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Original Studies |
Endocrine Unit, Flinders Medical Centre (S.J.), Adelaide; Metabolic Research Unit, University of Queensland, Princess Alexandra Hospital (R.C.C., J.D.W.) Brisbane; Endocrine Unit, Royal Brisbane Hospital (D.P-K.), Brisbane; Prince Henry’s Institute of Medical Research, and Body Composition Laboratory, Monash Medical Centre (H.B., S.L-T., B.S.), Melbourne; Ewen Downie Metabolic Unit, Alfred Hospital (J.S., D.T.), Melbourne; Endocrine Unit, St. Vincent’s Hospital (F.A., L.H.), Melbourne; Paediatric Endocrine Unit, Sydney Children’s Hospital (H.B.), Sydney; Andrology Unit, Royal Prince Alfred Hospital (A.C., D.H.), Sydney; Medical Psychology Unit, University of Sydney (S.D.), Sydney; Endocrine Unit, Westmead Hospital (S.B., N.W.C.), Sydney; and Department of Diabetes and Endocrinology, Royal Perth Hospital (D.H.), Perth, Australia
Address all correspondence and requests for reprints to: Ross C. Cuneo, University Department of Medicine, Princess Alexandra Hospital, Wooloongabba, Brisbane, 4102, Australia. E-mail: cuneo2{at}gpo.pa.uq.edu.au
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Treatment with GH has been reported to reverse many of these abnormalities (1, 2, 15, 16). Uncertainty remains regarding the definition of GH deficiency and the appropriate dose of GH for replacement. Differing studies have selected patients of markedly different degrees of GH deficiency, ranging from essentially no GH response to insulin-induced hypoglycemia to those with a peak GH of <10–20 mU/liter following oral clonidine (2). Recent data suggest that a peak GH of <5 ng/mL in response to insulin-induced hypoglycemia is abnormal for all adults (17). Most early reports used high daily doses of GH (0.4–0.49 U/kg per week), resulting in side effects caused by fluid retention (18, 19, 20, 21).
We undertook a large trial of GH treatment in adults with GH deficiency to assess the effects of a moderate dose of GH, in a group of patients selected on the basis of our current best definition of GH deficiency. The primary end points were assessment of biochemical responses, body composition, quality of life, and safety.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients were randomly allocated without stratification to treatment either with GH (Genotropin, Pharmacia AB, Stockholm, Sweden) or identically presented placebo for the first 6 months in a double-blind fashion. Thereafter, all patients received GH in an open study for a further 6 months. The two groups were labeled GH/GH or placebo/GH. Randomization to either treatment involved a computer-generated listing, with equal numbers being entered per group at each of the 10 centers.
The dose of GH (or placebo) was 0.125 U/kg per week (maximum 2 IU/day) for the first month, and 0.25 U/kg per week (or 0.55 mg/kg per week; maximum 4 IU/day) thereafter. Because the study remained blinded throughout, the dose for all subjects was lowered from month 6 until month 7, reverting to the full dose thereafter. The dose was reduced in response to the side effects of edema or arthralgia and remained at or was reduced to 0.125 IU/kg per week and increased only with resolution of the symptoms. Persistent side effects resulted in transient cessation of therapy, which was resumed with resolution of symptoms, with the dose remaining at 0.125 IU/kg per week thereafter. The dose was self-administered using the KabiPen (Pharmacia AB) from 16 IU/mL vials as sc injections 7 nights/week. The injection site was either the anterior thigh or abdomen, at the patient’s preference, but remained constant throughout the study. Compliance was checked by vial count and injection diary.
Patients were assessed at months 0, 6, and 12 for all end points, at months 1 and 7 for safety checks, and at months 3 and 9 for selected end-point assessment.
The study protocol was approved by the ethics committees of each participating unit. Center 1 participated only in the 6-month, double-blind phase of the study. All patients received written information and gave written consent according to the Declaration of Helsinki (1964 and later revisions) and the National Health and Medical Research Council (Australia) Ethics in Medical Research (1983). The study was conducted according to the Australian Guidelines of Good Clinical Research Practice (1991).
