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Endocrine Care |
Lilly Research Centre (A.K., P.C.B., P.F., M.B., P.M., A.F.A.), Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom; Eli Lilly \|[amp ]\| Co. (W.F.B.), Bad Homburg, D-61350 Germany; Mount Sinai Hospital (S.E.), Toronto, M5G 1X5 Canada; Garvan Institute (K.K.Y.H.), Darlinghurst, Sydney, NSW 2010, Australia; Frederico II University (G.L.), Naples, 80131 Italy; University Hospital (A.L.), A-1090 Vienna, Austria; University Hospital (J.M.), 128 01 Prague 2, Czech Republic; and St. Thomas Hospital (D.R.-J., P.S.), London SE1 7EH, United Kingdom
Address all correspondence and requests for reprints to: Dr. Anne Kehely, Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom. E-Mail: . Kehely_Anne{at}Lilly.com
Abstract
The aim of GH replacement therapy in GH-deficient adults is to optimize response with minimum incidence of adverse reactions, but optimal therapy regimens are still to be established. This two-arm parallel study examined effects of two GH dose algorithms in adults with GH deficiency of adult or childhood onset. Patients on low dose (LD; n = 302) received GH at 3 µg/kg per day for 3 months increasing to 6 µg/kg per day for 3 months, and those on conventional dose (CD; n = 293) started on 6 µg/kg per day for 3 months increasing to 12 µg/kg per day for 3 months. The proportion of patients completing therapy was greater for the LD group than the CD group for the first 3 months (93.0% vs. 88.1%; P = 0.037) and overall for the 6 months (90.7% vs. 84.0%; P = 0.013). Both dose groups showed significant increases in lean body mass and decreases in fat mass for all time points. Percent increase in lean body mass was less with LD than CD over the first 3 months (2.43 ± 4.33 vs. 3.58 ± 4.69%; P = 0.006) but not overall for the 6-month period (4.38% ± 5.34% vs. 5.21% ± 5.99%; P = 0.141). Percent decrease in fat mass was less with LD than CD for the first 3 months (-2.81% ± 7.81% vs. -5.53% ± 8.64%; P < 0.001) and overall for the 6-month period (-6.35% ± 9.42% vs. -9.45% ± 12.07%; P = 0.006). IGF-I SD score increased less with LD than CD for 0 to 3 and 0 to 6 months, although for IGF-binding protein-3 SD score, there was no significant difference between doses at any time. Arthralgia was the only adverse event that occurred significantly less frequently with LD than with CD. Calculated changes based on gender and onset indicated greater changes in males than females for body composition, but there was little difference in GH-related adverse events between males and females. The lower starting dose with dose titration appeared more favorable, but differences in response between genders and onset of GH deficiency need to be taken into account when setting an individual dose regimen.
ADULT HYPOPITUITARY PATIENTS with GH deficiency (GHD) suffer from diminished muscle strength and excess body fat, particularly in the waist region, compared with their non-GHD peers. Administration of recombinant human GH to GHD adults improves body composition as well as lipid profiles and quality of life. Replacement therapy is now a registered indication, and a dose of 6.25–12.5 µg/kg per day has been shown to be effective and well tolerated in the majority of patients (1). However, optimal therapy regimens and methods of assessing GH efficacy have not yet been established.
Response rates to GH in terms of changes in lean body mass and fat mass vary greatly, and a lack of correlation with changes in serum IGF-I has been shown (2). Many adult GHD patients do not have IGF-I levels below the age-adjusted reference range before commencing therapy (3). In addition, it has been shown that normalization of IGF-I level does not always equate with metabolic response (4), so IGF-I measurement cannot be used as a marker of response in all cases. Younger, male patients appear to be more responsive in terms of IGF-I and body fat loss (5). Women with GHD have lower IGF-I levels before replacement therapy (6), require higher GH doses to achieve IGF-I levels between the median and upper end of the age-related reference range, and take longer to reach their maintenance dose (7).
The most common side effects reported in adults include peripheral edema, arthralgia, myalgia, and paraesthesia, which are thought to be owing to the fluid-retaining effects of restoration of GH (8). These side effects commonly occur at the beginning of therapy (9) and usually resolve spontaneously or following a dose reduction. Older patients (10) and those with a higher body mass index (11) are more prone to adverse events, which also occur more frequently in patients on higher initial doses (12).
