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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0928
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6431-6440
Copyright © 2005 by The Endocrine Society

Efficacy of a Long-Acting Growth Hormone (GH) Preparation in Patients with Adult GH Deficiency

Andrew R. Hoffman, Beverly M. K. Biller, David Cook, Joyce Baptista, Bernard L. Silverman, Le Dao, Kenneth M. Attie, Paul Fielder, Thomas Maneatis, Barbara Lippe for the Genentech Adult Growth Hormone Deficiency Study Group

Veterans Affairs Palo Alto Health Care System and Stanford University (A.R.H.), Palo Alto, California 94304; Harvard Medical School and Massachusetts General Hospital (B.M.K.B.), Boston, Massachusetts 02114; Oregon Health Sciences University (D.C.), Portland, Oregon 97201; Medical Affairs (J.B., L.D., K.M.A., P.F., T.M., B.L.), Genentech, Inc., South San Francisco, California 94080; and Alkermes, Inc. (B.L.S.), Cambridge, Massachusetts 02139

Address all correspondence and requests for reprints to: Andrew R. Hoffman, M.D., Building 100, Room D4-132, Department of Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304. E-mail: arhoffman{at}stanford.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Treatment of adult GH deficiency (AGHD) with daily injections of GH results in decreased adipose mass, increased lean body mass (LBM), increased bone mineral density, and improved quality of life.

Objective: This study seeks to determine whether a depot preparation of GH given every 14 d would lead to comparable decreases in trunk adipose tissue as daily GH.

Design: This open-label, randomized study compares subjects receiving depot GH, daily GH, or no therapy.

Setting: The study was performed at 23 university or local referral endocrine centers.

Patients or Other Participants: One hundred thirty-five adults with AGHD syndrome participated in the study.

Intervention: Subjects were randomized to receive depot GH (n = 51), daily GH (n = 53), or no treatment (n = 31) for 32 wk. The dose of GH was titrated so that IGF-I was less than or equal to +2 SD of the age-adjusted normal range.

Main Outcome Measure: Trunk adipose tissue was the main outcome measure as measured by dual energy x-ray absorptiometry.

Results: The percentage of the trunk region that is fat increased by 0.4 in the no treatment group, but decreased by 3.2 (P = 0.001 vs. untreated) in the GH depot group and by 2.5 (P < 0.004 vs. untreated) in the daily GH group. Visceral adipose tissue area decreased by 9.1% in the GH depot group and by 6.8% in the daily GH group. LBM and high-density lipoprotein increased in both treatment groups. Side effect profiles were similar. Three subjects receiving GH experienced serious episodes of adrenal insufficiency.

Conclusions: GH diminishes trunk and visceral adipose tissue and increases LBM in AGHD. A depot form of GH that is administered every 14 d is as safe and effective as daily GH injections.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ADULT GH DEFICIENCY (AGHD) syndrome is characterized by reduced lean body mass, increased sc and visceral fat mass (VAT), and decreased bone density (1, 2). Patients have an adverse cardiovascular risk profile (3), reduced exercise capacity (4, 5, 6) and strength (7, 8), and diminished quality of life (9, 10, 11). Numerous reports confirm that GH therapy results in substantial improvements in the physiological and psychological disorders associated with the deficiency syndrome (12, 13, 14).

Many patients with AGHD are reluctant to embark upon lifelong daily hormone injections. Long-acting GH formulations can increase the serum GH and IGF-I levels for 3 d to 2 wk (15). However, concerns have been raised about their ultimate efficacy and safety. Because GH is normally secreted in episodic pulses of short duration (16), a long-acting preparation would present GH into the circulation in a nonphysiological manner. GH receptors might become desensitized, leading to tachyphylaxis, or conversely to undesirable acromegalic changes due to persistent activity.

