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Original Studies |
Department of Endocrinology, St Bartholomew’s and The Royal London School of Medicine and Dentistry, St Bartholomew’s Hospital, London EC1A 7BE, United Kingdom
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Abstract |
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Introduction |
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Subjects and Methods |
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Fifty GH-deficient (GHD) patients (17 male, 33 female, mean age 45 yr; range 18–69) were studied. GHD was diagnosed by a peak GH response of 9 mU/L or less during insulin-induced hypoglycemia or on a glucagon stimulation test. The GH deficiency was established after appropriate primary treatment in patients with the following diagnoses: 15 clinically nonfunctioning pituitary adenomas, 12 corticotropinomas, 12 prolactinomas, 1 Sheehan’s syndrome, 2 post-cerebral irradiation for acute lymphoblastic leukemia, 3 craniopharyngiomas, 1 somatotropinoma, 3 idiopathic, and 1 tuberculous meningitis. Of these, 19 patients had complete anterior pituitary failure, 10 had isolated GH deficiency, and the remainder had a combination of GH and at least one other anterior pituitary hormone deficiency. Eleven patients had cranial diabetes insipidus.
These fifty GH patients treated de novo with a titration regimen of rhGH were compared with a group of 21 patients (6 male, 15 female, mean age 34 yr; range 25–69) who had been treated previously on a weight-based regimen in a double-blind placebo-controlled trial of GH replacement, but who subsequently continued with GH replacement therapy and whose doses were then titrated during routine follow-up. In this group GH deficiency followed appropriate primary treatment for the following diagnoses: 5 clinically nonfunctioning pituitary adenomas, 2 corticotropinomas, 5 prolactinomas, 4 craniopharyngiomas, 1 granuloma, 1 gonadotropinoma, 2 somatotropinomas, and 1 idiopathic. Of the patients in this group, 9 had complete anterior pituitary failure, 3 had isolated GH deficiency, and the remainder had a combination of GH definitely and at least one other anterior pituitary hormone deficiency. Eight patients had cranial diabetes insipidus.
Treatment
Patients were treated and assessed prospectively using a defined protocol. Following confirmation of GHD patients were instructed on self-injection of somatotropin (Genotropin, Pharmacia & Upjohn) using an automated pen-injection device (Kabipen, Pharmacia) before retiring to bed. Forty-eight patients started at a dose of 0.8 IU (2 clicks of the pen) daily, and 2 patients with either essential hypertension or impaired glucose tolerance started at 0.4 IU daily. Serum samples were taken in the recumbent position and at the same time of day, every two weeks in all patients for IGF-I, for IGF binding protein 3 (IGFBP-3), and for acid-labile subunit (ALS) in 17 patients. All patients were reviewed every 4 weeks to document any side-effects and to review the dosage. Adjustments of the dose, if necessary, were made at 4, 8, and 12 weeks according to serum IGF-I levels measured 2 weeks earlier to maintain serum IGF-I concentrations between the median and the upper end of the age-related reference range.
Waist and waist to hip measurements
Measurements of waist and waist to hip ratio were made by a single observer (D.C.) in the patients treated with a titration regimen before treatment and, subsequently, after 6 and 12 months of treatment with rhGH. Each measurement was made in triplicate and the mean of 3 values recorded. Changes in waist measurement reflect changes in visceral fat mass.
Assessment of well-being
Patients completed the disease specific Adult Growth Hormone Deficiency Assessment (AGHDA) questionnaire (10) before treatment and after 3 and 6 months of treatment with rhGH. An AGHDA score of 25 represents the worst possible "well-being" score, and the score falls if patients improve. AGHDA scores of 4/25 or less have been recorded in a normal control population (11).
Assays
Serum GH was assayed using an immunoradiometric assay (IRMA) in the North East Thames Regional Immunoassay (NETRIA) reference laboratory based at St Bartholomew’s Hospital. Serum IGF-I was measured using an in-house radioimmunoassay (RIA) after formic acid-acetone extraction as previously described (12). Serum IGFBP-3 and ALS were measured using an ELISA kit from Diagnostic Systems Laboratories (Webster, TX). Age-related reference ranges for serum IGF-I were established in the same laboratory using serum derived from 150 healthy blood donors. The inter- and intraassay CVs were less than 10% for all assays.