Selection criteria
Patients were included if: 1) age was 18–65 yr and linear growth was completed as confirmed by epiphysial closure on wrist radiography for those <19 yr; 2) GH deficiency was documented as peak GH of <5 mU/liter following insulin-induced hypoglycemia (blood glucose <2.2 mmol/liter or with symptoms); and 3) other pituitary hormone deficiencies were replaced, with stable replacement therapy for at least 6 months before entry. Daily glucocorticoid doses were not to exceed 30 mg hydrocortisone, 37.5 mg cortisone acetate, 7.5 mg prednisolone, or 0.5 mg dexamethasone. T4 replacement was to result in normal serum-free T4 (fT4) and/or free T3 (fT3) concentrations. Parenteral or oral testosterone administration was to be used in men and estrogen (with/or without progesterone) administration in women under age 50 yr. Women of child-bearing potential were to be using adequate contraception (oral contraceptives or intrauterine device) and were required to have a negative pregnancy test at entry.
Preentry insulin-hypoglycemia testing was required within the last 5 yr after the age of 20 yr or after epiphysial closure unless: 1) the patient had had hypophysectomy with subsequent testing at any time; 2) the patient had radiotherapy. Testing was also specified to be 3) at least 6 months after normalization of serum PRL in a patient with prolactinoma; 4) at least 6 months after normalization of glucocorticoid status in a patient with Cushing’s disease; and 5) at least 12 months after cure of a TSH-secreting pituitary tumor.
Patients were excluded if any of the following were present: 1) GH treatment in the last 12 months; 2) a history of acromegaly; 3) estrogen deficiency uncorrected in women below age 50 yr; 4) active Cushing’s syndrome; 5) any acute severe illness in the last 6 months; 6) pregnancy or lactation; 7) severe chronic liver disease (defined as persistent elevation of transaminases more than twice the upper limit of normal); 8) chronic renal impairment (defined as serum creatinine > 0.12 mmol/liter or persistent hematuria or proteinuria); 9) diabetes mellitus; 10) history of malignancy other than cranial tumor or leukemia causing GH deficiency; 11) history of meningioma or currently active intracranial malignancy; 12) uncontrolled hypertension (diastolic blood pressure >90 mmHg); 13) overt cardiac dysfunction or ischemia on electrocardiogram; 14) severe chronic airway disease; 15) any medication thought to alter the response to treatment or the end points, especially high-dose glucocorticoids and diuretics (cholesterol-lowering agents were permitted, but doses of all medications were held as constant as possible); 16) history of noncompliance with medications, uncooperativity, or drug or alcohol abuse; and 17) known sensitivity to m-cresol.
Screening of patients before entry included complete history and physical examination, resting electrocardiogram, routine biochemistry and hematology, and urinalysis.
Biochemical responses
Fasting serum concentrations of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured at months 0, 6, and 12 in all centers. Samples were frozen and stored at -20 C and assayed in a central laboratory. IGF-I was measured by RIA after acid-ethanol extraction, using a truncated radiolabeled IGF as tracer (in- house assay, Pharmacia, Uppsala, Sweden). The detection limit was 20 ng/mL, and the intra- and interassay coefficients of variation (CVs) at 202 ng/mL were 3.1 and 10.0%, respectively. The concentration of IGF-I was also expressed as a standard deviation score (i.e. normal values range from +2 to -2), expressed in relation to normal age-adjusted adult values calculated as follows:
IGF-I SDS = (ln (IGF-I) - (5.95 - 0.0197 x age))/0.282
The reference population was Swedish, comprised of 83 male and 73 female healthy blood donors, with mean body weights of 80.9 kg (range 60–115 kg) and 66.1 kg (range 50–95 kg) for males and females, respectively, and mean body mass indexes of 25 and 23.7 kg/m2, respectively (Pharmacia, unpublished data). IGFBP-3 was measured by RIA using 125I-labeled recombinant human IGFBP-3 as tracer (in-house assay, Pharmacia). The assay’s detection limit was 0.9 ng/mL and the intra- and interassay CVs at 43.2 ng/mL were 4.9% and 7.2%, respectively. The assay had negligible cross-reactivity with IGFBP-1, -2, and -4 (<0.3%). The concentration of IGFBP-3 was also expressed as a standard deviation score from the same Swedish population data as IGF-I, calculated as follows: IGFBP-3 SDS = (s IGFBP-3 - exp (2.0466 - (0.0099 x age)))/ exp (0.6707 - (0.0099 x age))
Fasting serum was collected for lipid estimation at months 0, 6, and 12 in all centers. Routine assays were performed at individual centers. Total cholesterol was measured by enzymatic and colorimetric methods (Boehringer Mannheim, Mannheim, Germany) in all centers except one, with interassay CVs of <4.1%. HDL cholesterol was assayed following polyethylene glycol precipitation of other lipoproteins (phosphotungstic acid/Mg++ in one center), followed by identical analysis for cholesterol; CVs were <6.4%. LDL cholesterol was calculated from the Friedwald formula. Serum triglyceride was measured by enzymatic and colorimetric methods (Boehringer Mannheim) in all centers except one, with interassay CVs < 4.8%.
