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Department of Internal Medicine (R.K.-M.), Jorvi Hospita1, FIN-02740 Espoo, Finland; Division of Endocrinology (T.S., M.J.V.), Department of Medicine, and Department of Clinical Chemistry (H.M., U.-H.S.), Helsinki University Central Hospital, FIN-00029 Helsinki, Finland; Department of Public Health (H.S.), University of Helsinki, FIN-00014 Helsinki, Finland; Department of Statistics (E.L.), University of Turku, FIN-20014 Turku, Finland; Department of Medicine (L.N.), Kuopio University Hospital, FIN-70211 Kuopio, Finland; and National Public Health Institute (A.R.), FIN-00300 Helsinki, Finland
Address all correspondence and requests for reprints to: Ritva Kauppinen-Mäkelin, Department of Internal Medicine, Jorvi Hospital, FIN-02740 Espoo, Finland. E-mail: ritva.kauppinen-makelin{at}hus.fi.
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Abstract |
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Objective: The objective of this study is to examine the health-related quality of life (HRQoL) and its dependence on treatment outcome and modality in a nationwide survey of acromegalic patients.
Design, Setting, and Patients: All eligible patients with acromegaly, diagnosed from January 1980 through December 1999 in Finland, were invited to a follow-up study, carried out 11.4 ± 5.7 (mean ± SD) yr after initial treatment. HRQoL of the patients, measured by the generic 15D instrument, was compared with that of the general population. Factors related to HRQoL were analyzed by logistic regression.
Main Outcome Measure: HRQoL was the main outcome measure.
Results: Of 277 eligible patients, 231 (83.4%) participated in the follow-up study. Of them, 51.1% were in remission according to consensus criteria. The patients reported reduced HRQoL in comparison to the age- and gender-standardized general population (P < 0.001). HRQoL was related to nadir GH in oral glucose tolerance test (GHOGTT) in an inverted U-shaped fashion (overall P = 0.021). Patients with GHOGTT nadir values between 0.3–1.0 µg/liter had a better HRQoL than those with lower or higher values. A normal IGF-I (P = 0.038) and not having had radiotherapy (P = 0.004) were also associated with a better HRQoL.
Conclusions: HRQoL is reduced in treated patients with acromegaly. The best HRQoL may be achieved by normalization of IGF-I and by targeting the GHOGTT nadir to levels between 0.3 and 1.0 µg/liter. Radiotherapy is associated with adverse HRQoL.
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Introduction |
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Recent studies have shown that the life expectancy in acromegaly is normalized if the basal posttreatment GH concentration is reduced to levels less than 2.0 µg/liter (6, 7) or less than 2.5 µg/liter (8, 9, 10), or if IGF-I is normalized (7, 11). However, quality of life (QoL) has been reduced even in successfully treated acromegalic patients (12, 13, 14), and the prevalence of hypertension (HT) and diabetes (DM) has been high (13, 15). It is not known whether QoL and comorbidity are dependent on the target values for GH and IGF-I.
We carried out a nationwide study comprising all adult Finnish patients with acromegaly diagnosed during a 20-yr period. In this article we report the health-related QoL (HRQoL) among patients who survived on average more than 10 yr after the initial treatment in comparison to the general Finnish population. The dependence of HRQoL on treatment outcome and modality was assessed within the survey population. We also compared descriptively the prevalence of HT and DM among these patients with that of the general population.
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Patients and Methods |
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Patient records were examined retrospectively. The diagnosis of acromegaly was based on clinical signs, impaired serum GH suppression during an oral glucose tolerance test (GHOGTT) (
1 µg/liter), and the presence of a pituitary tumor. In diabetic patients, increased basal and postprandial serum GH values in addition to increased levels of IGF-I were used as biochemical criteria of acromegaly.
All eligible patients were invited to a follow-up study during 2001 and 2002. Forty-two patients had died by the end of 2000, and 14 died during the years 2001 and 2002. Of the remaining 277 patients, 231 (83.4%) responded to the invitation (participants). Forty-six eligible patients did not participate in the follow-up study (nonparticipants). The latest available GH concentrations recorded from patient charts were used to compare participants and nonparticipants.
