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Department of Internal Medicine (R.K.-M.), Jorvi Hospital, 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; National Public Health Institute (A.R.), FIN-00300 Helsinki, Finland; Department of Medicine (L.N., E.V.), Kuopio University Hospital, FIN-70211 Kuopio, Finland; Department of Statistics (E.L.), University of Turku, FIN-20014 Turku, Finland; Department of Internal Medicine (T.E., P.S.), Oulu University Hospital, FIN-90221 Oulu, Finland; Department of Internal Medicine (P.J., J.S.), Tampere University Hospital, FIN-33014 Tampere, Finland; and Department of Internal Medicine (H.L., P.N., J.V.), Turku University Central Hospital, FIN-20520 Turku, Finland
Address all correspondence and requests for reprints to: Ritva Kauppinen-Mäkelin, M.D., Ph.D., 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 purpose of this nationwide survey was to examine the all-cause mortality of patients with acromegaly and evaluate the impact of treatment outcome and mode of treatment on survival.
Design, Setting, and Patients: All-cause mortality of all patients with acromegaly diagnosed during January 1980 and December 1999 in the five university hospitals of Finland was followed up by the end of 2002 (12.5 ± 5.6 yr) and compared with that of the general population by using age- and gender-adjusted standardized mortality ratios (SMRs). Logistic regression analysis was used to investigate factors related to mortality within the survey population.
Main Outcome Measure: Mortality was the main outcome measure.
Results: Of the 334 patients, 56 (16.8%) had died during follow-up. SMR of the patients was 1.16 [confidence interval (CI) 0.85–1.54, not significant (NS)]. However, patients with basal serum GH concentration 2.5 µg/liter or greater (SMR 1.63, CI 1.10–2.35, P < 0.001) measured 5.2 ± 4.4 yr after the initial treatment, and those irradiated (SMR 1.69, CI 1.05–2.58, P < 0.001) showed excess mortality. In a multivariate model, the effect of radiotherapy was of borderline significance only (P = 0.083). Posttreatment IGF-I levels, available for 72.2% of the patients, did not have impact on mortality.
Conclusions: The posttreatment basal GH concentration less than 2.5 µg/liter in acromegalic patients is associated with a normal lifespan. Excess mortality is confined to poorly controlled patients and possibly those who have received conventional radiotherapy.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The assessment of excess total and cause-specific mortality in a disease-like acromegaly is hampered with many difficulties. First, the disease is quite rare, which makes the assessment of mortality difficult in small cohorts. Second, previous studies have reported results from single (5, 7, 8, 14) or selected centers (6, 11), which may be especially dedicated to treatment of acromegaly and thus show results that may not be generalized. In Finland, the treatment of acromegaly is centralized in five university hospitals, and the country has excellent mortality statistics with all causes of death registered centrally, which facilitates reliable epidemiological studies. This nationwide study was conducted to examine whether the all-cause mortality of the patients with acromegaly is increased in comparison with that of the general population, and to evaluate whether the survival of the patients is dependent on the treatment outcome and the mode of treatment.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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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. In addition to the values at the time of diagnosis, the latest available GH and IGF-I concentrations were recorded from the patient charts. The basal GH concentration at the last clinical visit was used because it was available for the majority of the patients (n = 314; 94%), whereas the last nadir GH concentration in OGTT was recorded for only half of the patients (n = 166; 49.7%). The correlation between the last basal GH concentration and the nadir GH concentration in OGTT was highly significant (r = 0.821, P < 0.001). IGF-I at the last clinical visit was available for 241 patients (72.2%). Biochemical measurements
During the years 1980–1999, GH measurements were made in five laboratories using seven assays. From the beginning of the 1980s, two laboratories used Phadebas hGH PRIST from Pharmacia Diagnostica Ab (Uppsala, Sweden). After the mid-1980s, the laboratories changed to Orion Diagnostica SPECTRIA HGH RIA test (Espoo, Finland). One laboratory initially used the HGHK-2 RIA from Sorin Biomedica (Saluggia, Italy) and then the immunoradiometric assay (IRMA) ELSA-HGH from CIS BioInternational (Gif-sur-Yvette Cedex, France), which was also used in one other laboratory. These assays, except the CIS ELSA-HGH, were calibrated against the World Health Organization (WHO) First International Reference Preparation 66/217. One laboratory used the Pharmacia hGH RIA assay calibrated against the First International Standard 80/505 from the WHO.