Body composition
All centers measured anthropometric characteristics and bioelectrical impedance (BIA) at months 0, 3, 6, 9, and 12. Five centers (centers 2–6) measured deuterium dilution (D2O) at the same intervals, plus the specialized body composition measurements at 0, 6, and 12 months [dual energy x-ray absorptiometry (DEXA) and total-body potassium scanning]. At centers 4–6, in vitro neutron activation analysis was also performed.
Anthropometric measurements included height, weight, skinfold thicknesses, midarm circumference, and waist/hip circumference ratio (WHR). A Harpenden caliper was used at four standard sites (biceps, triceps, subscapular, suprailiac). Training was given to researchers at each center before the commencement of the study to minimize between-center variability, and where possible, one observer performed all measurements. Skinfold measurements are reported as peripheral (sum of biceps and triceps), truncal (sum of subscapular and suprailiac) and total (sum of four). Waist circumference was recorded at the narrowest point or at the umbilicus and hip circumference at the level of the greater trochanter.
BIA was measured with the SEAC Bioimpedance Meter Model BIM 3.0 (Inderlec, Brisbane, Australia), except in center 4, where a BEI-101 Body Composition Analyzer (RJL Systems, Detroit, MI) was used. FFM and total-body water (TBW) were calculated according to formulae derived from healthy individuals (22, 23).
TBW was derived from the D2O method, following oral administration of D2O and spectrophotometric analysis of venous plasma samples (24). The minimum intraassay CV of the assay was <5.0% for a low standard and <2.2% for a high standard, and interassay CV was <2.9% over the duration of the study. DEXA measurements of the whole body and lumbar spine (results of the latter to be reported separately) were taken on two Lunar DPX System scanners (Lunar Corp., Madison, WI), one in both Brisbane and Melbourne. FFM, fat mass (FM), and total-body calcium were derived from the whole-body scans. Comparability of the two machines was assessed by scanning phantoms. Total-body potassium (TBK) was measured as 40K content using shadow shield counters in Brisbane and Melbourne. Subject measurements were calibrated against a phantom (25). Using the proportion of intracellular potassium as an index of FFM (64–68 mmol/kg) and the two compartment model of body composition, FFM and FM were derived. For the Melbourne scanner, the interassay CVs for measurements of the calibration and anthropometric phantoms were <3.8%. Comparability of the two machines was assessed by swapping the phantoms of known potassium content. In vitro neutron activation analysis measured total-body nitrogen, and hence total-body protein (TBP) (24). The interassay CVs for day-day measurement of the calibration and anthropometric phantoms were <3.8% (average 2.5%; within day) and <10.5% (average 5.7%; within month) throughout the study period. The mean accuracy was 99.5% for the anthropometric phantom.
Quality of life assessments
Questionnaires were administered at months 0, 3, 6, 9, and 12.
The Nottingham Health Profile (NHP) is a valid and reliable measure of perceived health, developed in the United Kingdom to assess physical, emotional, and social distress. It is regarded as valid for Australian populations (26, 27). Part I of the test was administered. Six subscales can be derived, including emotions, pain, physical mobility, sleep, energy, and social isolation. Analysis was based on the proportion of positive answers, with a score higher than 0 indicating a compromised state. A summary score (SUM) was also derived, with a positive score indicating a favorable quality of life.
