| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Division of Medical Sciences (J.A., M.C.S., P.M.S.), University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom; Department of Postgraduate Medicine (R.N.C.), University of Keele, Hartshill, Stoke-on-Trent, ST4 7QB, United Kingdom; Department of Diabetes and Endocrinology (A.S.B.), Birmingham Heartlands and Solihull National Health Service (NHS) Trust, B9 5SS, United Kingdom; and Regional Endocrine Laboratory (G.H.), Department of Clinical Biochemistry, University Hospital Birmingham NHS Trust, B29 6JD, United Kingdom
Address all correspondence and requests for reprints to: Professor P. M. Stewart, Division of Medical Sciences, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: p.m.stewart{at}bham.ac.uk.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
A recent consensus statement has defined the criteria for cure of acromegaly as a normal age-related serum IGF-I level and a GH of less than 1 µg/liter during an oral glucose tolerance test (OGTT) (10). However, only two studies to date have provided any support for the use of IGF-I as a marker of long-term outcome (6, 8).
In this study, data from the West Midlands Pituitary Database were used to determine whether the poor long-term outcome associated with acromegaly has improved with the advent of more effective treatment strategies, most notably the introduction of somatostatin analogs. More recently, the development of an effective therapeutic GH antagonist (11), where GH cannot be used to monitor treatment, has heightened the need for robust data confirming the utility of IGF-I as a biochemical marker of effective treatment. The outcome of patients with normal and elevated levels of IGF-I has been examined and contrasted with the outcome of patients with and without persistent GH hypersecretion. Because hypopituitarism is known to confer excess mortality in patients with nonfunctioning adenomas (12), the impact of other pituitary hormone deficiencies on long-term outcome was also assessed. Finally, we also examined the outcome of patients who have received radiotherapy amid ongoing concerns relating to its association with cerebrovascular disease (13, 14).
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The West Midlands Pituitary Database was established in 1990 and, on 31 December 2001, contained demographic and clinical details of 419 patients (241 female) with acromegaly from 16 referral centers across the West Midlands Region. All patients had a firm biochemical diagnosis of acromegaly based on currently accepted criteria (failure of GH suppression to less than 1 µg/liter after oral glucose loading and, in most cases, an elevated IGF-I). However, a small number of patients had died before the measurement of serum IGF-I came into routine clinical use across the region in the early 1990s. One hundred thirty-six patients were treated with surgery alone, 91 with radiotherapy alone (total dose, 45–50 Gy in 30 treatments via three ports), and 120 with both surgery and radiotherapy. Seventy-one patients were treated with primary medical therapy alone, having received no definitive treatment (surgery or radiotherapy) previously.
Patients were registered with the Office of National Statistics. Death certification data from the Office of National Statistics were reviewed to obtain information relating to cause of death.
Three hundred twenty-four patients were alive on the exit date of the study (31 December 2001) and 95 deceased. Median age at diagnosis was 47 yr (range, 12–84) in the entire cohort, 44 yr (range, 12–73) in those still alive, and 53 yr (range, 29–84) in those who had died. Median duration of follow-up was 13 yr (range, 0.5–48), which was similar in both the deceased and alive groups.
Endocrine evaluation
Serum GH levels were measured by an in-house RIA in a central laboratory as previously described (15). The limit of detection of the assay was 0.5 µg/liter, whereas the intraassay coefficient of variation (CV) was 4.1% and interassay CV 5.7% at 2 µg/liter. Assessment of GH secretion after treatment differed between units. Levels were recorded as the mean of five GH measurements across a 2-h 75-g OGTT, the mean of a GH day profile (the average of five GH measurements taken at 2-h intervals), or a random GH performed in an outpatient setting. Data on GH levels were available in all but five patients. The lowest GH achieved was considered to be less than 2 µg/liter if either the mean of five GH measurements across a 2-h 75-g OGTT or the mean of a GH day profile was below this limit or if at least two random GH measurements were less than 2 µg/liter.