Nutropin Depot, a long-acting GH preparation composed of microspheres formulated from a poly-D,L-lactide-coglycolide, was approved for use in pediatric GH deficiency (GHD) in 1999 (17). Recombinant human GH particles are embedded in the poly-D,L-lactide-coglycolide matrix, and the microspheres are injected sc. A single injection of the drug increased serum IGF-I to normal levels for 14–17 d in subjects with AGHD (15). The goal of this study was to evaluate the safety and efficacy of depot GH in AGHD as compared with a daily GH preparation. The primary efficacy endpoint was the change from baseline in trunk percent fat after a treatment period of 32 wk.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
A 32-wk, phase II/III, randomized, parallel-group, multiple-dose, multicenter study of long-acting GH (Nutropin Depot) and daily GH (Nutropin AQ) was initiated in December 2001. Subjects received approximately 26 wk of therapy at the target dose, a duration sufficient to detect significant changes in body composition in previous studies of GH therapy in AGHD (18, 19). Efficacy was assessed by the change from baseline in percent trunk fat after a treatment period of 32 wk. This serves as a surrogate measure of intraabdominal fat, or VAT, a well-described cardiovascular risk factor (20). Secondary endpoints included changes in other measures of body composition by dual energy x-ray absorptiometry (DXA), direct measurement of VAT by abdominal computed tomography (CT) scan, and lipid profile. Repeat-dose GH pharmacokinetics and biomarker pharmacodynamics were also assessed in a subset of subjects treated with depot GH.

Study subjects

The trial was conducted at 23 sites in the United States with a planned enrollment of 130 subjects who had either childhood-onset GHD (CO-GHD) or adult-onset GHD and had not been treated with GH for at least 12 months before study entry. GHD was defined as a peak GH level of less than or equal to 5.0 ng/ml after standard pharmacological stimulation tests (e.g. arginine, L-dopa, or insulin-induced hypoglycemia stimulation). Subjects with CO-GHD underwent repeat GH-stimulation testing as adults to confirm that they remained GH deficient. Women were required to take oral estrogen therapy (21). Doses of all hormone replacement therapies must have been stable for at least 1 month before study drug administration.

Protocol

The study was approved by institutional review boards at each of the participating centers. After informed consent was obtained, subjects were screened for study eligibility. A GH stimulation test of the investigators’ choice (unless recently performed), medical history, physical examination, electrocardiogram, laboratory assessments, DXA, abdominal CT, and a 2-h glucose tolerance test were performed at the screening visit. Eligible subjects were randomized to one of three groups: depot GH, daily GH injections, or no treatment. The intended enrollment was approximately 50 subjects in each of the depot GH and daily GH treatment groups, and approximately 30 subjects in the no treatment group. Subjects in the depot arm were dosed every 2 wk, and subjects in the daily GH arm were dosed daily; both forms of GH were administered sc. Training on preparation and administration of GH was given at the baseline visit, after which the study drug was self-administered at home. GH was dosed according to weight up to 100 kg. Subjects weighing more than 100 kg had their dose calculated based upon a body weight of 100 kg. Subjects in the no treatment group did not receive any drug or placebo but were offered the opportunity to take depot GH in a follow-up study.

Before randomization, subjects were stratified into three dosing groups: 1) men less than 35 yr old, 2) men 35 yr old and older, and 3) women. Eligible subjects were then randomized to the treatment groups in a 5:5:3 (depot-daily GH-no treatment) ratio. The study was powered as an efficacy study for the depot GH group vs. the nontreated group. Stratified randomization was used to achieve treatment balance within the strata. Target doses were: 0.3 mg/kg depot GH every 14 d or 0.006 mg/kg daily GH for men 35 yr old and older; 0.6 mg/kg depot GH every 14 d or 0.012 mg/kg daily GH for all women and men less than 35 yr old. GH doses were increased so that subjects reached their protocol-specified target dose by 6–8 wk of therapy. Subjects receiving daily GH were started at a dose of 0.002 mg/kg·d, which was increased to 0.003, 0.004, and 0.006 mg/kg·d at wk 2–4, 4–6, and 6–12, respectively, for men more than 35 yr old, or to 0.004, 0.008, and 0.012 mg/kg·d at wk 2–4, 4–6, and 6–12, respectively, in women and younger men. The first dose of the depot preparation was 0.1 mg/kg, which was increased to 0.15, 0.20, and 0.30 mg/kg at wk 2, 4, and 6, respectively, for men more than 35 yr old; younger men and women received 0.2, 0.4, and 0.6 mg/kg for their second, third, and four injections, respectively. In the event of intolerable adverse events or above-normal IGF-I levels, the dose was reduced to the level that had previously been tolerated.