During 1995–2000 four university laboratories changed to the AutoDelfia time-resolved immunofluorometric assay (Perkin-Elmer, Wallac, Turku, Finland) and one to a chemiluminescent immunometric assay (Immulite 2000, Diagnostic Products Corp., Los Angeles, CA). Both assays are calibrated against WHO First International Standard 80/505 (2.6 mU/µg). The AutoDelfia measures only the 22-kDa form, but Immulite 2000 also measures the 20-kDa form.
All GH values are expressed in mass concentrations (micrograms per liter), but there are notable differences in the concentrations obtained by the assays used (15). Our own comparison of the AutoDelfia with the Orion RIA, CIS IRMA, and Immulite 2000 reveals good correlation. The Orion RIA gives results that are 2-fold and the CIS IRMA and the Immulite 2000 1.4- to 1.5-fold those obtained by the AutoDelfia assay (Markkanen, H., T. Pekkarinen, M. Välimäki, H. Alftan, R. Kauppinen-Mäkelin, T. Sane, and U.-H. Stenman, unpublished observations). According to external quality assurance surveys, the Pharmacia RIA gives results about 1.4-fold that are those obtained by the AutoDelfia. The intra- and interassay coefficients of variation for the various assays at the cut-off level were in the range 3–6 and 5–10%, respectively.
Serum IGF-I was measured by RIA (INCSTAR, Stillwater, MN) or an IRMA (Nichols Institute Diagnostics, San Clemente, CA). The correlation between these methods is good (r = 0.97), but the results obtained by IRMA are on average 1.5-fold those obtained by RIA: y (Nichols, nanomoles per liter) = 1.53 (INCSTAR, nanomoles per liter) – 5.6. Because of this, various centers used different cut-off values for IGF-I.
Statistical methods
To compare the mortality between the survey population and the general Finnish population, the standardized mortality ratios (SMRs) were computed using the life tables of the Finnish population aged 30–79 yr, by 5-yr gender-specific age groups, for the years 1986–1990 as the reference (16). The mortality data from the patients with acromegaly until the end of 2002 and the causes of death were obtained from Statistics Finland. Note that the percentage distributions of the cause-specific mortalities in various categories are shown only for illustrative purposes but without statistical comparison due to small numbers for meaningful analyses. The deaths occurring at the age of 80 yr or older were excluded from the calculations because the impact of acromegaly on mortality after the age of 80 yr was considered minimal because the life expectancy of Finnish men is 74.9 yr and Finnish women 81.5 yr. The statistical significances of the SMRs obtained were tested by conventional 
2 statistics and the 95% confidence intervals (CIs) of the SMRs were computed as described earlier (17).
Investigation of the factors related to mortality within the survey population was performed using logistic regression analysis. Factors in the model were age at the time of diagnosis, gender, tumor size, GH concentration at the time of diagnosis, use of surgery, radiotherapy and GH-lowering medication, and treatment outcome measured by the last available GH concentration and IGF-I in the patient documents. These factors were selected to represent the most relevant demographic characteristics of the patients, disease activity at the time of diagnosis, mode of treatment, and biochemical treatment outcome. There was not any available parameter to measure the time from the initial treatment to the disease control. Age at the time of diagnosis was chosen to represent age factor because it was a comparable age parameter available for all patients.
Spearman correlation was calculated between selected continuous variables due to skewed distribution. Comparison of means between two continuous variables with a normal distribution was performed by the Student’s t test. If the data were not normally distributed, the Mann-Whitney U test was used. The 2 test was used to test the difference between categorical variables.
