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Growth Hormone Replacement Therapy in the Elderly with Hypothalamic-Pituitary Disease: A Dose-Finding Study

Department of Endocrinology, Christie Hospital National Health Service Trust, Manchester, United Kingdom M20 4BX

Address all correspondence and requests for reprints to: Dr. S. M. Shalet, Department of Endocrinology, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester, United Kingdom M20 4BX.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Adults over the age of 60 yr with organic disease of the hypothalamic-pituitary axis have a 90% reduction in GH secretion. This is distinct from the hyposomatotropism associated with increasing age and results in a significant reduction in serum insulin-like growth factor I (IGF-I), an increase in fat mass, abnormal bone turnover, and an adverse lipid profile compared with those in healthy subjects of the same age. These findings suggest that the elderly with organic GH deficiency might benefit from GH replacement therapy. However, the dose of GH required to maintain serum IGF-I levels in the normal range while minimizing side-effects in this group of patients is unknown. We have studied 12 patients with organic GH deficiency, aged 62.4–85.2 (median, 67.9 yr), each treated with three doses of GH (0.167, 0.33, and 0.5 mg/day). Each dose was administered for 12 weeks.

The serum IGF-I level rose in a dose-related manner over the course of the study (P < 0.0001). From a baseline median (range) IGF-I concentration of 101 (49–148) µg/L to 149 (49–227) µg/L at 12 weeks (P = 0.003 vs. baseline), 200 (70–453) µg/L at 24 weeks (P = 0.002 vs. baseline; P = 0.04 vs. 12 weeks), and 239 (122–502) µg/L at 36 weeks (P = 0.002 vs. baseline; P = 0.07 vs. 24 weeks). The age-specific IGF-I SD score exceeded normal in two subjects taking 0.33 mg/day and in six subjects taking 0.5 mg/day. Serum IGF-binding protein-3 also rose over the course of the study (P < 0.001); however, the greatest increase occurred during the first 12 weeks, after which the IGFBP-3 level plateaued. Body composition changed significantly during the study, with a fall in fat mass (P = 0.0003) and an increase in lean body mass (P = 0.0001).

GH was well tolerated in this elderly group, all of whom completed the study. Three patients developed side-effects while taking 0.5 mg/day; two developed headaches, and one developed arthralgia.

This study has demonstrated that the GH replacement dose in elderly subjects is considerably lower than that required by younger adults with GH deficiency. In 50% of the subjects a dose of 0.5 mg/day was excessive, whereas 83% maintained their serum IGF-I within normal limits while taking 0.33 mg/day. No patient exhibited a supranormal IGF-I level on 0.17 mg/day.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GH DEFICIENCY in adults is characterized by changes in body composition (1, 2), reduced bone mineral density (BMD) (3, 4), impaired exercise tolerance (5), and an abnormal serum lipid profile (6, 7). Adults over the age of 60 yr treated for hypothalamic pituitary disease have reduced GH secretion distinct from the hyposomatotropism associated with increasing age (8). Spontaneous GH secretion caused by organic disease of the hypothalamic-pituitary axis is reduced by 90% in this age group (9), causing pathophysiological changes similar in nature to those observed in younger adults with GH deficiency. The severity of the changes, however, seems to be attenuated in the elderly compared to that in younger GH-deficient adults. Serum concentrations of insulin-like growth factor I (IGF-I) are reduced, although 87% of the individual values observed in the patients fall into the range found in healthy subjects (10). There are significant changes in body composition, with an increase in fat mass; however, the reduction in lean mass present in younger adults with GH deficiency is not evident in the older patients (11); bone turnover is reduced, but this does not appear to impact significantly on bone mineral density (12, 13). The serum lipid profile is abnormal, triglycerides are raised, and high density lipoprotein cholesterol is reduced in the elderly patient with GH deficiency (14).

These findings suggest that elderly patients with organic GH deficiency may benefit from GH replacement therapy; however, the dose of GH required to improve these abnormalities without causing side-effects in patients over 60 yr of age is unknown. Early studies of GH replacement therapy in adults used a dose determined by weight or body surface area. This was an unphysiological approach, as it did not take into account the age-related decline in GH secretion (15, 16, 17) or the reduction in GH secretion associated with obesity; therefore, many patients were overtreated, as evidenced by the frequent occurrence of side-effects, such as arthralgia, peripheral edema, and paraesthesia (18, 19). Patients who developed side-effects were more likely to be older and heavier than those who did not (19).