The aim of GH replacement therapy is to optimize the therapeutic response with minimal incidence of adverse reactions. The objective of the present study was to explore the effects of 6 months of two different GH dosing algorithms, one standard and one set at half the standard dose, on body composition, IGF-I response, and risk of development of therapy-related side effects in a group of GHD adults.
Patients and Methods
Patients
This multinational study involved 56 study centers and included 595 adult patients with GHD of either childhood onset (CO) or adult onset (AO). Patient entry to the study was the decision of the attending physician. GHD was confirmed from peak serum GH levels of less than 3.0 µg/liter in standard GH stimulation tests (65% insulin tolerance tests, 11% arginine tests, 25% other tests) as well as clinical history including the presence of other pituitary hormone deficiencies. The demographic characteristics of the patients are summarized in Table 1
according to randomization group. The age ranged from 17.9–78.4 yr, and there was no significant difference between treatment groups. Only 40 (6.7%) patients had isolated GHD, with the largest proportion (44.4%) having three pituitary hormone deficiencies in addition to GHD, and there was no difference in the distribution of number of deficiencies between the treatment groups. All patients were receiving adequate and stable replacement therapy for other pituitary hormone deficiencies before study entry. Overall, 20.3% of the patients had received GH during childhood, but no patient was allowed to enter the study if they had received GH therapy in the previous 6 months. There were 16 (2.7%) patients included in the study who had diabetes mellitus recorded as a clinical condition at baseline. Patients with clinically significant pulmonary, cardiac, hepatic, renal, or neuromuscular disease or evidence of active tumors were not included.
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The study was carried out with approval from appropriate ethical review boards, and informed consent was obtained from all patients before starting study procedures. At baseline the patients were randomized to two groups using a block size of four and with stratification by country. The groups were assigned to receive GH (Humatrope, Eli Lilly \|[amp ]\| Co., Indianapolis, IN) replacement therapy at a dose of either 3 µg/kg per day (low dose, LD) or 6 µg/kg per day (conventional dose, CD) for the first 3-month treatment period. The dose was then doubled for a further 3-month treatment period to 6 µg/kg per day (LD) or 12 µg/kg per day (CD). Patients were assessed for safety and efficacy before commencing therapy, at 3 months (12 ± 1 wk) when the GH dose was increased and at 6 months (24 ± 1 wk). Dose of GH was recorded during each treatment period and in the event of a change. When side effects of therapy occurred, dose reductions of 30% initially, then to a maximum of 50%, were permitted. Safety of GH therapy was assessed from reporting of the occurrence of the following GH-related side effects: edema, headache, arthralgia, myalgia, paresthesia, or joint disorder. Efficacy was assessed from lean body mass (LBM) and fat mass (FM) measured by dual-energy x-ray absorptiometry at baseline and following 3 and 6 months of therapy. Percent LBM and percent FM were determined from the values as a proportion of body weight. Changes during the study were calculated as percentages of the values at baseline for 0–3 months and 0–6 months or of the values at 3 months for changes from 3–6 months.
Laboratory measurements
Serum samples were collected from each patient at baseline, 3 months, and 6 months and were shipped frozen to a central laboratory for assay. Serum IGF-I concentrations were measured by an IGF-binding protein (IGFBP)-blocked RIA and serum IGFBP-3 concentrations were measured by an established RIA (13). All IGF-I and IGFBP-3 measurements were converted to SD scores by reference to a normal population to allow for differences because of age and gender.
Statistical analyses
Baseline characteristics were compared between treatment groups using a two-sample t test for continuous variables or a Pearson 
2 test for categorical variables. Patient disposition during the study was compared using a Pearson 2 test. All efficacy analyses were performed on an intent-to-treat basis using last observation carried forward. Differences between groups for efficacy variables were assessed from an ANOVA model that included effects for treatment, onset, gender, and country. Safety was assessed from differences in the incidence of adverse events using a Pearson 2 test. All analyses used two-sided tests, and a P value of less than 0.05 was considered statistically significant.