The GH Deficiency Questionnaire (GHDQ) was developed for this trial. It was based on group discussions with adults with GH deficiency regarding their perceived major areas of disability, i.e. energy, mood, and sleep. The GHDQ consists of 30 questions relating to these three subscales or domains, each answered on a 10-cm visual analog scale, completed on an IBM portable computer, on which mean and range of responses was recorded. Mean responses are reported. A higher score represented a more positive status. The GHDQ has been validated in normal individuals and used as a trial in a small group of adults with GH deficiency (S. Dunn, unpublished data).
Social history was also assessed at months 0, 6, and 12. Data was collected regarding marital status, number of children, living arrangements, education level, occupation/employment/retirement status, sick leave in the past 6 months, physical activity at leisure and work, social activity and satisfaction, and significant life events.
Safety and adverse events monitoring
Safety assessments included complete physical examination, routine biochemistry, fT4, glycosylated hemoglobin A1c, full blood examination, supine blood pressure recorded in triplicate after 5 min rest, and urinalysis at months 0, 6, and 12. All adverse events were recorded, quantitated according to the patient’s estimation of severity, and specific inquiry was made as to features of fluid retention and arthralgias. The adverse events were classified according to the WHO codes and preferred terms.
Statistical analysis
The study was analyzed on an intention-to-treat basis. Missing data points were not estimated. Comparisons of continuous and categorical baseline data were analyzed by ANOVA and contingency table analysis, respectively. Treatment effects for NHP data were assessed using the mean score test, a weighted analysis of covariance (ANCOVA) using baseline data as the covariate (28); variance was partitioned between treatment, withdrawal status, baseline data as covariate, month, and relevant interactions. Treatment effects for other continuous variables and the GHDQ were assessed using ANCOVA with baseline data as the covariate. Results of treatment and baseline data were therefore presented as means adjusted for baseline differences (mean ± SEM); SEMS for baseline data are presented uncorrected, whereas all posttreatment SEMS are adjusted for baseline covariance. For body composition data, variance was partitioned between treatment, center, gender, month, and withdrawal status.
After ANCOVA, pairs of means were compared with the least significant difference, allowing comparison between groups at each time point. Maintenance of a treatment effect beyond the first 6 months was assigned if there was no significant change in the mean values in the GH/GH group from 6–12 months and no significant difference between the GH/GH and placebo/GH group means at 12 months.
Treatment effects for categorical data were assessed using contingency table analysis and a log linear model (29). Laboratory safety data were analyzed using Mann-Whitney U or Wilcoxon rank sum W tests. A P value of <0.05 was considered significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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One hundred sixty-six patients were entered. Three patients
withdrew consent before initiation of treatment. The demographic
characteristics of the patients are shown in Table 1
. The two treatment groups were similar
in all aspects except for the duration of GH deficiency, which was
shorter in the GH/GH group (estimated from the time of abnormal
insulin-hypoglycemia testing or pituitary surgery and/or radiotherapy;
P = 0.03). In addition to pituitary hormone
replacement, 10% of patients received bromocryptine; 9% received
antidepressants, anxiolytics, or hypnotic medications; 6%
anticonvulsants; 7% treatment for asthma; and 4% treatment for
hypercholesterolemia. The most frequent changes in medication during
the study were courses of antibiotics, increased bronchodilators or
corticosteroids, and short increments in glucocorticoid replacement.
There were no differences in medications between the two groups.
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Biochemical responses
Serum IGF-I concentrations. At baseline, there was no
difference between treatment groups (Table 2). The percentage of patients in the
entire study group at baseline with IGF-I SDS <2
and ±2 were 56.6% and 43.9%, respectively. There was a
significant increase in serum IGF-I with GH treatment for months 0–6
and 0–12, and a treatment x time interaction for months 0–12
(all P < 0.001). The percentage of patients who
developed supraphysiological serum IGF-I concentrations at 12 months
(>2 SD) who had subnormal (<2 SD) or normal
(±2 SD) pretreatment levels was 17.6% (12/68) and 68.9%
(31/45), respectively. Serum IGFBP-3 concentrations showed similar
changes (Table 2).