It is likely that GH-deficient patients over the age of 60 yr will require a lower dose of GH replacement to restore their GH status to normal. The aim of this study was to determine the dose of GH replacement required by patients over 60 yr of age who have organic GH deficiency to maintain the IGF-I level within the normal range and restrict side-effects to a minimum.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients

We studied 12 patients (9 men and 3 women), aged between 62–86 yr, who had organic disease of the hypothalamic-pituitary axis. All patients were recruited from our out-patient population. Nine patients had been treated for nonfunctioning pituitary adenoma; the remaining 3 had received treatment for prolactinoma, FSH-secreting adenoma, and meningioma. Before entering the study each patient underwent an arginine stimulation test, and only subjects with a GH peak response below 3 µg/L were included. The arginine stimulation test was chosen to avoid insulin-induced hypoglycemia in an elderly group at risk of ischemic heart disease. Eleven of the patients had 2 or 3 additional anterior pituitary hormone deficits; the remaining subject had isolated GH deficiency. All patients were receiving glucocorticoid and T₄ replacement as necessary, 7 of the men were receiving testosterone replacement, and none of the women was receiving treatment with estradiol. Patient 9 had previously received GH replacement therapy, but this had been stopped 2 yr before this study. The detailed characteristics of the patients are outlined in Table 1.

The protocol for this study was approved by the South Manchester Area Health Authority ethics committee. This was an open study examining the effects of three doses of GH (0.17, 0.33, and 0.5 mg/day; Genotropin, Pharmacia & Upjohn, Inc., Stockholm, Sweden), in a group of elderly patients with organic GH deficiency. The patient took each dose of GH for 12 weeks, commencing with 0.17 mg/day and finishing with 0.5 mg/day. GH was administered as a sc injection at 2200 h using a pen device (KabiPen, Pharmacia & Upjohn, Inc.). GH was discontinued after each patient had received 36 weeks of therapy. To determine the effects of withdrawal, the patients were reassessed again after 12 weeks without GH therapy.

Patients attended the ward for primary assessments at baseline and at 12, 24, 36, and 48 weeks. The patients also underwent secondary assessments at 4, 16, and 28 weeks. At each visit the patient fasted overnight. Blood was drawn for estimation of serum IGF-I and IGF-binding protein-3 (IGFBP-3). At the primary visits the patient underwent a total body dual energy x-ray absorptiometry (DXA) scan to determine body composition. Throughout the study each patient kept a diary of symptoms, which was collected at each visit and examined for evidence of side-effects.

Serum IGF-I assay

Serum IGF-I was measured, after acid-alcohol extraction, by an in-house RIA. The reference preparation used was NIBSC 87/518. The intraassay coefficients of variation for mean IGF-I concentrations of 46, 246, and 706 µg/L were 11.3%, 6.5%, and 4.7%, respectively. The sensitivity of this assay was 14 µg/L.

Serum IGFBP-3 assay

Serum IGFBP-3 was measured using an immunoradiometric assay (Diagnostic Systems Laboratories, Houston, TX). The intraassay coefficients of variation for mean serum concentrations of 1.0, 2.2, and 9.8 mg/L were 6.1%, 4.1%, and 4.4%, respectively. The sensitivity of this assay was 0.5 mg/L.

Serum IGF-I SD score

Blood was collected for measurement of serum IGF-I from 124 elderly adults (77 men and 47 women), aged 60–87 yr. These subjects were recruited from pensioner organizations. None of the women was receiving sex steroid replacement therapy. The relationship between age and serum IGF-I in this group is expressed by the following equation: serum IGF-I (µg/L) = (-1.9347 x age) + 286.14; SD = 52.67 µg/L. The age-specific SD score was calculated using the following formula: SD score = [serum IGF-I - (1.9347 x age)/52.665].

Body composition

The body composition of each patient was determined by DXA using a QDR4500A whole body scanner (Hologic, Waltham, MA). Patients were scanned supine, wearing a cotton gown. The coefficient of variation was 1.75% for fat mass and 0.56% for lean body mass.

Quality of life

Quality of life was determined using the Adult GH Deficiency Assessment (AGHDA) score (20). This is a quality of life questionnaire validated specifically for use in patients with GH deficiency in adult life. The patients were given the questionnaire at each primary assessment. The questionnaire provides a score for each patient at each time point between 0–25. The questionnaire is used to observe changes in quality of life within an individual. A falling score indicates an improvement in quality of life; a rising score indicates a deterioration.

Statistics

Results are expressed as the median (range). The Friedman test was used to determine whether there was a significant change in the parameters over the course of GH therapy. Comparisons between individual time points were made using the Wilcoxon signed ranks test. P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
All the patients completed the study without suffering any major adverse events. Three patients developed side-effects attributed to GH therapy while taking 0.5 mg/day. Two patients developed headaches; one required a permanent reduction of the GH dose to 0.33 mg/day, and the second reduced the dose to 0.33 mg/day for 7 days before increasing it back to 0.5 mg/day. A third patient developed arthralgia that settled when the GH dose was cut to 0.33 and 0.5 mg/L on alternate days.