The follow-up visit was carried out on average 11.4 ± 5.7 (mean ± SD) yr after the initial treatment. It comprised recording of the clinical history and physical examination. Oral glucose tolerance test (OGTT) was performed with ingestion of 75 g of glucose. Blood was sampled for determination of IGF-I.
Prevalence of HT and DM was assessed by drug use for these diseases. The information for the general population was collected from the 2003 nationwide registry of drug reimbursement by the Social Insurance Institution of Finland. For evaluation of the determinants of DM within the survey population, DM was defined by drug use for DM or by a fasting plasma glucose of 7 mmol/liter or greater or by a glucose concentration of 11 mmol/liter or greater at 2 h after OGTT (16).
HRQoL
HRQoL was measured by the 15D (17). It is a generic, 15-dimensional, standardized, self-administered HRQoL instrument that can be used both as a profile and a single index score measure. The 15 dimensions are: moving, seeing, hearing, breathing, sleeping, eating, speech, eliminating, usual activities, mental function, discomfort and symptoms, depression, distress, vitality, and sexual activity. For each dimension the respondent chooses one of the five levels that best describes his/her state of health at the moment. The valuation system of the 15D is based on an application of the multiattribute utility theory. A set of utility or preference weights, elicited from the general public through a three-stage valuation procedure, is used 1) to generate the level values for each dimension on a 0–1 scale (1, no problem on the dimension; 0, being dead) and 2) to aggregate them additively into the overall HRQoL score, i.e. the 15D score (a single index number) over all the dimensions on a scale of 0–1 (1, no problems on any dimension; 0, being dead). The minimal clinically important difference in overall score is 0.03 or greater (17, 18).
HRQoL of patients was compared with that of a representative sample of the general population in the Finnish National Health Survey in 1995/1996 (n = 3759) (19). The sample was weighted to correspond to the age and gender distribution of the patients.
Biochemical measurements
The latest available serum GH concentrations on patient charts used for comparison of the biochemical treatment outcome between the participants and the nonparticipants were determined by different methods, as described earlier (10). In samples drawn at the follow-up visit, serum GH was measured by the AutoDELFIA time-resolved immunofluorometric assay (PerkinElmer Wallac, Turku, Finland) locally in four of five university hospital laboratories, and the samples from the fifth were analyzed in the research laboratory. The detection limit of the method is 0.01 µg/liter. The interassay coefficients of variation were 3–7.5% at GH levels of 0.85–14.3 µg/liter.
Serum IGF-I was measured by an immunoradiometric assay (Nichols Institute Diagnostics, San Clemente, CA). All samples were analyzed in the same laboratory. The detection limit of the method is 0.5 nmol/liter, and the interassay coefficients of variation at relevant concentrations are 2.6–9.2%. The gender- and aged-matched reference ranges, which are based on reference ranges of the kit manufacturer, were created from samples from 101 men and 75 women. The reference ranges for various age groups were: 19–25 yr, 15–51 nmol/liter; 26–35 yr, 13.5–44 nmol/liter; 36–45 yr, 11–38 nmol/liter; 46–55 yr, 8–32 nmol/liter, and more than 55 yr, 5–28 nmol/liter. They were similar for men and women.
Statistical methods
The differences between patients and the general population in the 15D score were tested with the independent samples t test, which was also used for comparison of means between other continuous variables with a normal distribution. The Mann-Whitney U test was used for data that were not normally distributed. The 
2 test was used to test the difference between categorical variables. A P value of 0.05 or less was considered statistically significant.
Stepwise logistic regression analysis was used to study factors related to HRQoL and morbidity within the survey population. The tested factors are listed in Table 4
. The backward selection method was used, with a limit of P = 0.1. When the overall effect of GHOGTT nadir was statistically significant, pairwise comparisons among three classes were made. The classes for the GHOGTT nadir were less than 0.3 µg/liter (class 1), from 0.3 to less than 1.0 µg/liter (class 2), and 1.0 µg/liter or more (class 3).
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Ethics
The study was approved by the ethics committees of each university hospital, and informed consent was obtained from the patients.