Serum IGF-I was measured using an in-house RIA with acid-ethanol extraction performed to remove IGF-binding proteins, as previously described (16). The limit of detection of the assay was 2.0 nmol/liter. The interassay CV was 5.4–8.4% between 16–104 nmol/liter. Reference ranges were derived from adults with no known or suspected endocrine disorders. Results were calculated as the mean ± 2 SD and expressed by age. Values were 14–48 nmol/liter at 21–30 yr (n = 71), 13–37 nmol/liter at 31–45 yr (n = 123), and 8.9–32 nmol/liter (n = 75). IGF-I data were available in 360 of the 419 patients.
The presence or absence of hypopituitarism was defined by proven biochemical deficiency of at least one endocrine axis. The hypothalamo-pitutary-adrenal axis was deficient if the peak cortisol response to short synacthen testing was less than 530 nmol/liter (17) or less than 500 nmol/liter after an insulin stress test. The thyroid axis was deficient if the free T4 concentration was below the local reference range. A serum testosterone level below the local reference range defined hypothalamic-pituitary-gonadal dysfunction in males. In premenopausal females, deficiency was assumed if the serum PRL was normal and the patient amenorrheic; and in postmenopausal females, if the FSH was inappropriately low (<35 IU/liter).
Statistics
An external comparison of the entire cohort with the general population was made using the standardized mortality ratio (SMR) based on published mortality data for England and Wales by 5-yr age and calendar periods. Confidence intervals and P-values were obtained using the normal approximation in which the SE of the natural logarithm of the SMR is 1 divided by the square root of the observed number of deaths for the CI and the expected number of deaths for the P-value.
Internal comparisons between groups were made using the ratio of mortality rates (RR) obtained with the statistical package Stata Corp. 2001, Stata Statistical Software, release 7.0 (Stata Corporation, College Station, TX) using Poisson regression to control for age and sex. Multiple exponential regression was used to determine the effect of radiation therapy, serum GH, and IGF-I.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
All-cause mortality was significantly increased compared with the general population [SMR = 95/75.5 = 1.26 (range, 1.03–1.54); P = 0.046]. The causes of death are outlined in Table 1
. The excess mortality was due mainly to cerebrovascular disease [SMR = 20/7.5 = 2.68 (range, 1.73–4.15); P = 0.007].
|
shows the cause-specific SMRs for subjects treated with radiotherapy. There is a large excess in all-cause mortality in patients who had received external radiotherapy, compared with the general population [SMR = 59/37.4 = 1.58 (range, 1.22–2.04); P = 0.005]. This was predominantly due to cerebrovascular disease [SMR = 16/3.6 = 4.42 (range, 2.71–7.22); P = 0.005], although there was also a small increase in cardiovascular mortality [SMR = 20/12.5 = 1.60 (range, 1.03–2.48); P = 0.096].
|
Effect of GH reduction on mortality.
Previous studies have adopted arbitrary cutoff points to define an adequate response to treatment. There has been little scientific basis to the selection of these cutoff points. In this study, comparison of crude death rates per 1000 population suggests that a GH of 2 µg/liter is an appropriate target (Table 3).
|
Impact of age on the long-term effects of GH hypersecretion. Analysis by age suggests that younger patients who fail to achieve a GH target of 2 µg/liter are at greater risk than older patients. The RR, comparing subjects with GH more than 2 µg/liter with those with GH less than 2 µg/liter, was 4.46 (range, 0.9–23.0) in age group 40–50 yr, falling to 3.40 (range, 1.1–11.1) in the 50–60 yr group, 1.69 (range, 0.8–3.60) in the 60–70 group, and 0.70 (range, 0.3–1.4) in those between 70 and 80 yr old. The trend for the RR to decrease with increasing age is significant (P = 0.01).
Effect of IGF-I normalization on mortality. IGF-I data were available in 360 patients representing 86% of the cohort; 125 were classed as being above the age-related normal range, and 235 were within the normal range. Of the patients with a persistently elevated IGF-I, 36 had a lowest GH of less than 2 µg/liter (10% of the entire cohort); of those with a normal IGF-I, 69 had a lowest GH of more than 2 µg/liter (19% of the entire cohort). Thus, in total, there was a discrepancy between GH status and serum IGF-I in 29% of the cohort.