Results
Patient characteristics and disposition
The main cause of GHD in this patient population was pituitary adenoma (43.4%), most of which (160/258, 62.0%) were nonfunctional macroadenomas. Other causes included idiopathic (21.0%), craniopharyngioma (14.5%), empty sella (4.9%), other neoplasia (4.0%), and trauma or Sheehan’s syndrome (3.5%). There was no difference between the treatment groups in the pituitary disorders.
The numbers of patients who completed each of the two study periods, together with the number who withdrew because of adverse events, are shown in Table 2. Withdrawal for reasons other than adverse events were mainly because of patient decision or protocol variations. The proportion who completed the first 3-month treatment period was greater (P = 0.037) for the LD group (93.0%) than the CD group (88.1%). During the second 3-month treatment period, the proportion completing was not different between the dose groups. Overall for the 6-month study period, the number of patients completing was significantly (P = 0.013) higher in the LD group (274 patients, 90.7% ) than the CD group (246 patients, 84.0%) because of the lower withdrawal rate for adverse events (P = 0.023) in the LD group. Dose reductions because of adverse events occurred in the first 3 months in 11 (3.6%) of the LD patients, compared with 15 (5.1%) of the CD group. In the second half of the study, the numbers were 12 (4.3%) for LD, compared with 27 (10.5%) for CD patients.
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Baseline values for body composition are shown by treatment group in Table 3, and the percentage changes during the study are shown in Fig. 1. Both treatment groups showed significant increases in LBM and reductions in FM from baseline at the end of 3 months of GH therapy. Patients in the CD group gained significantly more lean tissue and lost significantly more body fat, compared with the LD group. Further significant changes were seen in both groups during the second 3-month therapy period, but there were no differences between doses. Overall, after 6 months, LBM was increased and FM was reduced, compared with baseline. The patients on CD had lost significantly more fat than the LD group, but the increased gain in lean tissue in the CD group, compared with the LD group, did not achieve significance.
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At 3 months there was a significant difference between the genders in the increase in LBM (P < 0.001) and decrease in FM (P < 0.001), with males demonstrating a better response than females. Between 3 and 6 months of therapy, there was no difference between the genders in increase in LBM, but females lost less fat than males (P = 0.013). Overall, during the 6-month study, males gained more LBM (males 5.73%; females 4.20%; P = 0.004) and lost more FM (males -10.07%; females -5.13%; P < 0.001). CO patients had a greater increase in LBM than AO patients from 0 to 3 (P = 0.017), 3 to 6 (P = 0.026), and overall from 0 to 6 months (CO 5.88%; AO 4.05%; P < 0.001), but there was no difference between the onsets in FM response at any time.
Serum IGF-I and IGFBP-3 levels
Baseline values for IGF-I and IGFBP-3 concentrations and SD scores are shown by treatment groups in Table 3
, and the changes in SD score values during the study are shown in Fig. 2. Both IGF-I and IGFBP-3 SD scores showed significant increases, compared with the previous visit during each of the two study periods and across the study as a whole. In the first 3 months and at the end of 6 months, the change in IGF-I SD scores was significantly higher in the CD group, compared with the LD group. There were no differences for change in IGFBP-3 SD scores seen between the groups at any point in the study.
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At baseline, 84.2% of the LD group and 78.7% of the CD group had IGF-I SD score values at or below -2.0. After 3 months of treatment, this had decreased to 38.1% for the LD group and 28.0% for the CD group and the majority of patients had IGF-I SD score values within the normal range of -2.0 to +2.0 for both treatment groups. The value was +2.0 or greater for only 0.7% of the lower-dose group and 4.2% of the higher-dose group. After 6 months of treatment, the majority of patients were still within the normal range (LD group 70.4%; CD group 60.6%). There were still 27.4% of the LD group and 21.1% of the CD group with values of -2.0 or less. The proportion with values +2.0 or greater had increased to 2.2% for the LD group and 18.3% for the CD group.
Of the 177 females used in the efficacy analysis, 30 were not hypogonadal. Of the remaining 147, only 15 were not receiving estrogen, thus providing two groups of widely discrepant sizes (132 vs. 15) precluding adequate comparison. Moreover, information regarding the route of estrogen administration was not systematically collected.