Clinic visits were scheduled at baseline (wk 0), and for physical examination, weight, waist circumference, vital signs, laboratory assessments (wk 20 and 32), dose adjustment (wk 20), glucose tolerance test (wk 32), DXA scan (wk 32), and abdominal CT scan (wk 32). Subjects receiving GH also had laboratory visits 4–7 d after the wk-16 and wk-18 time-points to assess levels of GH, IGF-I, and IGF binding protein 3 (IGFBP-3). If both the wk-16 and wk-18 IGF-I levels were more than +2 SD for age and sex, the dose was reduced to less than or equal to two thirds of the target dose. If the dose was reduced, a follow-up IGF-I level was obtained 4–7 d after the wk-24 dose.

All subjects who completed the study had the option of participating in an extension study during which they received depot. A subset of subjects (n = 15) receiving depot GH underwent additional sampling for pharmacokinetic (GH) and pharmacodynamic (IGF-I and IGFBP-3) analyses; fasting blood samples were drawn at wk 20 and wk 30 at the following time-points: predose and d 2, 7, and 10 postdose.

Laboratory testing and body composition

Serum GH levels were assessed using a two-site immunochemiluminescent assay that can detect levels of GH as low as 0.05 ng/ml. Serum IGF-I was measured using the IGF-I Nichols Kit (catalog no. 40-2100), a competitive-binding RIA performed after acid ethanol extraction can detect levels of IGF-I as low as 13.5 ng/ml. Serum IGFBP-3 was determined using the Esoterix RIA (Austin, TX) with a lower limit of 300 µg/liter. Serum acid-labile subunit (ALS) levels were measured using the Genentech, Inc. (South San Francisco, CA) colorimetric sandwich ELISA. C-reactive protein (CRP) was measured by Esoterix, Inc.

DXA (Hologic or Lunar machines) and CT scans were performed at local sites; Bio-Imaging Technologies (Newtown, PA) was the centralized quality assurance center. DXA scans were read by one technician blinded to treatment, with one set of software on one machine. DXA scans of the whole body were performed, from which trunk data were derived by omitting the head, arms, and legs. We measured the change in fat mass over time and, therefore, did not need to make adjustments between the two types of machines. Noncontrast abdominal CT images consisted of a minimum of five axial oblique (transverse) slices, 7–10 mm thick, centered at and parallel to the level of L4–L5 vertebral disk space.

Statistics

The primary analysis used the last available observation collected at or after the wk-20 visit for comparison with baseline. An intent-to-treat or sensitivity-to-dropout analysis was conducted, in which the postbaseline last observation carried forward (LOCF) was used unless missing. If the LOCF was missing, then the value was replaced by the mean change for the untreated group. The primary treatment comparison was between the depot GH group and the untreated group using a two-way ANOVA with treatment group and randomization stratum. The secondary treatment comparison was between the depot and the daily GH groups, using a two-sided 95% confidence interval (CI) on the difference between treatment group means for the change from baseline in trunk percent fat, also allowing for different variances between groups in the t test. The depot group was considered not inferior to the daily GH group if the upper limit of the 95% CI for the difference means between groups was less than 1.5%.