No effect of IGF-I on outcome could be demonstrated. Internal comparison of these groups, controlled for age and sex, revealed a RR of 1.20 (range, 0.71–2.02), P = 0.50. However, although numbers are small and uncontrolled for age and sex, comparison of crude death rates in groups with normal or elevated levels of serum IGF-I and serum GH greater or less than 2 µg/liter suggests that normalization of serum IGF-I may have some effect in reducing the mortality associated with elevated serum GH levels (Tables 4 and 5).
|
|
Effect of radiotherapy on mortality. The use of external radiotherapy (total dose ranging from 45–50 Gy in 30 treatments via three ports) was associated with increased mortality. A comparison of 211 patients who received external radiotherapy with 206 who did not, controlled for age and sex, confirmed a poor outcome in the former, with a RR of 1.67 (range, 1.1–2.56); P = 0.02. This effect was consistent despite controlling for the effects of GH, IGF-I, tumor size (macro/microadenoma), tumor extension (beyond sella), or hypopituitarism (any deficient axis).
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Evidence from several small studies has suggested that the increased mortality associated with untreated acromegaly is improved if GH secretion is reduced to less than 2.5 µg/liter, whether measured as the mean of a GH day profile (4) or a random GH level (5, 7). These studies have arbitrarily adopted a cutoff point of 2.5 µg/liter to define an adequate response to treatment, with little scientific basis to this selection. In this large study, comparison of crude death rates per 1000 population suggests that a GH of 2 µg/liter, measured either as the mean of a GH day profile or across an OGTT, or a random GH level, may be a more appropriate treatment target. Mortality was increased in the subgroup of patients with GH levels greater than 2 µg/liter.
There is also evidence from this study that younger patients may be at greater risk from exposure to levels of GH more than 2 µg/liter. This corroborates the findings of others who have also demonstrated higher mortality rates in younger patients (7). The ability to select patients who may benefit most from intervention with effective, but expensive, medical treatments is potentially of great value in clinical practice.
Other factors were also considered. Neither tumor size (macroadenoma vs. microadenoma) nor tumor extension (beyond the sella compared with within the sella) had any impact on survival. The presence or absence of hypopituitarism (one or more hypothalamic-pituitary axes deficient) did not have any effect on outcome, but there was a trend toward reduced survival in those with the greatest number of deficient axes. In patients with pituitary tumors, excluding those secreting GH, hypopituitarism is associated with increased mortality (12). This effect has been widely attributed to adult GH deficiency, although there is little direct evidence to support this conclusion. In our study of patients with GH excess, there is again some evidence to suggest that hypo-pituitarism is detrimental, arguing against a role for GH deficiency.
IGF-I levels have been proposed as a first-line investigation for the diagnosis and therapeutic monitoring of acromegaly (18, 19). Indeed, the imminent introduction of GH antagonists as medical treatment for acromegaly necessitates the use of IGF-I in the biochemical monitoring of patients treated with these agents.
However, only two small studies, both with few deaths, have attempted to examine the role of IGF-I as a marker of long-term outcome (6, 8). In the first of these studies (162 patients, 12 deaths), those patients who were surgically cured, defined by a normal IGF-I in 82%, had mortality similar to that of the general population of the United States, whereas those with active disease as defined by a persistently elevated IGF-I had reduced life expectancy for the period that the IGF-I was elevated (6). In the study by Beauregard et al. (8) (103 patients, 18 deaths), the impact of IGF-I on mortality is less clear, because the association between IGF-I alone and mortality was not reported. In our much larger study, there was no increase in mortality in the subgroup of patients with raised serum IGF-I levels. On the basis of this data, serum IGF-I does not appear to be a reliable marker of long-term risk. There are a number of potential explanations for this finding. IGF-I is bound to specific serum-binding proteins whose levels are influenced not only by GH but also by non-GH-dependent mechanisms such as sex steroids, insulin secretion, and nutrition (20). The relationship between serum GH and IGF-I is linear only up to GH values of approximately 12.5 µg/liter, beyond this IGF-I levels plateau resulting