Statistical analysis
Statistical analysis was performed using Microsoft Excel (Version 5.0, Microsoft, Redmond, WA). Student’s paired t test was used to compare sequential data from patients within a group. Student’s unpaired t test was used to compare data between groups of patients. A P value of less than 0.05 was taken to indicate a statistically significant difference.
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Results |
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The median dose requirements of rhGH were significantly lower in males (0.8 units daily, range 0.4–1.6) than females (1.2 units daily, range 0.8–2), P < 0.0001. The median time taken to reach a maintenance dose of rhGH was significantly shorter in males (4 weeks, range 2–12) than in females (11 weeks, range 2–26), P < 0.0001. Analysis of the dose requirements and the time taken to reach a maintenance dose in the women treated with a titration regimen (n = 33) showed no difference between those women who were eugonadal (n = 15, median dose 1.2 IU/day; range 0.8–1.6), hypogonadal (n = 6, median dose 1.6 IU/day; range 1.2–1.6), or hypogonadal on estrogen replacement (n = 12, median dose 1.6 IU/day; range 0.8–2).
The median maintenance dose in the group of 21 patients whose initial doses had been determined by weight but had subsequently been adjusted during clinical follow-up, was significantly higher (1.5 units daily, range 0.4–3.2) than the dose requirements of the titrated group as a whole (P < 0.02).
Serum IGF-I concentrations
Mean serum IGF-I concentrations before treatment were lower in females [89 ng/mL ± 27 (SD); range 57–154] than in males [95 ± 42 (SD); range 42–150]. Mean serum IGF-I levels on the maintenance dose of GH were significantly lower in females [198 ng/mL ± 44 (SD); range 88–272] than in males [225 ± 44 (SD); range 176–354], P < 0.001, as was the mean increment in serum IGF-I with treatment [112 ng/mL ± 45 (SD); range 14–197 vs. 130 ± 36 (SD); range 71–204]. No patient had a serum IGF-I level recorded during the titration period that was above the age-related reference range. Mean serum IGF-I levels on the maintenance dose of GH in those patients initially treated with a weight-based regimen and whose doses were subsequently reduced during clinical follow-up, were significantly higher [231 ng/mL ± 78 (SD); range 139–371] than in the titrated group as a whole [206 ± 44 (SD); range 118–354], P = 0.02.
Timing of IGF-I measurements
Figure 1
shows the mean serum
IGF-I ± SD with duration of treatment in males and
females. There was no statistically significant difference between mean
serum IGF-I at 2 and 4 weeks, 6 and 8 weeks, or 10 and 12 weeks in
either men or women. Serum IGF-I increased significantly between 0 and
2 weeks in males and remained stable thereafter. In contrast, serum
IGF-I increased between both 0 and 2 weeks and 4 and 6 weeks in
females.
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Mean serum IGFBP-3 concentrations before treatment were 1.88
mg/L ± 0.82 (SD), range 0.54–3.14 in males and 2.37
mg/L ± 0.33 (SD), range 1.97–2.95 in females,
although this difference was not statistically significant. After 2
weeks of treatment with rhGH, serum IGFBP-3 levels had risen
significantly in both males (P < 0.0001) and females
(P < 0.01). This increase was sustained in males, but
subsequent measurements of IGFBP-3 in females were variable (Fig. 2).
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Mean serum ALS concentrations before treatment were not
significantly different between males and females [males 9.5 mg/L
± 8.6 (SD), range 1–28.6; females 12.9 mg/L ± 6,
range 7.5–23.5]. Subsequent measurements of ALS, following initiation
of treatment, were highly variable (Fig. 3).
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Mean waist measurements before treatment with rhGH were 98 cm
(range 75–125) and 92.9 cm (range 67–127) for men and women
respectively. After 6 months of treatment with rhGH these had fallen
significantly to 94.1 cm (range 72–121) and 84.9 cm (range 63–115);
P < 0.001 for both males and females. Values at 12
months in those patients into their second year of GH replacement were
not statistically different from those at 6 months. Mean waist to hip
ratio before treatment was 0.93 (range 0.8–1.07) for men and 0.88
(range 0.78–0.99) for women. After 6 months of treatment with rhGH
these values had fallen to 0.91 (range 0.8–1.07) and 0.83 (range
0.73–0.92), P < 0.01 for males and females (Fig. 4). Values at 12 months were not
statistically significant different from those at 6 months. There was
no significant gender difference in the extent of change in waist
measurement or waist to hip ratio.