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There was a significant decrease in total cholesterol with GH treatment
for months 0–6 (P = 0.040) but not for months 0–12
(P = 0.103), with a significant difference in response
between centers (P = 0.03 and 0.014 for months 0–6 and
0–12, respectively). There was a significant decrease in LDL
cholesterol with GH treatment for months 0–6 and months 0–12
(P = 0.005 and 0.019, respectively), with no difference
between centers. For serum HDL cholesterol concentration, there was no
treatment effect or treatment x time interaction, but there was a
significant difference between centers (P = 0.001 and
0.008 for months 0–6 and 0–12, respectively). For serum triglyceride
concentration, there was no treatment effect, treatment x time
interaction, or difference between centers.
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Results of body composition are shown in Table 4.
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Anthropometry. At baseline, the total sum of skinfold thicknesses was significantly different between males and females (76.2 ± 2.7 vs. 93.7 ± 3.9 mm; P < 0.001) and between centers (P < 0.001) but not between treatment groups. There was a reduction in total sum of skinfold thicknesses with GH treatment for months 0–6 and 0–12 (P < 0.001 and P = 0.003, respectively). At baseline, the sum of truncal skinfold thicknesses was significantly different between males and females (44.7 ± 1.6 vs. 50.5 ± 2.1 mm; P < 0.001) between centers (P < 0.001) and between treatment groups (GH 49.3 ± 1.9 vs. placebo 45.1 ± 1.8 mm; P = 0.015). There was a reduction in truncal skinfold thickness with GH treatment for months 0–6 and 0–12 (P < 0.001 and P = 0.001, respectively). At baseline, the sum of peripheral skinfold thicknesses was significantly different between males and females (31.1 ± 1.4 vs. 44.6 ± 2.2 mm; P < 0.001) and between centers (P < 0.001) but not between treatment groups. There was a reduction in peripheral skinfold thickness with GH treatment for months 0–6 and 0–12 (P = 0.021 and P = 0.063, respectively). None of these treatment responses was influenced by gender. At baseline, WHR was different between centers (P = 0.007), but not between treatment groups. There was a significant reduction in WHR with GH treatment for months 0–6 and 0–12 (P = 0.001 and P = 0.015, respectively). Parallel reductions in total-body FM as measured by DEXA were also observed for months 0–6 and 0–12 (both P < 0.001; data not shown).
FFM derived from BIA. At baseline, there were significant differences between males and females (57.4 ± 1.3 vs. 42.3 ± 0.9 kg; P < 0.001) between centers (P = 0.002) and between treatment groups (GH/GH group: 53.4 ± 1.5 vs. placebo/GH group: 47.7 ± 1.3 kg; P < 0.001). There was an increase in FFM with GH treatment for months 0–6 and 0–12 (both P < 0.001) and a treatment x time interaction for months 0–12 (P < 0.001). This response was influenced by gender (for the 0–6- and 0–12-month periods, treatment x gender interaction P = 0.029 and 0.079, respectively) indicating a greater increment in FFM in males. FFM measured by DEXA, TBK, and TBP showed similar increments following GH treatment at both 6 and 12 months (P < 0.001 for all; data not shown).
TBW derived from BIA. At baseline, there were significant differences between males and females (39.1 ± 0.8 vs. 27.6 ± 0.6 l; P < 0.001), between centers (P = 0.001), and between treatment groups (GH/GH group: 35.9 ± 1.0 vs. placebo/GH group: 31.8 ± 0.9 l; P < 0.001). There was an increase in TBW with GH treatment for months 0–6 and 0–12 (P < 0.001 and P = 0.005, respectively) and a treatment x time interaction for months 0–12 (P < 0.001). This response was not influenced by gender (for the 0–6- and 0–12-month periods, treatment x gender interaction P = 0.6 and 0.3, respectively). TBW derived from D2O showed a similar increment with GH treatment (P < 0.013; data not shown).