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Results |
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The characteristics of the participants and nonparticipants are given in Table 1. The age of the participants at the follow-up study was 57.3 ± 11.9 (mean ± SD) yr, and their age at diagnosis had been 45.8 ± 11.9 yr. Most participants had had a macroadenoma. Patients with a macroadenoma were younger than those with a microadenoma (age at the follow-up study 56.1 ± 12.0 yr vs. 60.8 ± 11.3 yr, P = 0.01). Of the 231 participants, 92.2% had been operated on, the majority transsphenoidally (95.8% of the operated patients), and 11.7% had been reoperated. A third of the participants (33.3%) had been given radiotherapy (almost all conventional two-field radiotherapy). About one third (31.2%) used GH-lowering medication; 21.2% used somatostatin analogs, 13.0% dopamine agonists, and 3% used both drugs. Of the participants, 31.6% had been both operated on and given radiotherapy, and 10.8% also used GH-lowering medication. Only two patients had not received any specific acromegaly treatment. The use of radiotherapy decreased during the 1990s, and especially after 1995, when somatostatin analogs became available. The geographic distribution of the patients was similar to that of the general Finnish population.
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). The participants and nonparticipants had received similar treatment with comparable treatment outcome as assessed by the last available posttreatment GH concentration. Biochemical treatment outcome of the participants
At the follow-up visit, 87.4% of the participants had a basal GH concentration less than 2.5 µg/liter, and 70.1% had the nadir GHOGTT less than 1 µg/liter. The IGF-I concentration was within the age- and sex-specific reference range in 55.8% of the patients, low in four patients (1.7%), and elevated in 41.1%. A nadir GHOGTT less than 1 µg/liter and a normal IGF-I concentration were observed in 51.1% of the participants, and thus they fulfilled the consensus criteria for remission.
Of the participants, 19.9% had both elevated IGF-I and inadequate GH suppression in OGTT (1 µg/liter), and 23.8% had discordant IGF-I and GHOGTT nadir levels; 6.5% had a normal IGF-I but nonsuppressed GHOGTT, and 17.3% had a GHOGTT nadir less than 1.0 µg/liter but an elevated IGF-I.
Hypopituitarism
Of the participants, 24.2% had hypopituitarism, defined as a substitution therapy for deficiency of at least two pituitary hormones. Twenty-nine percent of the participants had hypothyroidism, but in some of them, the hypothyroidism was probably primary; 23.4% had hypocortisolism; 23.8% had hypogonadism; and 4.8% had diabetes insipidus. Hypopituitarism was more common among patients with than without radiotherapy (47.4 vs. 12.6%, P < 0.001).
HRQoL
HRQoL among the participants in comparison to the general population.
The total 15D HRQoL score of the participants was lower than that of the age- and gender-matched general population (0.858 vs. 0.929, P < 0.001). The difference is also clinically important (the difference in the score 0.03). The patients were statistically significantly worse off on every dimension of health except for eating (Fig. 1).
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). In univariate analysis, IGF-I or basal GH concentration did not separate patients with better or lower HRQoL (Table 2). There was no significant linear association, but an inverted U-shaped association between the GHOGTT nadir and the HRQoL, with a GH concentration between 0.3 µg/liter and less than 1.0 µg/liter after OGTT being associated with better HRQoL (P = 0.014) (Table 3 and Fig. 2).
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). The HRQoL was related to the GHOGTT nadir classes (overall P = 0.021), with HRQoL being better for class 2 than for class 1 [odds ratio (OR) 0.40, 95% confidence interval (CI) 0.17–0.92] or for class 3 (OR 0.30, 95% CI 0.12–0.74). When IGF-I was added to the model, its normality associated with better HRQoL (OR 0.37, 95% CI 0.15–0.95, P = 0.038), with the GHOGTT nadir still remaining as a significant determinant of HRQoL (overall P = 0.012). Gender, GH concentration at diagnosis, having or not having been operated on, current use of GH-lowering medication, hypopituitarism, HT, and DM were not significantly associated with HRQoL. Comorbidity of the participants
Prevalence of HT and DM. Of the participants, 39.4% received medication for HT and 13.9% for DM. Both HT and DM were more common among the patients than in the general population in all age groups. The prevalences for HT among the participants and the general population were 21.5 and 1.5% in those younger than 50 yr, 45.0 and 18.8% in the age group from 50–69 yr, and 57.1 and 19.8% in those aged 70 yr or older, respectively. The respective prevalences for DM were 3.1 and 0.9% in those aged less than 50 yr, 17.6 and 5.0% in those aged from 50–69 yr, and 20.0 and 9.9% in those aged 70 yr or older.