in a curvilinear relationship (21). In addition, our study, like others, has shown that there is a considerable degree of discrepancy between GH and IGF-I when using clinically relevant cutoff points such as GH values of less than 2–2.5 µg/liter, which are known to be associated with improved outcomes (21, 22). Bates et al. found that nine of 24 (37.5%) patients with GH levels of less than 2.5 µg/liter still had elevated IGF-I levels; whereas a much smaller number of patients, 3/56 (5%), had normal IGF-I levels despite persistently elevated serum GH (>2.5 µg/liter). The cohort studied by Kaltsas et al. (21) displayed similar discrepancies, with persistently elevated IGF-I levels in three of 23 patients (13%) with GH values less than 2.5 µg/liter and normal IGF-I levels in eight of 44 patients (18%) with GH levels more than 2.5 µg/liter. In this study, 10% of the cohort had GH values less than 2 µg/liter but persistently elevated age-related IGF-I levels, whereas 19% of the cohort had GH values greater than 2 µg/liter but normal age-related IGF-I levels. Thirty-four of the 69 patients with normal age-related IGF-I and elevated GH were female, 25 of them postmenopausal; only eight were on estrogen replacement, which is known to modify the relationship between serum GH and IGF-I (23). Thus, although there is a correlation between GH and IGF-I concentration, at least when GH is less than 12.5 µg/liter, at defined cutoff values, there are marked discrepancies between cured or safe GH values and normal IGF-I concentrations. This may reflect the fact that not all actions of GH are mediated by IGF-I (24), or conversely that IGF-I is not the only growth factor regulated by GH (25). In addition, many factors other than GH contribute to the determination of serum IGF-I, including nutritional state, liver function, serum protease activity, IGF-I-binding proteins, and sex hormones (20). Other proposed mechanisms include persistent GH dysregulation following cure (26), alteration of the normal IGF-I/GH relationship by somatostatin analogs (27), and disruption of somatostatin tone due to radiotherapy (28). Our data indicate that the benefits of reducing serum GH to less than 2 µg/liter far outweigh the benefits of reducing serum IGF-I to normal levels, and this should therefore remain the principal target of treatment. However, there is a suggestion that normalization of IGF-I may confer a small additional benefit.
The benefits of reducing serum GH discussed in this study pertain predominantly to mortality, but previous studies have demonstrated persistent morbidity, including cardiac disease (29) and sleep apnea (30), even when serum GH levels less than 2.5 µg/liter are achieved. This has led to speculation as to whether this is due to irreversibility of symptoms and signs or continuous low-grade GH hypersecretion (31). However, before current criteria for remission are altered, further research is required to determine the levels to which serum GH can be suppressed without inducing hypopituitarism in patients with acromegaly.
A number of studies in patients with pituitary tumors have suggested that radiotherapy may be associated with an increase in mortality (13, 14), although patients with acromegaly have been universally excluded. This is the first study to show that this group of patients is also subject to reduced life expectancy after pituitary radiotherapy. This effect was consistent despite controlling for the effects of serum GH, serum IGF-I, tumor size (macro/microadenoma), tumor extension (beyond sella), or hypopituitarism (any deficient axis). The strength of the association between increased mortality and radiotherapy is further enhanced by the fact that the predominant cause of death in this group of patients was cerebrovascular disease. These findings are consistent with the results of a recent large prospective study examining total and cause-specific mortality in over 1000 patients with a diagnosis of hypopituitarism. In the 353 patients treated with external beam radiotherapy, Tomlinson et al. (12) demonstrated a 2-fold increase in mortality, predominantly due to an increase in cerebrovascular deaths [SMR, 4.36 (2.48–7.68); P = 0.001].
There is mounting evidence that, in a subgroup of patients in whom surgery is unlikely to result in a cure, long-term treatment with depot somatostatin analogs as primary therapy is a safe and effective option (32). In addition, emerging data suggest that somatostatin analogs may cause significant tumor shrinkage (33, 34). This needs to be set against the undoubted benefit of pituitary radiotherapy in patients with invasive pituitary tumors, but these data will result in a reappraisal of the current indications for external radiotherapy in patients with acromegaly.