For secondary efficacy, endpoints missing changes from baseline were not replaced, but postbaseline LOCF was used and t tests and the Wilcoxon rank sums test, as appropriate, were used to test treatment group differences. Within treatment group differences were tested with the paired t test and the Wilcoxon signed-rank test as appropriate.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Study subjects

A total of 135 subjects with GHD were randomized into the study (Table 1Go): 66% of the subjects were men, 21% had childhood onset GHD, and 24% had previously received GH replacement therapy. The average duration of GHD was 6.9 yr since diagnosis in the subjects with adult-onset GHD and 19.2 yr for the subjects with CO-GHD. Isolated GH deficiency was diagnosed in 21% of the subjects, but there was documented underlying pathology in half of them, including trauma, congenital hypopituitarism, pituitary disease, pituitary macroadenoma, cerebellar astrocytoma, eosinophilic granuloma, and empty sella; the etiology of the AGHD in the other subjects is not known. The baseline IGF-I levels were lower in the women [SD score (SDS) = –4.0 ± 2.6] than in the men (SDS = –2.9 ± 2.6) (P = 0.02). A total of 41% of the subjects had baseline IGF-I levels that were within the normal range (Fig. 1Go). Sixteen subjects withdrew from the study early; three withdrew consent from the observation only group, 10 withdrew from the depot group (five because of adverse events), and three withdrew from the daily GH group, all because of adverse events.


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  		TABLE 1. Baseline characteristics

 


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  		FIG. 1. Baseline IGF-I SDS by age, sex, and treatment group. Normal range for IGF-I SDS is from –2 to +2. A, Women (n = 44, mean ± SD = –4.0 ± 2.6). B, Men (n = 85, mean ± SD = –2.9 ± 2.6). The women had lower IGF-I SDS (P = 0.02). At baseline, none of the subjects had SDS over +2 SD. IGF-I SDS were less than –2 SD in 12 (48%) of the untreated subjects, in 30 (59%) of the subjects receiving depot GH, and in 34 (64%) of the subjects receiving daily GH.

 
Subjects in the GH depot group did not miss any scheduled doses, although some doses were not given in their entirety for technical reasons. In the daily group, 29% of subjects reported missing no doses during the study, whereas another 56% reported missing fewer than 5% of doses.

Hormonal response to treatment

Serum IGF-I levels remained low in the subjects who did not receive therapy. Both the depot GH and the daily GH treatment groups achieved serum IGF-I levels that were close to the normal age-adjusted mean (Fig. 2Go). In the depot group, mean IGF-I SDS was –3.1 at baseline and mean predose (trough) IGF-I SDS was –1.0 after dose titration. Mean postdose (d 4–7 after drug administration) IGF-I SDS was +0.8 (wk 16), +0.9 (wk 18), +1.2 (wk 24), and +0.7. In addition, at wk 20 and wk 32, predose levels of GH, IGF-I, and ALS remained generally unchanged, suggesting that there is not likely to be progressive increase or accumulation at these dosing regimens (Table 2Go).



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  		FIG. 2. IGF-I SDS during the study. Normal range for IGF-I SDS is from –2 to +2. A, Untreated (n = 26). B, Daily GH (n = 53). C, Depot GH: baseline and predose during the study (n = 51). D, Depot GH: baseline and postdose, 4–7 d from injections during the study (n = 51, postdose data were only obtained at baseline and wk 16, 18, 20, 24, and 30).

 

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  		TABLE 2. Predose concentrations of pharmacokinetic/pharmacodynamic markers at baseline, wk 20, and wk 32 for subjects receiving depot GH (mean ± SD)

 
After administration of the depot GH, pharmacokinetic data at wk 20 (data not shown) and wk 30 (Fig. 3Go) showed an initial rise followed by a decline in GH and IGF-I levels. No subjects in the pharmacokinetic subset had dose reductions after the wk-20 to wk-22 dose. In most subjects, levels of GH began to decline 2 d after drug administration. However, circulating GH levels were maintained above 0.3 µg/liter for 10 d postdose. In some subjects, the IGF-I SDS transiently exceeded the normal range on d 2, returning to values within the normal range (±2 SD) by d 7 and maintained in this range through d 10 postdose.



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  		FIG. 3. Pharmacokinetics of depot GH after the wk-30 injection. A, Serum GH concentrations. B, IGF-I SDS. Normal range for IGF-I SDS is from –2 to +2. All subjects have at least a day-2 value.