The analyses within the patient population were carried out using the SPSS 10.0 for Windows statistical software (SPSS, Inc., Chicago, IL).
Ethical approval
The study protocol was approved by the ethics committee of each university hospital.
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Results |
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Patient population.
The characteristics of the patients are shown in Table 1
. There was a total of 334 patients, giving an incidence of 4.0 per million per year, corresponding well to the previous estimates of 3–4 per million per year (2, 3). The sex distribution was equal. The mean age at diagnosis was 47.5 ± 12.9 yr. Most patients had a pituitary macroadenoma. The median basal GH concentration at diagnosis, measured by different assays was 17.9 µg/liter. IGF-I at the time of diagnosis was elevated in 42.5% of the patients, normal in 9.6%, and not available for 47.9%. At the time of diagnosis, men were younger than women (45.2 ± 11.7 vs. 49.8 ± 13.6 yr; P = 0.001), but there was no difference between sexes in the basal GH concentration (36.6 ± 51.7 vs. 31.7 ± 41.2 µg/liter, P = 0.108) or the size of the pituitary tumor (the proportion of macroadenomas 70.2 vs. 64.7%; P = 0.193).
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The mode of treatment according to the 5-yr intervals is shown in Fig. 1. The proportion of operated patients stayed fairly constant, but during the last 10 yr, the already high proportion of patients operated transsphenoidally still increased. The use of radiotherapy decreased, especially during the last 5 yr, whereas the use of medical treatment increased as the somatostatin analogs became available.
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shows the characteristics of the patients who had or had not been operated and who had or had not received pituitary radiotherapy. The 43 patients who had not been operated (12.9%) were older and had more often a microadenoma and lower mean GH concentration at the time of diagnosis than the patients who had been operated (Table 2A). There were more women than men among the nonoperated patients. GH concentrations less than 2.5 µg/liter at the last clinical visit were more common in operated than nonoperated patients. In comparison with the nonirradiated patients, the 116 patients having received radiotherapy (34.7%) were younger at the time of diagnosis and more often had a macroadenoma and higher GH concentration (Table 2B). There was no difference in the frequency of operation, but the patients having received radiotherapy had been reoperated more frequently and had a poorer treatment outcome than the nonirradiated patients. The outcome was poorer among the irradiated patients also when only the operated patients were taken into account (posttreatment basal GH concentration less than 2.5 µg/liter in 46.1 vs. 69.0%, P < 0.001).
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The mean follow-up time for mortality from the diagnosis to the end of 2002 was 12.5 ± 5.6 yr (median, 12 yr; range, 3–22 yr). By the end of 2002, 56 (28 men and 28 women) of all patients had died (16.8%), at an average age of 66.6 ± 12.9 yr, men at age 64.1 ± 12.3 and women at age 69.2 ± 13.2 yr (P = 0.129). Forty-eight patients (25 men and 23 women) under the age of 80 yr had died. The proportion of deceased patients ranged from 16.1 to 18% in the five university hospitals (P = 0.999).
For the patients aged younger than 80 yr, the overall SMR was 1.16, not different from that of the general age- and sex-matched population (CI 0.85–1.54).
Effect of baseline factors, treatment outcome, and radiotherapy on all-cause mortality
Gender, age, and size of tumor. The SMR for women (1.34) was slightly higher than that for men (1.06), but neither differed from that of the general population. In the age group of 30–49 yr, the SMR was 1.78 (CI 0.71–3.66, NS), and in the age group of 50–79 yr, it was 1.10 (CI 0.79–1.49, NS). The size of the tumor did not affect mortality, with SMR being 1.29 (CI 0.78–2.01, NS) for patients with a microadenoma and 0.94 (CI 0.58–1.43, NS) for those with a macroadenoma.
Treatment outcome.