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Mean AGHDA score fell from a pre-treatment level of 14.2 ±
5.9 (SD) to 7.4 ± 4.5 (SD) at 3 months,
P < 0.001 (Fig. 5).
There were no gender differences in either the absolute values or the
degree of improvement. Mean AGHDA score at 6 months [7 ± 5.5
(SD)] was not statistically different from that at 3
months. Mean AGHDA scores in patients treated with rhGH for 12 months
or more were not statistically different from the 6-month scores.
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The only adverse symptom recorded was arthralgia, which occurred in eight patients. In each case, this resolved following a reduction in dose of 0.4 IU/day for 2 weeks and did not recur when the original dose was restored.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It is well-recognized that a substantial proportion of patients with GH deficiency have serum IGF-I levels within the age-related reference range (17). With this in mind we elected, empirically, to treat patients with sufficient rhGH to keep the serum IGF-I above the median, but below the upper limit, of the age-related reference range. Whilst recognizing that there is no ideal marker of adequacy of GH replacement in adult patients, we determined the dose solely on the basis of serum IGF-I levels, provided there were no adverse symptoms. Alternative strategies raise the wider question as to whether chronic elevation of serum IGF-I during GH replacement is acceptable. There are no data on the long-term effects of supraphysiological levels of serum IGF-I in hypopituitary adults, although there are good theoretical arguments as to why this should be avoided. Analogy with clinical experience in acromegaly suggests that long-term exposure to excess GH could have adverse effects, such as induction of left ventricular hypertrophy (18), exacerbation of insulin resistance (19), and development of colonic neoplasia (20). The cardiac consequences may be particularly important, bearing in mind the relatively narrow window between normalization of cardiac function and induction of left ventricular hypertrophy in adult onset hypopituitary patients on GH replacement (21). Furthermore, the reported decreased incidence of mortality from malignant disease in male hypopituitary adults (22) and the increased incidence of some forms of malignancy in acromegaly (20) emphasizes the importance of caution in restoring GH status.
The greater requirement for GH in women is striking, although not altogether surprising. Analysis of 24-h GH profiles in normal weight, middle-aged healthy volunteers shows that to maintain an equivalent serum IGF-I level, mean daily production is approximately three times greater in women than in men, due largely to an amplitude-specific divergence in the pulsatile mode of GH secretion (23). This is consistent with the observation that, in our GH deficient patients, pretreatment IGF-I levels were lower in females than males, and it confirms why, despite significantly higher maintenance doses of rhGH, mean increment in serum IGF-I level with treatment was significantly lower.
Not only were dose requirements higher and increments in serum IGF-I lower in females, but the time taken to achieve a maintenance dose was significantly longer in females. The mechanism underlying this gender difference is unclear, but modulation by estrogen was an obvious candidate (24). However, we found no systematic difference between median doses and increment in IGF-I in our female patients subdivided by gonadal status and use of estrogen replacement.
The clinical effects of GH replacement in our patients were evaluated using measurements of waist and waist to hip ratio and by using the AGHDA disease specific questionnaire for assessment of well-being. The AGHDA questionnaire was developed using the most frequently reported symptoms by patients with adult-onset GHD and has subsequently been validated in GH deficient hypopituitary adults and control populations. Improvement of variable degree in AGHDA score was observed in 94% of our patients, with the majority demonstrating a maximum response within 3 months of commencement of GH, despite the fact that many female patients had not reached maintenance dose by this timepoint. This improvement was sustained at 6 months and at 12 months in those patients in their second year of GH replacement. There were no gender differences in either the absolute AGHDA scores or the degree of improvement after commencement of rhGH, suggesting that this aspect may, at least in part, be dependent on GH directly rather than on IGF-I generation. Interestingly, in the 21 patients initially treated with a weight-based regimen followed by dose adjustment during clinical follow-up, maintenance AGHDA scores were not significantly different from patients whose dose of rhGH was titrated de novo. Despite the fact that many of the original weight-based regimen treated patients had their dose of GH reduced during clinical follow-up, median GH dose and mean serum IGF-I were both significantly higher in this group than in the patients on a titration regimen de novo. These data suggest that, at least in terms of the criterion of improvement in well-being, efficacy is not compromised by the use of a dose titration regimen.