Whole-body BMD. At baseline, there were significant
differences between males and females (1.193 ± 0.013
vs. 1.097 ± 0.017 g/cm2; P
< 0.001), between centers (P = 0.024), but not between
treatment groups (P = 0.084). At baseline, the BMD
represented 97.4 ± 1.3% and 97.4 ± 1.6% of young adult
BMD, and 96.3 ± 0.35% and 96.4 ± 0.27% of age-matched BMD
for the GH/GH and placebo/GH groups, respectively. There was no
treatment effect (for the 0–6- and 0–12-month periods,
P = 0.30 and 0.19, respectively) or treatment x
time interaction. Secondary analysis (by least significant difference)
revealed a significant reduction in BMD in both groups by 12 months
(see Table 4
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Efficacy: quality of life assessment
NHP. At baseline, analysis of the NHP revealed no difference
between the GH/GH and placebo/GH groups with respect to energy, pain,
sleep, and physical mobility (Table 5).
The mean baseline scores were low (indicating little or no impairment).
The proportion of patients with 0 scores (no impairment) was: energy
36.5%, pain 77%, emotional reaction 45.5%, sleep 43.5%, social
isolation 70.5%, and physical mobility 59.5%. Improvement in quality
of life in patients who score 0 at baseline cannot be measured with the
NHP. Analysis of the data for efficacy by assessing only patients with
positive scores at baseline revealed no differences from that presented
(i.e. analyzing all data).
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GHDQ. There were no differences between the groups at baseline, and there were no significant treatment effects for either mood, energy, or sleep scales throughout the study. For the sleep scale, there was a significant treatment x time interaction for months 0–12 (P = 0.011), indicating an improvement in sleep in the GH/GH group.
Social history. Physical activity at work and at leisure, each quantitated into five categories, showed no change throughout the study. There was no change for the number of full sick days taken in the previous 6 months throughout the study, but the absolute numbers were small in each group (GH/GH group: 0.45 ± 0.11 days sick/patient over 6 months vs. placebo/GH group: 0.41 ± 0.09 by month 6). The frequency of meeting friends and satisfaction with life, quantitated into five categories or yes/no, respectively, showed no change. At baseline, 63% of the GH/GH and 73% of the placebo/GH groups were satisfied with their lives, rising to 85% and 83%, respectively, by 12 months. There was no change in the occurrence of significant life events between the groups.
Safety monitoring
At baseline, there was no difference in fasting serum glucose
between treatment groups, but serum glucose increased with GH treatment
for months 0–6 and 0–12 (P = 0.001 and
P = 0.014, respectively; Table 3). At baseline, there
was a no difference in systolic blood pressure between treatment
groups, and there was no change in with GH treatment for months 0–6
and 0–12 (P = 0.17 and P = 0.093,
respectively). At baseline, there was no difference in diastolic blood
pressure between centers or treatment groups. There was no change in
diastolic blood pressure with GH treatment for months 0–6 and 0–12
(P = 0.087 and P = 0.23, respectively),
but there was a significant treatment x month interaction
(P = 0.002) for the months 0–12, indicating a
progressive fall in the GH/GH group from 0–9 months (with an increase
at 12 months returning to pretreatment levels).
Alkaline phosphatase and white cell count increased, and serum urea,
potassium, alanine aminotransferase, aspartate aminotransferase, and
-glutamyltranspeptidase decreased in the GH/GH compared with the
placebo/GH group (data not shown). The magnitude of such changes
rendered these of doubtful clinical significance. There was no change
in red cell count or glycosylated hemoglobin A1c.
Adverse events
Overall, the incidence of reported adverse events was high, partly relating to the method of documenting separate but related events. In months 0–6, 290 events in 70 of the 83 GH/GH patients (84%) and 219 events in 60 of the 80 placebo/GH patients (75%) were recorded. During the open phase of GH treatment, 411 new events were reported in 99 patients.
Events were considered either to relate to known GH actions or to be
unexpected. Predictable side effects (Table 6) included edema (which included
generalized, peripheral, or facial edema, carpal tunnel symptoms, and
peripheral swelling or tightness; 48% of GH/GH patients vs.