To evaluate the effect of treatment outcome on mortality, the biochemical data on the last clinical visit were used for all patients. Basal GH data were available for 314 of the 334 patients (94.0%). Of the patients, 185 (55.4%) had the basal GH concentration at the last clinical visit less than 2.5 µg/liter (Table 1
). More men than women fulfilled this criterion of treatment outcome (62.1 vs. 49.1%, P = 0.017). There were 11 deaths at the age of less than 80 yr among these patients, compared with 31 deaths in the group with GH 2.5 µg/liter or more. Data for the last GH concentration were not available for six deceased patients. The SMR was lower than expected for patients with their last GH less than 2.5 µg/liter (0.48, CI 0.23–0.88, P < 0.001) and higher than expected for those with levels 2.5 µg/liter or more (1.63, CI 1.10–2.35, P < 0.001).
IGF-I at the last clinical visit was available for 241 patients (72.2%). Of all 334 patients, 54.8% had normal and 17.4% elevated IGF-I, and there was no difference between sexes (P = 0.791). Of the patients with data for the last known IGF, 75.9% had normal and 24.1% elevated IGF-I. There were 16 deaths among patients with a normal last clinical visit IGF-I (SMR = 0.70, CI 0.40–1.14, NS). Eleven deaths occurred among the patients with elevated last clinical visit IGF-I (SMR =1.67, CI 0.87–3.00, NS). Twenty-one deaths occurred among the patients lacking data for the last clinical visit IGF-I. For these patients the SMR was 1.75 (CI 1.09–2.68, P < 0.05).
Most deceased patients missed reliable data on hypopituitarism, and therefore the effect of hypopituitarism on mortality could not be tested (of all 334 patients, 20.1% were known to have hypopituitarism at the last clinical visit, defined as a deficiency of at least two pituitary hormones).
Conventional radiotherapy. Of the patients, 116 (34.7%) had been radiated. Twenty-one patients (18.1%) having received radiotherapy had died under the age of 80 yr, compared with 27 (12.5%) of those not having received radiotherapy. The SMR for irradiated patients was 1.69, which was significantly higher than in the general age- and sex-matched population (CI 1.05–2.58, P < 0.001). The SMR for those not irradiated was 0.94 (CI 0.62–1.37, NS).
Predictors of overall mortality in multivariate analyses among the acromegalic patients
Table 3 shows the determinants of mortality according to logistic regression analysis incorporating into a multivariate model age at the time of diagnosis, gender, tumor size, GH concentration at the time of diagnosis, use of surgery, radiotherapy, use of GH-lowering medication, and the last known GH concentration. Higher age at the time of diagnosis, male gender, and poorer treatment outcome (last known GH concentration 2.5 µg/liter) were independent predictors, whereas radiotherapy was of only borderline significance (P = 0.083).
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Distribution of causes of death (descriptive)
Except for a pituitary tumor-related mortality, causes of death were similar to the general population (Table 4). Eight of the 28 deceased men died from coronary artery disease, six men died from a cerebrovascular disease, and three men from a malignancy. Five of the 28 deceased women died from coronary artery disease, two women from a cerebrovascular disease, and nine women from a malignancy, four of them from a breast cancer.
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). None of those dying from a malignancy had the last clinical visit GH concentration less than 2.5 µg/liter, but in two patients the last clinical visit GH value was not available.
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). Six of the eight patients (five of six men and one of two women) dying from a cerebrovascular disease and four of 13 patients dying from coronary artery disease had received radiotherapy. |
Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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2.5 µg/liter) showed excess mortality. This confirms the recent results that the increased mortality risk in acromegaly is confined to those with high posttreatment GH levels (4, 6, 9, 10, 11). In the mortality analysis, we used the latest GH concentrations available in the patient records for evaluation of the treatment result. This carries some inaccuracy because different assays were used to measure GH concentration at different times and in different university hospitals. Unfortunately, it is not possible to later adjust the results on the basis of correlation between the methods. This is a common problem for clinical studies on GH. Despite this, a cutoff level of less than 2.5 µg/liter was independently associated with a good prognosis.