In conclusion, these results again demonstrate that mortality in acromegaly is increased. Our findings suggest that a GH value of 2 µg/liter should be regarded as an appropriate therapeutic target, because values above this level are associated with increased mortality. A raised IGF-I level does not adequately predict increased mortality, suggesting that the recommendation to use IGF-I as the sole biochemical risk marker of cure is premature. This study also highlights the potential harmful effect of external radiotherapy and supports the view that medical therapy may now be a more appropriate second-line treatment in many patients.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
The following additional investigators contributed patients to the West Midlands Acromegaly Database: D. A. Heath, J. A. Franklyn, R. Walsh, R. Mitchell, A. Johnson (Queen Elizabeth and Selly Oak Hospitals, Birmingham); H. Connor (County Hospital, Hereford); P. Dodson (Heartlands Hospital, Birmingham); P. R. Daggert (Staffordshire District General Hospital); K. Taylor, R. Ryder, S. Jones (City Hospital, Birmingham); E. Hillhouse, F. Vince (Coventry and Warwick Hospital); D. Jenkins (Worcester Royal Infirmary); S. Walford, D. Singh (New Cross Hospital, Wolverhampton); C. Carter (Alexandra Hospital, Redditch); J. Benn (Burton District Hospital); D. Robertson, P. Davies (Sandwell Hospital); T. West (Telford District General Hospital); T. Harvey, A. D. Wright (Manor Hospital, Walsall); and A. Zalin (Wordesley Hospital).
Abbreviations: CI, Confidence interval; CV, coefficient of variation; OGTT, oral glucose tolerance test; RR, ratio of mortality rates; SMR, standardized mortality ratio.
Received September 15, 2003.
Accepted January 13, 2004.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A. Colao and G. Lombardi Should We Still Use Glucose-Suppressed Growth Hormone Levels for the Evaluation of Acromegaly? J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1181 - 1182. [Full Text] [PDF]
|
|
|
|
|
|
A. M. Arafat, M. Mohlig, M. O. Weickert, F. H. Perschel, J. Purschwitz, J. Spranger, C. J. Strasburger, C. Schofl, and A. F. H. Pfeiffer Growth Hormone Response during Oral Glucose Tolerance Test: The Impact of Assay Method on the Estimation of Reference Values in Patients with Acromegaly and in Healthy Controls, and the Role of Gender, Age, and Body Mass Index J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1254 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Alexopoulou, M. Bex, R. Abs, G. T'Sjoen, B. Velkeniers, and D. Maiter Divergence between Growth Hormone and Insulin-Like Growth Factor-I Concentrations in the Follow-Up of Acromegaly J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1324 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. M. Dekkers, N. R. Biermasz, A. M. Pereira, J. A. Romijn, and J. P. Vandenbroucke Mortality in Acromegaly: A Metaanalysis J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 61 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Colao, R. Pivonello, R. S Auriemma, M. Galdiero, S. Savastano, and G. Lombardi Beneficial effect of dose escalation of Octreotide-LAR as first-line therapy in patients with acromegaly Eur. J. Endocrinol., November 1, 2007; 157(5): 579 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bogazzi, L. Battolla, C. Spinelli, G. Rossi, S. Gavioli, V. Di Bello, C. Cosci, C. Sardella, D. Volterrani, E. Talini, et al. Risk Factors for Development of Coronary Heart Disease in Patients with Acromegaly: A Five-Year Prospective Study J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4271 - 4277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bex, R. Abs, G. T'Sjoen, J. Mockel, B. Velkeniers, K. Muermans, and D. Maiter AcroBel the Belgian registry on acromegaly: a survey of the 'real-life' outcome in 418 acromegalic subjects Eur. J. Endocrinol., October 1, 2007; 157(4): 399 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. T'Sjoen, M. Bex, D. Maiter, B. Velkeniers, and R. Abs Health-related quality of life in acromegalic subjects: data from AcroBel, the Belgian Registry on acromegaly Eur. J. Endocrinol., October 1, 2007; 157(4): 411 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Maison, A.-I. Tropeano, I. Macquin-Mavier, A. Giustina, and P. Chanson Impact of Somatostatin Analogs on the Heart in Acromegaly: A Metaanalysis J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1743 - 1747. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. M. Dekkers, N. R. Biermasz, A. M. Pereira, F. Roelfsema, M. O. van Aken, J. H. C. Voormolen, and J. A. Romijn Mortality in Patients Treated for Cushing's Disease Is Increased, Compared with Patients Treated for Nonfunctioning Pituitary Macroadenoma J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 976 - 981. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Melmed Acromegaly N. Engl. J. Med., December 14, 2006; 355(24): 2558 - 2573. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D Maiter, R Abs, G Johannsson, M Scanlon, P J Jonsson, P Wilton, and M Koltowska-Haggstrom Baseline characteristics and response to GH replacement of hypopituitary patients previously irradiated for pituitary adenoma or craniopharyngioma: data from the Pfizer International Metabolic Database. Eur. J. Endocrinol., August 1, 2006; 155(2): 253 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Jenkins, P. Bates, M. N. Carson, P. M. Stewart, J. A. H. Wass, and on behalf of the UK National Acromegaly Register S Conventional Pituitary Irradiation Is Effective in Lowering Serum Growth Hormone and Insulin-Like Growth Factor-I in Patients with Acromegaly J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1239 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Cozzi, M. Montini, R. Attanasio, M. Albizzi, G. Lasio, S. Lodrini, P. Doneda, L. Cortesi, and G. Pagani Primary Treatment of Acromegaly with Octreotide LAR: A Long-Term (Up to Nine Years) Prospective Study of Its Efficacy in the Control of Disease Activity and Tumor Shrinkage J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1397 - 1403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bogazzi, C. Cosci, C. Sardella, A. Costa, L. Manetti, M. Gasperi, G. Rossi, L. Bartalena, and E. Martino Identification of Acromegalic Patients at Risk of Developing Colonic Adenomas J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1351 - 1356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J Ayuk and M C Sheppard Growth hormone and its disorders Postgrad. Med. J., January 1, 2006; 82(963): 24 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ayuk, M. C. Sheppard, A. S. Bates, and P. M. Stewart Letter re: Monitoring the Response to Treatment in Acromegaly J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4980 - 4980. [Full Text] [PDF]
|
|
|
|
|
|
S. Melmed, R. Sternberg, D. Cook, A. Klibanski, P. Chanson, V. Bonert, M. L. Vance, D. Rhew, D. Kleinberg, and A. Barkan A Critical Analysis of Pituitary Tumor Shrinkage during Primary Medical Therapy in Acromegaly J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4405 - 4410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kauppinen-Makelin, T. Sane, A. Reunanen, M. J. Valimaki, L. Niskanen, H. Markkanen, E. Loyttyniemi, T. Ebeling, P. Jaatinen, H. Laine, et al. A Nationwide Survey of Mortality in Acromegaly J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4081 - 4086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Puder, S. Nilavar, K. D. Post, and P. U. Freda Relationship between Disease-Related Morbidity and Biochemical Markers of Activity in Patients with Acromegaly J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 1972 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Ronchi, V. Varca, C. Giavoli, P. Epaminonda, P. Beck-Peccoz, A. Spada, and M. Arosio Long-Term Evaluation of Postoperative Acromegalic Patients in Remission with Previous and Newly Proposed Criteria J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1377 - 1382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Colao, C. Di Somma, A. Cuocolo, M. Filippella, F. Rota, W. Acampa, S. Savastano, M. Salvatore, and G. Lombardi The Severity of Growth Hormone Deficiency Correlates with the Severity of Cardiac Impairment in 100 Adult Patients with Hypopituitarism: An Observational, Case-Control Study J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5998 - 6004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Clemmons and C. Strasburger Monitoring the Response to Treatment in Acromegaly J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5289 - 5291. [Full Text] [PDF]
|
|
|
|
|
|
I. M. Holdaway, R. C. Rajasoorya, and G. D. Gamble Authors' Response: Evidence for the Use of IGF-I as a Predictor of Mortality in Acromegaly Is Lacking J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5868 - 5868. [Full Text] [PDF]
|
|
|
|
|
|
J. Ayuk, M. C. Sheppard, R. N. Clayton, A. S. Bates, and P. M. Stewart Evidence for the Use of IGF-I as a Predictor of Mortality in Acromega |