 
Body composition responses to treatment

In the population in which efficacy was evaluated (with DXA scans at baseline and wk 20 or later), the difference in mean change from baseline for percent trunk fat for the depot GH group (n = 41) minus the untreated group (n = 24) was –3.5% (ANOVA, P = 0.0011), and the change for the daily GH group (n = 49) minus the no treatment group was –2.9% (P = 0.0002). The intent-to-treat analysis showed differences of –2.9% (P = 0.0002) and –2.6% (P = 0.0007), respectively (Table 3Go and Fig. 4Go).


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  		TABLE 3. Difference between treatment group means for change in percent trunk fat at wk 32 relative to baseline

 


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  		FIG. 4. Change in trunk fat (kilograms) assessed by dual energy absorptiometry and visceral fat (square centimeters) assessed by computed tomography at wk 32 compared with baseline. Percent change = 100 x [last postbaseline observation carried forward (kg or cm2) – baseline (kg or cm2)] / baseline (kg or cm2). P values are from two-sample t tests vs. the untreated group.

 
The difference between the depot GH group and the daily GH group in trunk percent fat was not significant (P = 0.42), and the 95% CI for this difference demonstrated that depot GH treatment was not inferior to daily GH treatment.

Data for all of the DXA measurements are shown in Table 4Go. None of the differences between the depot GH and daily GH groups was significantly different from each other. Mean total body percent fat decreased and mean total body percent lean increased in both the depot and daily GH groups (P < 0.005), but these parameters were unchanged in the untreated group.


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  		TABLE 4. Body composition baseline, wk 32 change, and percent change from baseline

 
There was a significant difference between the depot and untreated control groups for mean kilogram change in trunk fat (–1.5 kg; P = 0.001) and total body fat (–2.4 kg; P = 0.012). The mean change for the daily GH group compared with the no treatment group was also significant for trunk fat and total body lean mass. There were no significant differences between the depot GH and daily GH groups. The mean percent change from baseline in trunk fat was +2.3% in the no treatment group, –10.5% in the depot group, and –5.4% in the daily group. There was no significant within-group mean kilogram change or percent change from baseline in mean total body fat or lean mass in the untreated control group. However, there was a significant decrease in mean total body fat in the depot GH group compared with untreated control subjects, and a significant increase in mean total body lean mass in both active treatment groups, but not all comparisons with the untreated group were statistically significant. The mean percent change in total body fat was +0.2% in the no treatment group, –8.4% in the depot group, and –3.0% in the daily GH group. The mean percent change in total body lean mass was –0.7% in the untreated group, +1.7% in the depot group, and +3.6% in the daily GH group.

Abdominal CT scans were used to quantify changes in VAT specifically (Fig. 5Go). The difference between depot GH and untreated groups for change in VAT was significant (P = 0.023). Significant within-group decreases were seen in both active treatment groups, with a mean percent change of –9.1% in the depot GH group and –6.8% in the daily GH group. The depot GH group, but not the daily GH group, had a significant decrease and percent change from baseline in mean waist circumference that approached significance compared with the untreated group (P < 0.05 to 0.07). These changes were accompanied by salutary changes in lean mass.



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  		FIG. 5. CT scans of the abdomen at baseline and wk 32 showing changes in visceral and sc adipose tissue. CT images of the lumbar region and lower abdomen were performed without contrast enhancement, consisting of a minimum of five axial oblique (transverse) slices of the abdomen 7–10 mm thick, centered at and parallel to the level of L4–L5 vertebral disk space. A, Subject received daily GH; the difference between baseline and wk 32 visceral adipose tissue was –45 cm2. B, Subject received depot GH; the difference between baseline and wk 32 visceral adipose tissue was –15 cm2. Thin arrows point to visceral fat; thick arrows point to sc fat.

 
Lipid profile and CRP responses to treatment

Total cholesterol and low-density lipoprotein (LDL) cholesterol did not change significantly (Table 5Go). There was a small but significant increase in high-density lipoprotein (HDL) cholesterol in both active treatment groups, but triglyceride levels decreased significantly only in the depot GH group, which had the highest mean triglyceride level at baseline. Mean changes in CRP levels were minimal (±0.3 mg/liter) in each treatment group.