Changes in serum IGF-I

There was a significant rise in serum IGF-I over the 9 months of GH therapy (P < 0.0001). The median (range) serum IGF-I rose from 101 (49–148) µg/L at baseline to 149 (49–227) µg/L at 12 weeks (P = 0.003 vs. baseline), 200 (70–453) µg/L at 24 weeks (P = 0.002 vs. baseline), and 239 (122–502) µg/L at 36 weeks (P = 0.002 vs. baseline). There was a significant rise in IGF-I between 12 and 24 weeks when the dose of GH was increased from 0.17 to 0.33 mg/day (P = 0.04), but the rise between 24 and 36 weeks did not reach statistical significance (P = 0.07). The rise in serum IGF-I occurred rapidly after each change in dose, attaining a steady state within 4 weeks of a dose change.

The age-corrected IGF-I SD score was between -2 and 0 in all subjects at baseline and remained within normal limits in all subjects taking 0.17 mg/day. When the dose of GH increased, the IGF-I SD score rose above +2 in two subjects taking 0.33 mg/day and in six patients taking 0.5 mg/day (Fig. 1).

View larger version (48K): [in this window] [in a new window]   Figure 1. Changes in serum IGF-I SD score during the study. The hatched area is the normal range.

Serum IGFBP-3 also rose significantly over the GH treatment period (P < 0.0001). The median (range) serum IGFBP-3 at baseline was 2.04 (0.67–2.98) mg/L, rising to 2.53 (0.97–4.18) mg/L (P = 0.007 vs. baseline) at 12 weeks, 2.94 (1.70–4.28) mg/L (P = 0.002 vs. baseline) at 24 weeks, and 2.84 (1.24–4.57) mg/L (P = 0.003 vs. baseline) at 36 weeks. Although IGFBP-3 remained elevated compared with the baseline measurement, levels did not change significantly between 12 and 24 weeks or 24–36 weeks.

Changes in body composition

There was a significant reduction in fat mass (P = 0.0003) and a significant increase in lean body mass (P = 0.0001) over the 9 months of the study. Fat mass did not fall significantly during the first 12 weeks (0.17 mg/day) of the study (P = 0.08). Fat mass was significantly reduced compared with the baseline value at 24 weeks (0.33 mg/day) of GH therapy (P = 0.009 vs. baseline; P = 0.028 vs. 12 weeks), but did not fall further when the GH dose was increased to 0.5 mg/day (P = 0.004 vs. baseline; P = 0.11 vs. 24 weeks; Fig. 2).

View larger version (31K): [in this window] [in a new window]   Figure 2. Changes in fat mass and lean body mass after treatment with 0.17, 0.33, and 0.5 mg/day GH. Grey lines represent individual subjects; the black line represents the median change within the group.

There was a significant improvement in quality of life determined using the AGHDA score (P = 0.002). The improvement was evident after 12 weeks of the lowest dose of GH (P = 0.017, baseline vs. 12 weeks) and was maintained throughout the study (P = 0.012 baseline vs. 24 weeks; P = 0.007, baseline vs. 36 weeks; Table 2).

Effects of GH withdrawal

During the final 3-month period of the study when GH therapy was discontinued, serum IGF-I and IGFBP-3 concentrations fell significantly and were close to baseline values. The beneficial changes that were observed in fat mass and lean mass also reversed and were similar to the values seen at the baseline visit (Fig. 1 and Table 2).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study has demonstrated that the elderly with organic GH deficiency respond to doses of GH replacement therapy considerably lower than those required in younger GH-deficient patients. The majority of the studies reported in the literature used dosing strategies derived from pediatric practice, based on the patient’s weight. This strategy failed to take into account factors that influence the daily production of GH in healthy subjects; for example, sex, age, fat mass (15, 21), and the variability of absorption of GH after sc injection (22). This method of determining the GH dose led to patients receiving an inappropriately high dose of GH, resulting in side-effects that required the dose of GH to be reduced in many cases (18, 19, 23, 24). It is now recommended practice to commence a patient on a low dose of GH and increase it in the light of an individual’s clinical and biochemical responses (25). Recent studies have demonstrated that this strategy results in a reduction of the GH dose required by GH-deficient adults (26, 27).

When choosing a marker for monitoring any treatment it is important that that marker is altered by the disease state and responds in a dose-dependent manner to the specific treatment for the condition. Serum levels of IGF-I and IGFBP-3 are reduced in patients with GH deficiency of all ages (10, 28, 29, 30), although the proportion of patients with values below the normal range falls with increasing age (31). Both IGF-I and IGFBP-3 levels rise in a dose-dependent manner; however, serum IGF-I is more sensitive to changes in GH dose and provides a better indicator of GH excess than serum IGFBP-3 (32). In this study, six of the subjects had serum IGF-I SD scores above normal when receiving GH at a dose of 0.5 mg/day. The serum IGFBP-3 concentration, however, rose above the normal range in only one of those subjects. These findings are similar to those of a previous study in younger GH-deficient adults (32) and confirm that IGF-I is the most appropriate marker of GH replacement therapy in an elderly group.