30% placebo/GH; P = 0.016), arthralgias, and myalgias
(which included arthritis, arthrosis, myalgia, muscle stiffness,
tendonitis, and muscle weakness; 30% GH/GH vs. 13%
placebo/GH; P = 0.007), paresthesia and anesthesia
(12% GH/GH vs. 4% placebo/GH; P = 0.056),
and increased sweating (3.6% GH/GH vs. 0% placebo/GH;
P = 0.078). Overall, 19 patients from the GH/GH group
and 11 from the placebo/GH group withdrew. The primary reason for
withdrawal was a GH-related adverse event in 40% of these
patients.
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Withdrawn patients
Analysis of completed vs. withdrawn patients revealed no difference with respect to baseline characteristics. Those who withdrew, compared with those completing the study, were characterized by 1) a tendency to have lower FFM for the 0–6- and 0–12-month periods (P = 0.089 and 0.025, respectively); 2) having a progressively worse NHP energy score for months 0–12 (P = 0.003); 3) having a worse NHP pain score for both the 0–6- and 0–12-month periods (P = 0.031 and 0.010, respectively); 4) those in the GH/GH group who withdrew having a worse NHP emotional reaction score than in the placebo/GH group for months 0–6 and 0–12 (both P < 0.001); 6) those in the GH/GH group who withdrew having a worse NHP sleep score than in the placebo/GH group for months 0–6 (P = 0.006) and 0–12 (P < 0.001); 7) having a worse summary NHP score for months 0–6 and 0–12 (P = 0.037 and 0.005, respectively), and those in the GH/GH group who withdrew having a worse score than those in the placebo/GH group (P = 0.004 and 0.002, respectively).
Maintenance of treatment effects from 6–12 months
All biochemical end points remained stable (serum IGF-I, IGFBP-3, total cholesterol, and LDL cholesterol). Significant improvements in body composition end points were evident at 3 months (all three skinfold estimates, WHR, FFM by BIA, and TBW by BIA) and showed a gradual improvement (total and peripheral skinfolds) or stable course until 12 months. For FFM by DEXA, FM by DEXA, TBK, and TBN, improvements were evident at 6 months and were maintained to 12 months, with the placebo/GH group still below the GH/GH group values by 12 months for the last two end points.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The GH dose during this study was approximately half that used in the original treatment trials (0.25 IU/kg per week vs. 0.49 IU/kg per week) (18, 19, 20, 21). Nevertheless, the incidence of GH-related adverse events was high. In comparing the results of treatment between this and other studies, it seems likely that GH-deficient adult patients with more profound degrees of GH deficiency (i.e. this study group) may be likely to have a greater response to GH treatment than those with lesser degrees of GH deficiency (i.e. studies using responses to clonidine or arginine) (31). Assuming IGF-I can act as a guide for optimizing GH dose, we found that the a substantial proportion of patients developed a supraphysiological serum IGF-I concentration following GH treatment, particularly in those with normal pretreatment serum IGF-I concentrations. This strongly suggests that the mean dose is still too high, and that certain subgroups may require even lower doses. Given the high rate of reported adverse events in patients receiving placebo treatment, it was not possible to predict those at risk of GH-mediated adverse events.
Adults with GH deficiency have increased risk factors for premature vascular disease, i.e. increased total and LDL cholesterol concentrations, reduced HDL concentrations, increased apolipoprotein B concentrations, increased number of small LDL particles, and increased WHRs, visceral adiposity, and varying degrees of insulin resistance (8, 32, 33). Such abnormalities may explain the increased mortality rates caused by vascular disease in adults with conventionally treated hypopituitarism (7, 34). With respect to vascular risk factors, GH treatment in our study induced small reductions in total (1.8%) and LDL cholesterol (7.0%) concentrations, and substantial reductions in truncal adiposity (9.2–14.1%; see below). The increase in serum glucose with GH treatment is well described, and appears to represent transient worsening of insulin resistance (35, 36). Previous studies have shown prominent reductions in intraabdominal or visceral fat following GH treatment (21), changes that would be expected to improve insulin resistance (37). There were no changes in other risk factors. Thus, whether continued GH treatment alters the long-term vascular mortality rate remains unknown.