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  		TABLE 5. Lipid profile and CRP baseline and wk 32 change from baseline

 
Effect of sex, age of GHD onset, and baseline IGF-I levels on response to GH treatment

The differences in mean changes of trunk percent fat were significant for the depot GH group compared with the no treatment group in men, but not in women; for the group that received daily GH administration, the difference in trunk percent fat compared with the no treatment group was significant only in the older men (Fig. 4Go). The depot and daily GH groups did not differ significantly for any stratum.

The change in trunk percent fat showed a greater degree of change in subjects with CO-AGHD (–6.2%) than in those with AO-AGHD (–2.4%) in both active treatment groups. Exploratory analyses show that change in percent trunk fat (or the change in any of the other measures of body composition) did not correlate with baseline IGF-I level, change in IGF-I level, or change in IGF-I SDS (data not shown).

Adverse events

Adverse events assessed as being potentially related to study drug by the investigator were reported in 66% of subjects receiving depot GH and 50% of subjects receiving daily GH. The most frequent adverse events included edema (in 24% of subjects taking the depot and in 29% of subjects taking daily GH) and arthralgias (in 34% taking depot and in 31% taking daily GH). No intracranial hypertension was reported. There were no significant changes in mean fasting or 2-h postglucose challenge serum glucose, insulin, or glycosylated hemoglobin levels. Mean glycosylated hemoglobin increased 0.2% in both the depot and daily GH treatment groups. Isolated elevations in serum glucose levels returned to normal during treatment. There were no reports of new onset diabetes mellitus in the no treatment group; fasting glucose levels were more than 126 mg/dl at the end of the study in two subjects receiving daily and in one subject receiving depot GH (postdose only).

Two deaths were reported in subjects who were receiving depot GH. One death was due to a motor vehicle accident, reported by the investigator as unrelated to treatment, and the other death was a result of adrenal crisis, reported by the investigator as possibly related to GH. The latter was a 35-yr-old woman with panhypopituitarism who was taking replacement hydrocortisone (10 mg bolus twice daily). She developed gastroenteritis and was found dead at home 14 d after her first dose of the GH depot. Twelve serious adverse events occurred in 10 subjects (four receiving depot and six receiving daily GH). There were three serious, including one fatal, and three nonserious cases of adrenal crisis or insufficiency. Three cases occurred in subjects receiving daily GH, and three occurred in those receiving depot GH; all of these subjects had previously diagnosed secondary adrenal insufficiency and were currently being treated with glucocorticoid replacement therapy. The relationship between GH and these events is possible in some cases, but there were alternative explanations such as failure to increase steroid dose during an intercurrent illness.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrates proof of the concept that a long-lasting GH preparation that leads to relatively constant GH blood levels can provide effective hormone replacement therapy without evidence of tachyphylaxis or increased side effects in adults with GHD. Serum IGF-I levels increased in a similar manner in the patients who received every 2 wk GH depot treatment when compared with those subjects who received traditional daily injections of GH. Daily GH administration leads to significant changes in body composition in patients with AGHD (1, 22, 23, 24). In this study, we have demonstrated that depot GH replacement therapy in adults leads to decreased adipose mass and increased lean body mass. Whereas all groups responded to GH treatment, those subjects with CO-GHD had a greater decrease in fat mass than did the adult-onset patients. There was also a suggestion that men had a greater decrease in adipose tissue in response to GH treatment.

We have confirmed the beneficial effects of GH on decreasing VAT (25). Although most studies of GH replacement therapy in this group of patients have reported that insulin sensitivity declines (26, 27, 28) or does not change (29, 30, 31), this rapid loss of visceral fat could have beneficial effects in lowering cardiovascular risk factors. In our study, total and LDL cholesterol did not change, but HDL cholesterol levels did increase in both treatment groups. A recent metaanalysis demonstrates that GH therapy usually results in a slightly lower LDL and total cholesterol, but HDL cholesterol levels do not change significantly (32).