The impact of IGF-I on mortality in acromegaly has remained controversial. In recent studies by Holdaway et al. (11) and Biermasz et al. (18), posttreatment IGF-I had a significant impact on survival, whereas no association was found in a large study by Ayuk et al. (9). In our study, the usefulness of IGF-I in evaluation of the prognosis was hampered by a considerable number of missing values of IGF-I. However, normalization of IGF-I had no significant impact on mortality in either univariate or multivariate analysis, but there was a nonsignificant trend toward increased mortality among the patients with elevated last clinical visit IGF-I levels in univariate model. Therefore, in accordance with the study by Ayuk et al. (9), our data do not support the view that IGF-I is a significant prognostic marker for survival in acromegaly.
Another finding in our study is the increased mortality among patients having received irradiation. This is possibly linked, at least in part, to more aggressive disease and poorer control of acromegaly in irradiated patients because these determinants were associated with radiotherapy. This explanation is supported by the multivariate analysis, in which radiotherapy was of only borderline significance (P = 0.083). Therefore, the independent role of radiotherapy per se should be assessed by further studies and metaanalyses. Most of the patients of the present study were given fractionated conventional radiotherapy used in the earlier years. If radiotherapy per se is associated with increased mortality risk, it remains to be determined whether the association applies only to the conventional or also to the modern stereotactic radiotherapy.
In a Swedish study, a high risk for cerebrovascular deaths was observed among patients with hypopituitarism (19). Because many of the patients had received cranial irradiation, the association between cranial radiotherapy and increased mortality was discussed by the authors. Increased mortality due to cerebrovascular causes was also found in the West Midlands Prospective Hypopituitary Study in patients with hypopituitarism and cranial radiotherapy (20). Recently Ayuk et al. (9) reported increased cerebrovascular mortality in patients with acromegaly having received external cranial irradiation. Erfurth et al. (21) did not find any relationship between radiation and mortality in patients with operated and irradiated pituitary adenomas, but untreated hypopituitarism before operation increased the risk of death. In a recent report from the Spanish Acromegaly Registry (10), pituitary radiotherapy and poor treatment outcome but not hypopituitarism were associated with an increase in mortality. Our data support the notion of a harmful effect of conventional pituitary radiation to cerebrovascular health. In addition to a direct harmful effect of radiation on cerebrovascular health, a more long-lasting GH hypersecretion in irradiated vs. nonirradiated patients or both could explain the detrimental effect of radiotherapy on survival, but direct adverse effect of radiation on cerebral circulation cannot be excluded.
In the multivariate model, age at the time of diagnosis, male gender, and the last known basal GH concentration 2.5 µg/liter or more were independent predictors for premature death. The male gender emerged as a predictor for death in the multivariate model probably because there were equal number of deceased men and women, albeit men should have had a better prognosis due to more frequent surgery and a better treatment outcome in terms of the achieved posttreatment GH concentration. It is notable that there was no difference between men and women in the severity of the disease at the time of diagnosis. There was no evident difference between men and women in coronary artery disease mortality, but men seemed to die more often than women from a cerebrovascular disease. Five of six men dying from a cerebrovascular disease had been given radiotherapy, compared with only one of the eight men dying from coronary artery disease. It can therefore be speculated that pituitary radiotherapy increased male patients’ risk to die from a cerebrovascular event.
Malignancy was a common cause of death among women. Only four of the nine women dying from cancer had been operated, and none (GH data were missing for one) had the GH concentration at the last clinical visit less than 2.5 µg/liter. Thus, the excessive death rate from cancer among women may be attributed to less effective treatment than in men. Women received radiotherapy as frequently as men, but they were a few years older when acromegaly was diagnosed. Therefore, it is possible that they died before the harmful effects of radiotherapy on cerebrovascular health emerged.
Older patients were less actively operated and achieved a poorer treatment outcome than younger patients. This probably contributed to their higher mortality, but despite this, age at the time of diagnosis emerged as an independent predictor for mortality.
