Relationship between disease-related morbidity and biochemical markers of activity in patients with acromegaly

The criteria for biochemical control of acromegaly that will best reduce disease-related morbidity in acromegaly are debated. We therefore studied the relationship of biochemical markers with an important metabolic parameter, insulin sensitivity, and clinical parameters reflecting disease activity in acromegaly. Newly diagnosed and postoperative patients with acromegaly underwent assessment of fasting IGF-I and fasting and postoral glucose tolerance test GH and insulin levels and completed a numeric signs and symptoms questionnaire. Insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) and the composite insulin sensitivity index. Patients were divided into three groups: group I, normal IGF-I and nadir GH less than 0.14 mug/liter (n = 21); group II, normal IGF-I and nadir GH 0.14 mug/liter or more (n = 20); group III (active), elevated IGF-I (n = 25). Age, sex, and body mass index were comparable in these groups. Insulin sensitivity was reduced in group III (QUICKI: 0.33 +/- 0.01 and composite index: 3.44 +/- 0.54), compared with group II (0.38 +/- 0.01, P = 0.002 and 8.18 +/- 1.21, P = 0.0008), group I (0.38 +/- 0.01, P = 0.0008 and 8.91 +/- 1.34, P = 0.00001), and healthy controls (0.37 +/- 0.008, P = 0.009). When other nadir GH cut-offs were analyzed, insulin sensitivity remained relatively reduced in the elevated IGF-I group. IGF-I was a significant predictor for decreasing insulin sensitivity as calculated by QUICKI (r = 0.6, P < 0.0001) independently of nadir GH. Signs and symptom scores were higher in group III (mean 38.5 +/- 3.6%), compared with group II (mean 23.5 +/- 3.2%, P = 0.004) and group I (mean 20.5 +/- 3.7%, P = 0.0008) but not between the latter two groups. Our data indicate that overall and specifically in the presence of discordant serum IGF-I and nadir GH levels, IGF-I was more predictive than GH levels of insulin sensitivity and clinical symptom score in patients with acromegaly.     

Long-term follow-up results of postoperative radiotherapy in 36 patients with acromegaly

In acromegaly, pituitary irradiation is a slow, but effective, intervention in decreasing GH concentration. Few studies addressing the outcome of radiotherapy have used the currently accepted strict criteria for remission in the analysis of data. These studies report a low percentage of remission after radiotherapy. Doubt has especially been raised as to whether radiotherapy is effective in normalizing serum insulin-like growth factor (IGF)-I concentration. We analyzed the long-term follow-up data of postoperatively administered radiotherapy in 36 patients with postoperative persistent acromegaly, using both the normalization of GH suppression during oral glucose loading (GTT) and the normalization of IGF-I concentration as criteria for remission. Before radiotherapy, mean suppressed GH was 9.8 +/- 1.9 mU/L (n = 31), and mean IGF-I concentration was 44.3 +/- 3.9 nmol/L, equivalent to + 4.76 +/- 0.78 age-related IGF-I SD score (n = 13). The median radiation dose was 40 Gray (range, 25-50 Gray). At 5, 10, and 15 yr follow-up, 18 out of 30 patients (60%), 23 out of 31 patients (74%), and 16 out of 19 patients (84%), respectively, achieved normal serum IGF-I concentration. At the last assessment of all patients, after a mean follow-up period of 139 +/- 12 months, 27 out of 36 (75%) patients had a normal IGF-I concentration without additional medication, whereas 5 patients still required treatment with octreotide. Remission, as judged by normalization of GH suppression during GTT, was documented in 65% of patients from 2-5 yr after radiotherapy (n = 34); in 69% of patients, up to 10 yr after radiotherapy (n = 29); and in 71% of patients, up to 15 yr post irradiation (n = 17). At the latest assessment, a mean of 125 +/- 11 months after radiotherapy, 71% of patients (n = 35) were in remission, as defined by normal suppression of serum GH during GTT. Remission, as judged by normalization of both GTT and IGF-I, was found in 40% of patients 3-5 yr after radiotherapy (n = 30); in 61% of patients, 6-10 yr after radiotherapy (n = 28); in 65%, after 11-15 yr after radiotherapy (n = 17); and in 63% of patients, at the end of the follow-up period (n = 35). Substitution of one or more pituitary hormone deficiencies was required in 11% of patients postoperatively; in 29%, 5 yr after radiotherapy; in 54%, 10 yr after radiotherapy; and in 58%, more than 15 yr after radiotherapy. Our findings support the use of radiotherapy as an effective intervention in the treatment of residual clinical activity of disease after surgery for acromegaly.     

Fluctuation analysis of postoperative secretory status in patients operated for acromegaly

ObjectiveThe aim of this study was to describe endocrinological outcome in patients operated on for acromegaly.MethodsA retrospective study included 167 patients. Patients were assessed in the early postoperative period (EPP), at 3 months (M3), at 1 year (Y1), and then annually. They were classified as grade I (IGF-1 level normal-for-age and positive GH response on oral glucose tolerance test [nadir <0.4 ng/L]); grade II (discordant); or grade III or IV (acromegaly, controlled or uncontrolled under medical therapy, respectively).ResultsTaking all patients with all grades, 35% changed grades between EPP and M3, 26% between M3 and Y1 and 9% after Y1. In grade I, respectively 22%, 15% and 2% of patients changed grades between EPP and M3, between M3 and Y1, and after Y1, compared to 31%, 6% and 6% in grade IV. Respectively 57%, 67%, and 47% of grade II patients changed grades between EPP and M3, between M3 and Y1, and after Y1; between EPP or M3 and last follow-up (>1 year), respectively 74% and 75% of grade II patients changed grades. Knosp category, resection quality and abnormal GH response (vs. abnormal IGF-1) significantly impacted grade II patients’ outcome.ConclusionsWhereas outcome in grades I and III–IV seems to be determined by 1 year, grade II discordant patients’ outcome remains uncertain even after 1 year.     