In the elderly who have GH deficiency resulting from organic disease of the hypothalamic-pituitary axis, GH secretion was reduced by approximately 90% (9). This resulted in a significant reduction in serum IGF-I, although 87% of subjects had a serum IGF-I concentration that fell into the lower part of the age-specific normal range (10). In the present study, all the subjects had an IGF-I SD score in the lower half of the normal range, although all but two of the subjects had severe GH deficiency, as determined by the GH response to arginine (10).

It would seem important to maintain normal serum IGF-I concentrations in the light of two recent studies that have suggested an association between IGF-I status and the potential risk of malignancy in a normal population (33, 34). In the present study a GH dose of 0.5 mg was associated with an IGF-I SD score greater than +2 in 50% of the subjects and caused side-effects in 25%. Even a dose as low as 0.33 mg/day caused the IGF-I concentration to be excessively elevated in 17% of the subjects. These doses are considerably less than those used for younger adults with GH deficiency. Two studies have assessed low dose GH therapy in adults with GH deficiency (26, 27). A dose of 0.45 mg/day was sufficient to normalize the serum IGF-I in patients with a mean age of 48 yr (27). In another group (mean age, 47 yr), replacement doses of 0.2 and 0.4 mg/day increased serum IGF-I levels into the normal range in men and women, respectively.

The results of this study suggest that the elderly with organic GH deficiency should be commenced on 0.17 mg/day, and the dose increased taking into account the IGF-I SD score and clinical response.

The primary end points assessed in this study were biochemical markers of GH status and side-effects. We believed, however, that it was necessary to demonstrate that GH had a biological effect in this group of elderly patients even at these low doses. We chose to study body composition, as we have shown in a previous study using DXA that GH deficiency in adults over 60 yr of age results in a significant increase in fat mass compared to that in healthy age-matched controls (11). Unlike younger patients with GH deficiency, however, we did not find a significant decrease in lean body mass (11). It was surprising, therefore, to find that in the present study, our subjects gained, on the average, 2.4 kg of lean mass in response to the first 6 months of GH therapy. This significant gain in lean body mass probably represents a gain in both lean tissue and total body water, as DXA is not able to distinguish between the two. DXA is a reliable method of determining fat mass, which fell significantly over the course of the study.

Diminished quality of life is currently one of the major indications for GH replacement therapy in adults with GH deficiency (35). In this study there was a significant improvement in quality of life among the patients determined by the AGHDA score. However, these data should be viewed with caution for two reasons. Firstly, the baseline values in this group were relatively low, indicating that they do not perceive a great deal of distress, suggesting that their quality of life is not severely affected by GH deficiency. Secondly, the subsequent changes in AGHDA scores observed during the study, although significant, were small. These findings may be explained by the age of the patients studied. The AGHDA was developed in patients with a mean age of 35 yr (20) compared with that in patients with a mean age of 67 yr in the present study.

Despite these limitations, the changes in quality of life appeared to have real significance for the patients. When the patients were reassessed at the end of the study, having discontinued GH for 12 weeks, 75% expressed a wish to continue therapy. Thus, although the changes in quality of life detected by the AGHDA were subtle, the patients perceived sufficient benefit to warrant continuing to self-administer a daily injection.

This study has clearly demonstrated that the replacement dose of GH therapy is considerably less in patients over the age of 60 yr than that used in younger GH-deficient adults. In 50% of patients over the age of 60 yr a replacement dose of 0.5 mg/day is excessive, and the majority of patients maintain an IGF-I SD score between 0 and +2 on a dose of 0.33 mg/day. In a minority, however, a dose as low as 0.17 mg/day is adequate for this purpose. Further studies are required in elderly subjects with hypothalamic-pituitary disease to determine the effects of stable, long term GH therapy on body composition, quality of life, and other biological end points adversely affected by GH deficiency.

	Acknowledgments

 
We are grateful to Prof. J. E. Adams, Department of Diagnostic Radiology, University of Manchester, for performing the DXA scans, and to Jenny Jones, Department of Medicine, Kings College Hospital School of Medicine and Dentistry (London, UK), for measuring serum IGF-I and IGFBP-3. We also acknowledge the support of Pharmacia & Upjohn, Inc. Ltd.

Received July 22, 1998.

Revised October 1, 1998.

Accepted October 8, 1998.

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