Determinants of HT and DM. The prevalence of HT among the participants was not dependent on either basal or post-OGTT nadir GH concentrations or on IGF-I.
In univariate analysis, DM was more common among participants with elevated vs. normal IGF-I (P = 0.042), but the prevalence of DM was not dependent on serum GH. In stepwise logistic regression analysis, DM was associated with higher BMI (OR 1.20, 95% CI 1.08–1.34, P = 0.001), higher age (OR 1.08, 95% CI 1.03–1.13, P = 0.001), and with GHOGTT nadir (OR 1.36, 95% CI 1.00–1.83, P = 0.047), but not with IGF-I when GHOGTT nadir was included in the model.
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Discussion |
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Reduced QoL in patients treated for acromegaly has recently been observed by Biermasz et al. (12, 13) and Rowles et al. (14). The study of Biermasz et al. (12, 13) comprised 118 patients in remission (a serum GH <1.9 µg/liter or GHOGTT nadir <0.38 µg/liter, and a normal IGF-I for age), and the QoL was assessed by four general health questionnaires and the disease-specific Acromegaly Quality of Life Questionnaire. In the study of Rowles et al. (14), there were 80 acromegalic patients with a GH concentration ranging from levels less than 0.3 to 23.7 µg/liter, and the QoL was assessed by four different questionnaires (Acromegaly Quality of Life Questionnaire, Psychological General Well-Being Index, Signs and Symptoms Score, and European Quality of Life-5 Dimensions). We used the 15D instrument to measure the HRQoL, for which we had scores for a representative sample of the general Finnish population. Aside from most of the important properties (reliability, content validity, discriminatory power, and responsiveness to change), the 15D compares at least equally with other HRQoL instruments of a similar kind (17, 21, 22).
In the studies of both Biermasz et al. (12) and Rowles et al. (14), radiotherapy was related to reduced QoL. We also found a similar association in the multivariate model. Because hypopituitarism was more common among the patients with than without radiotherapy, pituitary damage could be one explanation for reduced HRQoL. However, hypopituitarism did not associate with lower HRQoL in our study, but we did not test GH deficiency by stimulation tests, and except for GH deficiency, hypopituitarism was appropriately treated with substitution therapy. Joint problems were associated with lower QoL in the Dutch study (13). In comparison with the general population, the acromegalic patients of our study experienced poorer mobility, but unfortunately, we did not have data on arthritis and related complaints. In contrast to our study, there was no association between the QoL and the GH or IGF-I levels in the studies of Biermasz et al. (12) and Rowles et al. (14). Of note is that the biochemical treatment result of our patients was wider than in the study of Biermasz et al. (12) in which all patients were in remission.
HT and DM were more common among the participants than among the general population in all age groups. In the age group from 50–69 yr, the prevalence of HT was 2.4-fold and the prevalence of DM was 3.5-fold that in the general Finnish population. These figures are probably biased, because HT and DM in acromegalic patients are more closely monitored than in the general population. Nevertheless, the prevalence of HT and DM was increased in acromegalic patients.
Increased prevalences of HT and DM in treated acromegaly patients have also been reported in other studies (13, 15). In the study of Biermasz et al. (13), 37% of the acromegalic patients in remission suffered from HT and 11% suffered from DM. The prevalence of HT was increased in comparison with the general Dutch population in the age group from 50–70 yr, but not in those younger than 50 or older than 70 yr. The prevalence of DM was comparable to that of the general Dutch population. In the Spanish Acromegaly Registry, 39.1 and 37.6% of the patients were found to have HT and DM, respectively (15).