In accordance with the study by Bengtsson et al. (3) and the United Kingdom Acromegaly Study (6), our patients with inadequate treatment outcome often died from malignant diseases. In the United Kingdom Acromegaly Study (6), there was a significant increase in the colon cancer mortality and a nonsignificant increase in breast cancer mortality. Nabarro (12) found increased incidence of breast cancer in female patients with acromegaly, but breast cancer mortality was not increased. In our study, breast cancer was the most common cancer death, but it is also the most common malignancy in the whole female population in Finland. Acromegaly has been associated with increased incidence of colon cancer (22), but in our study there was only one death from colon cancer. However, a metaanalysis would assess the cause-specific mortality in acromegaly in a more comprehensive manner because the deaths in specific diagnostic categories has been quite low in all studies.
In conclusion, patients with acromegaly achieving a posttreatment serum basal GH concentration less than 2.5 µg/liter appear to have no increased risk of death. The relationship between cranial irradiation and increased mortality risk warrants further consideration.
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Footnotes |
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First Published Online May 10, 2005
Abbreviations: CI, Confidence interval; IRMA, immunoradiometric assay; OGTT, oral glucose tolerance test; OR, odds ratio; SMR, standardized mortality ratio.
Received July 15, 2004.
Accepted April 22, 2005.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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A Raitila, M Georgitsi, A Karhu, K Tuppurainen, M J Makinen, K Birkenkamp-Demtroder, K Salmenkivi, T F Orntoft, J Arola, V Launonen, et al. No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia Endocr. Relat. Cancer, September 1, 2007; 14(3): 901 - 906. [Abstract] [Full Text] [PDF]
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L. Sze, C. Schmid, K. E Bloch, R. Bernays, and M. Brandle Effect of transsphenoidal surgery on sleep apnoea in acromegaly Eur. J. Endocrinol., March 1, 2007; 156(3): 321 - 329. [Abstract] [Full Text] [PDF]
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S. Cannavo, B. Almoto, G. Cavalli, S. Squadrito, G. Romanello, M. T. Vigo, F. Fiumara, S. Benvenga, and F. Trimarchi Acromegaly and Coronary Disease: An Integrated Evaluation of Conventional Coronary Risk Factors and Coronary Calcifications Detected by Computed Tomography J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3766 - 3772. [Abstract] [Full Text] [PDF]
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R. Kauppinen-Makelin, T. Sane, H. Sintonen, H. Markkanen, M. J. Valimaki, E. Loyttyniemi, L. Niskanen, A. Reunanen, U.-H. Stenman, and and the Finnish Acromegaly Study Group Quality of Life in Treated Patients with Acromegaly J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3891 - 3896. [Abstract] [Full Text] [PDF]
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 O. Vierimaa, M. Georgitsi, R. Lehtonen, P. Vahteristo, A. Kokko, A. Raitila, K. Tuppurainen, T. M. L. Ebeling, P. I. Salmela, R. Paschke, et al. Pituitary Adenoma Predisposition Caused by Germline Mutations in the AIP Gene. Science, May 26, 2006; 312(5777): 1228 - 1230. [Abstract] [Full Text] [PDF]
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 H. Markkanen, T. Pekkarinen, M. J. Valimaki, H. Alfthan, R. Kauppinen-Makelin, T. Sane, and U.-H. Stenman Effect of Sex and Assay Method on Serum Concentrations of Growth Hormone in Patients with Acromegaly and in Healthy Controls Clin. Chem., March 1, 2006; 52(3): 468 - 473. [Abstract] [Full Text] [PDF]
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A. Colao, R. Attanasio, R. Pivonello, P. Cappabianca, L. M. Cavallo, G. Lasio, A. Lodrini, G. Lombardi, and R. Cozzi Partial Surgical Removal of Growth Hormone-Secreting Pituitary Tumors Enhances the Response to Somatostatin Analogs in Acromegaly J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 85 - 92. [Abstract] [Full Text] [PDF]
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