A significant factor in the rationale behind treating adult hypopituitary patients with rhGH is the probability that cardiovascular morbidity and mortality is increased in this group compared with age-matched controls, despite adequate replacement with glucocorticoids and sex steroids (22, 25). This may relate, at least in part, to the increased prevalence of cardiovascular risk factors, including central adiposity and insulin resistance (19, 26). In our patients, significant reductions both in waist measurements and in waist to hip ratios were observed by 6 months. These improvements were sustained at 12 months in those patients into their second year of GH replacement. There were no gender differences in the degree of reduction in waist measurements and waist to hip ratios, in contrast to previous reports of greater growth hormone-induced changes in body composition in males (27, 28). However, in those earlier studies, which utilized weight-based regimens, male patients invariably received higher doses of GH. Although they clearly demonstrated gender differences in IGF-I generation, the differences observed in change in body composition were likely to be, at least in part, related to systematic dose differences.
An additional aim of this study was to document the optimum timing of
serum IGF-I measurements after individual dose adjustments. In men,
there was a sharp rise in serum IGF-I between 0 and 2 weeks, after the
commencement of GH, but thereafter the changes seen in serum IGF-I were
not statistically significant (Fig. 1
, A). This reflects the fact that
the starting dose of 0.8 units was sufficient to restore serum IGF-I to
the upper part of the reference range in most men, following which
serum IGF-I remained relatively constant. In the women, by contrast,
after a similar increment in serum IGF-I between 0 and 2 weeks, there
was then a plateau between 2 and 4 weeks, followed by an additional,
statistically significant, increment in serum IGF-I between 4 and 6
weeks (Fig. 1, B). This reflects the fact that a longer titration
period was required for women to restore serum IGF-I to the upper part
of the reference range and that only a minority of women reached their
maintenance dose by 4 weeks. A second plateau was then followed by a
further, nonsignificant, increment in mean serum IGF-I. This reflects
the fact that, although a few women required further dose increments
after 8 weeks to restore serum IGF-I into the upper part of the
age-related reference range, the numbers were insufficient to make the
increment between 8 and 10 weeks statistically significant. These data
show that serum IGF-I levels increase and then plateau at 2 weeks after
an alteration in GH dose, and therefore measurements at this time
reliably reflect GH activity for titration purposes.
In this study, dose titration was based solely on measurements of serum
IGF-I, although supplementary observations were made, in 17 patients,
of serum IGFBP-3 and ALS levels. Expression of these proteins is, at
least in part, GH-dependent, and they are, therefore, additional
potential candidates for use as indices of GH status during dose
titration. Although levels of IGFBP-3 and ALS increased following
initiation of rhGH treatment, subsequent measurements, particularly of
serum ALS, were too variable to be of significant clinical use (Figs. 2 and 3). We conclude, as others have done (8), that measurement of serum
ALS and IGFBP-3 adds nothing to measurement of serum IGF-I for the
purpose of monitoring GH therapy, at least during the titration
phase.
In summary, we have used a standardized dose titration regimen to treat 50 consecutive adult-onset hypopituitary patients with rhGH. This regimen minimizes side-effects and reduces maintenance dose, compared with our patients treated with a weight-based regimen. Efficacy is maintained in terms of improvement in well-being and reduction in central fat distribution. We conclude that GH replacement therapy is most appropriately commenced using a dose titration regimen based on measurements of serum IGF-I. The gender differences in susceptibility and time taken to achieve a maintenance dose indicate that, in females, larger increments in dose may be appropriate during initial titration. Changes in serum IGF-I are stable 2 weeks after an adjustment in dose, suggesting that the timing of serum IGF-I samples during the initial titration period may be more flexible than originally thought. This titration system allows lower doses to be used with satisfactory clinical responses, while maintaining serum IGF-I levels within the physiological range and avoiding systemic side effects. Furthermore, the lower maintenance dose of rhGH that may be used in a titration regimen compared with a weight-based schedule is likely to have significant cost benefits.
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Acknowledgments |
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Footnotes |
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Received April 14, 1998.
Revised July 14, 1998.
Accepted July 29, 1998.
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References |
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