Treatment-emergent adverse events
From baseline to 3 months, significantly (P = 0.012) fewer patients in the LD group (135, 44.7%) than the CD group (161, 54.9%) reported at least one adverse event. The lower incidence with the lower dose occurred for females (P = 0.006) although not males (P = 0.251) and for AO (P = 0.002) although not CO (P = 0.983) patients. During months 4 to 6, the proportion of patients reporting at least one adverse event was not significantly different (P = 0.317) between the two treatment groups (LD 93 patients, 33.1%; CD 96 patients, 37.2%), and there were no significant differences between doses for either gender (female P = 0.616; males P = 0.347) or either onset (CO P = 0.900; AO P = 0.274). Overall from baseline to 6 months, fewer patients in the lower-dose group reported at least one adverse event (LD 169 patients, 56.0%; CD 194 patients, 66.2%; P = 0.010). Between-dose differences were not significant for females (P = 0.056), males (P = 0.060), or CO patients (P = 0.423) but were significant for AO patients (P = 0.008). The distribution of GH-related adverse events by treatment group during the study is shown in Table 4. Arthralgia was the only event that occurred significantly more frequently in the CD group.
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For patients who had values determined at each time point, the percentage changes in LBM and FM, change in IGF-I SD scores, and the incidence of GH-related adverse events were determined. The mean values at each of the three study periods are shown in Table 5 by gender, onset, and GH dose.
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The risk of a GH-related adverse event was significantly affected by GH dose during 0–3 months (P = 0.012) and 0–6 months (P = 0.004) of therapy but during 3–6 months was only affected by GHD onset (P < 0.001). Although there was no strict relationship between IGF-I levels and adverse events, a trend was observed for higher IGF-I levels on the CD, which was also associated with more frequent adverse events.
Discussion
Because of its anabolic and lipolytic action, GH administration to adult GHD patients improves lean tissue and body fat abnormalities when assessed by a wide variety of methods (1, 11, 12, 14, 15, 16). Gains in lean mass of 2–5.5 kg and reductions in fat mass of 4–6 kg have been reported (17). The present study was much larger than any previous single study of this nature in GHD adults and achieved a mean gain of 2.33 kg in lean tissue in the CD group but a mean gain of only 1.81 kg in the LD group. The smaller reduction in FM in the present study, compared with previous studies, is likely to be owing to the higher GH doses used in earlier studies.
Experience with GH therapy is growing, and it has become apparent that subgroups of GHD adults vary in their response to GH. This is in line with higher GH concentrations in normal women (18, 19) but greater changes in IGF-I and body fat in GHD men than GHD women treated with the same GH dose by body surface area (5). The present study confirms the beneficial impact of male gender on FM reduction and also shows an increased gain in lean tissue in males, compared with females. Onset of GHD had an effect on lean body mass increase, with CO patients showing a better response, although onset did not appear to influence fat mass reduction. These variations in responsiveness are likely to be due to the baseline differences that occur in gender and GHD-onset groups (1).
Many of the actions of GH are mediated through IGF-I, and serum levels rise in a dose-dependent fashion when GH is administered. Serum IGF-I is currently the best biochemical marker of GH action, and regular measurement is recommended to avoid overreplacement (20, 21). However, IGF-I levels may be within the reference range in individuals, particularly in the older population (22), who are clearly GH deficient before commencing therapy. Gender and onset differences in basal levels occur, with significantly lower levels in females and subjects with CO GHD (1, 22, 23). In addition, there is a subgroup of GHD patients in whom conventional doses of GH replacement fail to normalize IGF-I levels. These differences were observed in the present study population and, in accordance with the body composition data, CO patients and male patients demonstrated a superior IGF-I SD score response. The increases observed in IGF-I and LBM, and the decreases in FM, in the present study are of a similar order of magnitude to previous studies with similar doses (7) but less than has been observed with much higher GH doses (17).
GH-related adverse events most commonly occur early after commencing therapy (9), and the present findings support this with the majority of adverse events, approximately 75%, reported in the first half of the study for both treatment groups. The dose of 6 µg/kg per day precipitated more adverse events when patients received it as a starting dose in the CD group than in the LD group, who received it during the second 3 months following the first 3 months of therapy with a lower dose.