Many subjects with AGHD have serum IGF-I levels within the normal age-range despite having an inadequate GH response to provocative testing (33). It is possible that GHD patients with "normal" IGF-I levels have concentrations that are inappropriately low for their bodies’ needs. In this study, 41% of the GHD subjects had serum IGF-I levels which were within the normal range, but there was no correlation between clinical improvements and changes in serum IGF-I level with therapy or with baseline IGF-I SDS.

The incidence of adverse events did not differ in the active-treated groups. The most frequent serious adverse advent was the development of adrenal crisis. GH therapy will change the requirements for thyroid hormone (34, 35) and glucocorticoids (36, 37) in panhypopituitary patients. In part, this is because GH-stimulated IGF-I inhibits regeneration of cortisol from the inactive cortisone (38, 39, 40). GH also increases the activity of cytochrome p450 enzymes which affect cortisol metabolism (41). Relatively high dose GH may also lead to a slight decrease in serum cortisol binding globulin levels (38)

Our data demonstrate that a long-acting GH preparation can maintain normal adult serum IGF-I levels on a chronic basis, and that this form of GH replacement therapy is as safe and efficacious as daily GH injections in treating the clinical AGHD syndrome. Although the depot preparation used in this study is no longer commercially available, the efficacy of this preparation has prompted further investigation into the development of long acting GH formulations.


   Acknowledgments
 
We thank all of the study nurses, coordinators, and investigators for all of their help implementing the study, and we acknowledge Ari Illeperuma for his invaluable assistance.


   Footnotes
 
The study was supported by Alkermes, Inc. (Cambridge, MA) and Genentech, Inc.

In addition to the authors, the site principal investigators were: Mary Lee Vance, M.D. (University of Virginia Health Sciences Center, Charlottesville, VA); Samer Nakhle, M.D. (VA Southern Nevada Health Care System, Las Vegas, NV); David Sutton, M.D. (North East Florida Endocrine and Diabetes Research Center, Jacksonville, FL); Thomas Moshang, M.D. (Children’s Hospital of Philadelphia, Philadelphia, PA); Thomas Tse, M.D. (Diabetes, Thyroid & Osteoporosis Center of Southern Illinois, Bellville, IL); Richard Levy, M.D. (Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL); Lewis Blevins, M.D. (Vanderbilt University Medical Center, Nashville, TN); Ali Iranmanesh, M.D. (VA Medical Center, Salem, VA); Gertrude Costin, M.D. (Children’s Hospital, Los Angeles, CA); Jay Cohen, M.D. (Endocrine Clinic, Memphis, TN); James W. Snyder, M.D. (Lovelace Scientific Resources, Las Vegas, NV); Stephen L. Aronoff, M.D. (Research Institute of Dallas, Dallas, TX); Sam Lerman, M.D. (The Center for Diabetes and Endocrine Care, Hollywood, FL); Dana S. Hardin, M.D. (Southwest Medical School, Dallas, TX); George Merriam, M.D. (VA Puget Sound Health Care System, Tacoma, WA); Fernando Ovalle, M.D. (University of Alabama, Birmingham, AL); Mark Kipnes, M.D. (Diabetes & Glandular Disease Research Associates, San Antonio, TX); Baha Arafah, M.D. (University Hospitals of Cleveland, Cleveland, OH); and Wayne Moore, M.D. (Children’s Mercy Hospital, Kansas City, MO).

First Published Online September 13, 2005

Abbreviations: AGHD, Adult GH deficiency; ALS, acid-labile subunit; CI, confidence interval; CO-GHD, childhood-onset GH deficiency; CRP, C-reactive protein; CT, computed tomography; DXA, dual energy x-ray absorptiometry; GHD, GH deficiency; HDL, high-density lipoprotein; IGFBP-3, IGF binding protein 3; LBM, lean body mass; LDL, low-density lipoprotein; LOCF, last observation carried forward; SDS, SD score(s); VAT, visceral fat mass.

Received April 28, 2005.

Accepted September 1, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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