In our study, GHOGTT nadir was a stronger predictor of DM than IGF-I, and the lowest probability of DM was among those with a GHOGTT nadir less than 0.3 µg/liter. Recently Puder et al. (23) reported IGF-I to be a better predictor than GHOGTT nadir of insulin sensitivity in patients with acromegaly when the two parameters were discordant. Serri et al. (24) found that IGF-I and GH nadir cutoff of 0.25 µg/liter, but not a cutoff of 1.0 µg/liter, were significant predictors of abnormal glucose tolerance. In a small study of Colao et al. (25), reduced glucose tolerance was observed significantly more often in patients with active acromegaly than in those with inactive disease and least often in controls. Minniti et al. (26) and Jaffrain-Rea et al. (27) reported an improvement of glucose tolerance after successful surgery. Taken together, these results indicate that the abnormal glucose metabolism may not fully be corrected by normalization of serum IGF-I, but may be alleviated by targeting with the GHOGTT nadir to levels at least less than 1.0 µg/liter.
HT was common among our patients irrespective of the IGF-I or nadir GHOGTT levels, suggesting that long-lasting oversecretion of GH or elevation of IGF-I may cause irreversible cardiovascular changes. Reports on the reversibility of HT by treatment of acromegaly are contradictory. Increased prevalence of HT even in acromegalic patients in remission was recently observed by Biermasz et al. (13). Alleviation of HT by successful surgical therapy was observed by Minniti et al. (26). In the study of Serri et al. (24) the prevalence of HT or systolic blood pressure was not associated with the biochemical treatment outcome, but diastolic blood pressure was significantly lower in patients with normal vs. elevated IGF-I. Colao et al. (25) found that 30% of patients with an active acromegaly but only 13.3% of those with an inactive disease and none of the controls had HT.
The participants of the follow-up study represented moderately well patients alive over 10 yr after the initial treatment, because the nonparticipants differed from the participants only by being more often of male gender and by having higher average basal GH concentration at diagnosis, but there was no difference between the groups in the age at diagnosis, treatment modality, or in biochemical outcome assessed by the last available basal GH concentration.
Of the participants, 70.1% had a GHOGTT nadir less than 1.0 µg/liter, but only 51.1% also had normal age- and gender-specific IGF-I values. Of the participants, 19.9% had both elevated IGF-I and inadequate GH suppression in OGTT, whereas discordant IGF-I and GHOGTT nadir levels were observed in 23.8%. Discordance of IGF-I and nadir GH levels after OGTT has been discussed in the literature by Freda et al. (4, 28), Trainer (3), Shalet (5), and Puder et al. (23). Freda et al. (28) showed that some acromegalic patients with an active disease, defined by increased serum IGF-I levels, have adequately suppressed GH concentration after OGTT as evidenced by levels as low as 0.33 µg/liter determined by highly sensitive GH assays. In another study, Freda et al. (4) showed that some patients with normal IGF-I but abnormal GH suppression in OGTT developed an elevated IGF-I level after a few years of follow-up. On the basis of these findings, it is probable that nearly half of the participants in our study had an active disease.
Among others, we earlier found that the life expectancy of the acromegalic patients is normal if the basal posttreatment GH concentration can be brought to levels less than 2.5 µg/liter (10). However, although random posttreatment GH concentration less than 2.5 µg/liter eliminates the increased risk for death in acromegalic patients, HRQoL remains reduced and cardiovascular risk factor morbidity high. Treatment of excessive GH secretion or normalization of IGF-I does not cure HT and DM, although normalization of IGF-I and suppression of GH in OGTT to at least levels less than 1.0 µg/liter may probably alleviate disturbed glucose metabolism. The best HRQoL seems to be achieved if IGF-I is normalized and GHOGTT nadir is targeted to levels between 0.3 µg/liter and less than 1.0 µg/liter. Conventional radiotherapy worsens the HRQoL.
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Footnotes |
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This work was supported by Novartis Finland Oy through the Research Institute of Helsinki University.
First Published Online July 18, 2006
1 See Acknowledgments for other members of the Finnish Acromegaly Study Group. 
Abbreviations: BMI, Body mass index; CI, confidence interval; DM, diabetes; GHOGTT, GH in oral glucose tolerance test; HRQoL, health-related QoL; HT, hypertension; OGTT, oral glucose tolerance test; OR, odds ratio; QoL, quality of life.
Received March 28, 2006.
Accepted July 10, 2006.
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