, biologically active IGF-I during rhGH treatment. On the other hand, we did not find a change in free IGF-I in patients with childhood-onset GHD; the molar ratio of IGF-I/IGFBP-3 was normal at baseline and did not change during GH treatment. Therefore, it seems that decreased GH secretion at childhood decreases serum IGF-I and serum IGFBP-3 similarly, whereas in adults with adult-onset GHD, IGFBP-3 levels can be maintained, and IGF-I levels are decreased.
In summary, this study demonstrates differences in the biochemical characteristics of childhood-onset and adult-onset GHD. In patients with adult-onset GHD, serum IGFBP-3 levels are not significantly decreased and can, therefore, not be used as a screening tool for GHD or as a dose-finding parameter. GH therapy at doses of 0.6 and 1.2 IU/day in male and female patients, respectively, is, in general, able to increase serum IGF-I to the normal range after 12 weeks of treatment, without reaching supranormal levels. This dose could, therefore, be a starting dose in the treatment of GH-deficient adults.
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Footnotes |
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Received May 30, 1996.
Revised August 14, 1996.
Accepted September 4, 1996.
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A. Mukherjee, W. D. J. Ryder, A. Jostel, and S. M. Shalet Prolactin Deficiency Is Independently Associated with Reduced Insulin-Like Growth Factor I Status in Severely Growth Hormone-Deficient Adults J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2520 - 2525. [Abstract] [Full Text] [PDF]
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N. R. Biermasz, A. M. Pereira, J. W. A. Smit, J. A. Romijn, and F. Roelfsema Morbidity after Long-Term Remission for Acromegaly: Persisting Joint-Related Complaints Cause Reduced Quality of Life J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2731 - 2739. [Abstract] [Full Text] [PDF]
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N. R Biermasz, N. A T Hamdy, A. M Pereira, J. A Romijn, and F. Roelfsema Long-term maintenance of the anabolic effects of GH on the skeleton in successfully treated patients with acromegaly Eur. J. Endocrinol., January 1, 2005; 152(1): 53 - 60. [Abstract] [Full Text] [PDF]
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C. L Boguszewski, L. H F Meister, D. C T Zaninelli, and R. B Radominski One year of GH replacement therapy with a fixed low-dose regimen improves body composition, bone mineral density and lipid profile of GH-deficient adults Eur. J. Endocrinol., January 1, 2005; 152(1): 67 - 75. [Abstract] [Full Text] [PDF]
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N. R. Biermasz, S. W. van Thiel, A. M. Pereira, H. C. Hoftijzer, A. M. van Hemert, J. W. A. Smit, J. A. Romijn, and F. Roelfsema Decreased Quality of Life in Patients with Acromegaly Despite Long-Term Cure of Growth Hormone Excess J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5369 - 5376. [Abstract] [Full Text] [PDF]
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A. F. Attanasio, E. Shavrikova, W. F. Blum, M. Cromer, C. J. Child, M. Paskova, J. Lebl, J. J. Chipman, the Hypopituitary Developmental Outcome Study Grou, and S. M. Shalet Continued Growth Hormone (GH) Treatment after Final Height Is Necessary to Complete Somatic Development in Childhood-Onset GH-Deficient Patients J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4857 - 4862. [Abstract] [Full Text] [PDF]
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N. R. Biermasz, F. W. Dekker, A. M. Pereira, S. W. van Thiel, P. J. Schutte, H. van Dulken, J. A. Romijn, and F. Roelfsema Determinants of Survival in Treated Acromegaly in a Single Center: Predictive Value of Serial Insulin-Like Growth Factor I Measurements J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2789 - 2796. [Abstract] [Full Text] [PDF]
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M. Rosilio, W. F. Blum, D. J. Edwards, E. P. Shavrikova, D. Valle, S. W. J. Lamberts, E. M. Erfurth, S. M. Webb, R. J. Ross, K. Chihara, et al. Long-Term Improvement of Quality of Life During Growth Hormone (GH) Replacement Therapy in Adults with GH Deficiency, as Measured by Questions on Life Satisfaction-Hypopituitarism (QLS-H) J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1684 - 1693. [Abstract] [Full Text] [PDF]
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 N. R. Biermasz, A. M. Pereira, M. Frolich, J. A. Romijn, J. D. Veldhuis, and F. Roelfsema Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly Am J Physiol Endocrinol Metab, January 1, 2004; 286(1): E25 - E30. [Abstract] [Full Text]
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A. Mukherjee, J. P. Monson, P. J. Jonsson, P. J. Trainer, and S. M. Shalet Seeking the Optimal Target Range for Insulin-Like Growth Factor I during the Treatment of Adult Growth Hormone Disorders J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5865 - 5870. [Abstract] [Full Text] [PDF]
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K. Yuen, K. Ong, S. Husbands, P. Chatelain, L. Fryklund, P. Gluckman, M. Ranke, D. Cook, R. Rosenfeld, J. Wass, et al. The Effects of Short-Term Administration of Two Low Doses Versus the Standard GH Replacement Dose on Insulin Sensitivity and Fasting Glucose Levels in Young Healthy Adults J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1989 - 1995. [Abstract] [Full Text] [PDF]
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E. M. McConnell, A. B. Atkinson, C. Ennis, D. R. Hadden, D. R. McCance, B. Sheridan, and P. M. Bell The Effects on Insulin Action in Adult Hypopituitarism of Recombinant Human GH Therapy Individually Titrated for Six Months J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5342 - 5347. [Abstract] [Full Text] [PDF]
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N. R. Biermasz, N. A. T. Hamdy, Y. J. H. Janssen, and F. Roelfsema Additional Beneficial Effects of Alendronate in Growth Hormone (GH)-Deficient Adults with Osteoporosis Receiving Long-Term Recombinant Human GH Replacement Therapy: A Randomized Controlled Trial J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3079 - 3085. [Abstract] [Full Text] [PDF]
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N. R. Biermasz, H. van Dulken, and F. Roelfsema Ten-Year Follow-Up Results of Transsphenoidal Microsurgery in Acromegaly J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4596 - 4602. [Abstract] [Full Text]
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A. M. Rosenfalck, S. Maghsoudi, S. Fisker, J. O. L. Jørgensen, J. S. Christiansen, J. Hilsted, A. Vølund, and S. Madsbad The Effect of 30 Months of Low-Dose Replacement Therapy with Recombinant Human Growth Hormone (rhGH) on Insulin and C-Peptide Kinetics, Insulin Secretion, Insulin Sensitivity, Glucose Effectiveness, and Body Composition in GH-Deficient Adults J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4173 - 4181. [Abstract] [Full Text]
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N. R. Biermasz, H. van Dulken, and F. Roelfsema Long-Term Follow-Up Results of Postoperative Radiotherapy in 36 Patients with Acromegaly J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2476 - 2482. [Abstract] [Full Text]
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