The nature of the adverse events reported in the study reflects the pattern of expected events in this group of patients (9, 10). Previous studies have varied widely in incidence of adverse events following GH administration, ranging from none (24) to almost 70% (25). Doses used in early studies were approximately 25 µg/kg per day, derived mainly from experience in the pediatric population in whom endogenous GH levels are higher than in adulthood. It was recognized some time ago that these doses were too high and that a decrease by 50% was associated with fewer side effects, less requirement for dose reductions, and less incidence of supraphysiological IGF-I levels. A further decrease to a starting dose of 3 µg/kg per day for 3 months was associated with significant reductions in the increase in LBM and the decrease in body fat. Much of the difference in LBM increase was regained with the up-titration of dose for the second 3-month period, but the difference in decrease of body fat remained over the 6-month study. However, the differences between genders and GHD onsets must be balanced with the differences in adverse events, and little is known of the likelihood of developing adverse events based on gender or onset.
In the first 3 months of this study, females and AO patients were less likely to develop adverse events if assigned to the LD group, but males and CO patients developed similar numbers of adverse events regardless of dose group assignment. The advantage for AO patients applied to the entire study period. However, male patients, particularly those with AO GHD, were much more likely to have supraphysiological increases in IGF-I levels.
Based on observation that the proportion of patients who discontinued treatment because of adverse events was significantly greater in the higher-dose arm and that both gender and onset significantly influenced treatment responses, we would recommend that GH replacement therapy of adult GH-deficient patients should be initiated at the lower dose of 3 µg/kg per day. The dose should be titrated upward at approximately 3-month intervals by 30–50% until signs and symptoms of GHD are corrected. The rate of dosage escalation should be modified by the occurrence and severity of GH-related adverse events while maintaining IGF-I levels in the age-adjusted normal range, as recommended by the Growth Hormone Research Society (20).
The daily doses of 6 µg/kg per day and 12 µg/kg per day serve as useful dosage guidelines in the context of individualizing treatment. Because IGF-I levels were normalized by the lower dose in nearly 70% of patients, the majority do not require further dose increment. This particularly applies in men and those with AO disease in whom nearly 10% show supranormal IGF-I concentration at the lower dose. Women and those with CO disease are more likely to require higher doses because 78% had subnormal IGF-I levels at a dose of 6 µg/kg per day. Daily doses of more than 12 µg/kg per day may be required because 55% of CO female and 34% of CO male patients still had subnormal IGF-I levels at this dose. With this approach, appropriate GH replacement therapy of adult patients with GHD can be achieved and individualized with the lowest risk of adverse events.
Acknowledgments
The principal investigators in the GDED Study Group were: G. Biesenbach, G. Finkenstedt, G. Galvan, C. Schnak (Austria); S. C. Boyages, H. Burger, T. Greenaway, D. Wilson, G. Wittert (Australia); C. L. Clarson, S. Ezzat, R. G. Josse, E. J. Keely, O. Serri, E. Ur, G. E. Wilkins (Canada); M. Korsic (Croatia); J. Cap, R. Dolecek, V. Olsovska (Czech Republic); M. Goth, F. Laczi, K. Racz (Hungary); F. Cavagnini, G. Delitala, G. Faglia, G. Giordano, G. Giorgino, A. Giustina, A. Pinchera, M. Terzolo, R. Valcavi, R. Vigneri, M. Zaccaria (Italy); I. L. Kinalska, B. Krzyzanowska-Swiniarska (Poland); V. Peterkova (Russian Federation); A. Kreze, J.-H. Prof (Slovakia); M. Pfeifer (Slovenia); J. J. Staub (Switzerland); S. Aitkin, J. M. Connell, M. Cummings, O. M. Edwards, I. Macfarlane, J. Reckless, R. Ross, D. P. Sandeman, M. F. Scanlon, J. Vora (United Kingdom).
Footnotes
This work was supported by Eli Lilly \|[amp ]\| Co.
Abbreviations: AO, Adult onset; CD, conventional dose; CO, childhood onset; FM, fat mass; GHD, GH deficiency; IGFBP, IGF-binding protein; LBM, lean body mass; LD, low dose.
Received January 19, 2001.
Accepted January 16, 2002.
References
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