We were able to confirm the findings that GH treatment in adults with GH deficiency influenced body composition. In the 6-month controlled phase, FFM increased 4.5% as measured by BIA. In a subset of patients, other indices of lean tissue mass also increased: 4.4% by DEXA, 6.6% by TBK, and 8.6% by TBP. TBW measured by BIA in all patients increased by 3.2%. FM reflected in total skinfold thickness, truncal, or peripheral skinfold thicknesses declined 12.0%, 14.1%, and 9.3%, respectively, and when measured by DEXA declined 9.2%. WHR decreased by 2.0%. The different magnitudes of increase in lean tissue mass between the various methodologies may be partially explained by inaccuracies induced by concomitant shifts in other body compartments (38), differing specificities of the tools, and that some measurements were performed on subsets of patients. Our data confirm the prominent lipolytic action of GH in adults with GH deficiency, and that more subcutaneous fat was lost from the trunk than the periphery. Overall, the magnitude of such changes was slightly less than reported in the early trials, reflecting the lower dose of GH used in the current trial (18, 19, 21). Additionally, we have shown that the GH-induced changes in body composition were sustained to 12 months. Males showed greater increments in FFM measured by BIA than females; the physiological explanation may relate to interactions between testosterone and GH in stimulating growth and protein anabolism (39), or in stimulating greater IGF-I responses (40). Mean whole-body BMD declined 2.5% in the GH/GH group and 1.7% in the placebo/GH group over 12 months, with no GH treatment effect. Such findings are consistent with an early GH-mediated increase in bone remodeling (41).
Adults with GH deficiency perceive their own quality of life to be worse than that of normal subjects (5, 42), and have poor social performances in employment and marriage (43, 44). The NHP questionnaire used in this study has been validated for a variety of diseased populations and in different cultures. Although we did not assess a control population under similar circumstances, between one third and two thirds of our patients before treatment felt little or no impairment in their quality of life. Hypothetically, the long-term presence of GH deficiency may have habituated them to accept their condition. Despite this favorable pretreatment quality of life, GH treatment still resulted in measurable beneficial effects for energy, emotional reaction, the overall score, and possibly pain and sleep. Detrimental effects were recorded for physical mobility in the 3 months following initiation of GH treatment, most likely relating to the high prevalence of adverse effects of peripheral edema or arthralgias. The perceived beneficial effects of GH treatment, the high compliance rate, and the percent of patients completing the study is encouraging given the high incidence of adverse events.
The nature of the adverse events correspond with previous reports, and can be summarized as those caused by sodium retention (resulting in edema or carpal tunnel symptoms) or arthralgias/myalgias (which may relate to articular cartilage swelling and skeletal muscle growth or edema). Although a variety of disorders were reported under the heading of edema, carpal tunnel syndrome was the least common, with an incidence of 4.8% in the GH/GH group, 1.3% in the placebo/GH group, and 3.4% during the open phase of treatment. Such effects are clearly dose dependent and in many individuals self-limiting. One adverse event not previously reported was glucocorticoid deficiency. Such events were infrequent (five events in approximately 180 patient years of treatment), making causality difficult to ascribe to GH. Increased glucocorticoid catabolism has been reported following GH treatment, with reduced 24-h serum cortisol profile of hypopituitary patients on stable glucocorticoid replacement therapy (45), and induction of cytochrome P-450 enzymes (29).
Adults with GH deficiency treated with GH at a dose of 0.25 IU/kg per week (0.55 mg/kg per week) for 6–12 months benefit by means of 1) a doubling in serum IGF-I concentration; 2) substantial benefits in body composition such as increased FFM and reduced FM; 3) modest reductions in cardiovascular risk factors with as yet unproven biological consequences; and 4) improvements in self-perceived quality of life. Whether these changes translate into improved cardiovascular morbidity and mortality rates and enhanced physical and psychological function in the long term requires careful ongoing study. Optimization of the dose, with attendant reductions in adverse events that relate predominantly to sodium and fluid retention, remains an important objective for the future development of this therapy.
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Acknowledgments |
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Footnotes |
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Received May 6, 1997.
Revised September 3, 1997.
Accepted September 12, 1997.
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