Long-term effects of pegvisomant in patients with acromegaly

Despite improved surgical and radiotherapy techniques and the development of long-acting somatostatin analogs, some patients with acromegaly cannot attain biochemical remission. As a consequence they continue to endure debilitating symptoms and mortality remains high. Pegvisomant, a recombinant growth-hormone-receptor antagonist, suppresses production of insulin-like growth factor I. Since the introduction of this drug several years ago, long-term studies involving hundreds of patients have established efficacy of more than 85%. Raised transaminase concentrations have, however, been reported as a side effect of therapy, albeit an infrequent one. In addition, increases in tumor volume have been reported in several cases. In this Review we present the long-term data that have been gathered on pegvisomant therapy, discuss the related risks and benefits, and frame a potential therapeutic approach.     

Long-term outcome of patients with acromegaly and congestive heart failure

Cardiovascular complications are a major cause of morbidity and mortality in patients with acromegaly. Normalization of GH secretion is associated with an improvement in structural and functional cardiac abnormalities. However, the long-term cardiac effects of treatment for acromegaly have not been studied in patients who have already developed chronic congestive heart failure (CHF).We reviewed the charts of 330 consecutive patients with acromegaly treated in two French and Belgian centers since 1985. Ten patients with both acromegaly and CHF (eight men, two women, mean age 49.7 yr) were studied retrospectively. One of them was excluded because CHF was due to severe aortic stenosis.CHF (New York Heart Association stages III-IV and echocardiography showing dilated hypokinetic cardiomyopathy with left ventricular systolic dysfunction and a left ventricular ejection fraction less than 45%) was diagnosed before, concomitantly, or after acromegaly in, respectively, two, five, and two patients. Three patients were referred with terminal heart failure requiring transplantation.One patient had transient CHF associated with a hypertensive crisis. The other eight patients had symptomatic chronic CHF. Control of GH hypersecretion failed, totally or partially, in three patients: one had a long-term survival, and the two others died at 1 and 5 yr. Good GH control was achieved in five patients: four of these are still alive 2-16 yr after diagnosis of CHF, their clinical status is stable or improved, and their quality of life is good. Overall, the 1- and 5-yr mortality (or transplantation) rates for patients with chronic symptomatic CHF were 25% (2 of 8 patients) and 37.5% (3 of 8 patients), respectively.In conclusion, less than 3% of acromegalic patients developed CHF in this study. Although effective treatment of acromegaly improved short-term cardiovascular status, its impact on long-term survival is questionable.     

Long-term postoperative status of tetralogy of Fallot

From 1965 to 1984, 279 patients with tetralogy of Fallot underwent corrective surgery at Niigata University Hospital, and 228 patients were closely followed postoperatively. Late deaths occurred in 12 cases (5.3%), and overall event-free rate at 20 years postoperatively was 76.9%. The most common events were heart failure due to residual cardiac anomaly and symptomatic ventricular arrhythmias. Treadmill test by Ellestad protocol was performed on 74 postoperative patients, 49% of whom could not complete the protocol. These patients had higher RVEDP and lower RVEF than completing patients. Holter ECG was done on 48 long-term postoperative patients, 48% of whom showed complex ventricular arrhythmias. The age at operation was older and postoperative elapsed time was longer in patients with complex ventricular arrhythmias. Although most postoperative TF patients are able to enjoy a normal social life, the treadmill test and Holter ECG revealed that many patients had latent RV dysfunction and complex ventricular arrhythmias with or without significant symptoms. Since the number of symptomatic patients increases after 15 years postoperatively, a regular check-up with cautious observation is important for the patients' care.     

Long-term treatment with 2-Br-alpha-ergocryptine in acromegaly.

Thirty acromegalic subjects underwent chronic CB154 therapy (10-20 mg daily) for periods ranging from 3 months up to 2 years. In 18 out of 21 patients, who exhibited consistent HGH reduction following acute administration of the drug, there was also during chronic treatment, a suppression of the plasma HGH levels exceeding 50% of base line values, e.g. from mean daily values between 14-197 ng/ml (mean +/- SEM = 57.8 +/- 12.4 ng/ml pre-treatment) to 2-19 ng/ml (mean 8.3 +/- 1.2 ng/ml post-treatment). In 12 of the subjects who responsed to chronic CB154 treatment, the mean daily values of HGH were below 10 ng/ml. The suppression of plasma HGH was maintained unaltered throughout the whole course of therapy. In the 9 subjects, in whom no consistent HGH decrease was evidenced with acute CB154 administration, there was accordingly a minor or no suppression of HGH values during the chronic treatment. In 13 subjects, irrespective of the degree of their GH responses, the plasma prolactin levels were constantly inhibited by CB154; instead the drug failed to modify significantly the TRH or insulin-induced GH release. These changes in the hormonal parameters were paralleled by marked clinical amelioration and improvement of some of the metabolic alterations frequently encountered in acromegaly, e.g. reduced carbohydrate tolerance, increased insulin resistance, diminished fall of plasma phosphorus after insulin, decreased urinary excretion of phosphate, hyper-hydroxyprolinuria and hyper-calciuria. Collectively, these data demonstrate that CB154 thrapy is effective in reducing HGH hyper-secretion in many acromegalic patients during long-term treatment.     

Long-term treatment of acromegaly with bromocriptine.

Treatment with bromocriptine, 30-55 mg daily, in 13 acromegalics for 1-15 months, resulted in a 60% decrease in growth hormone secretion, as judged from the excretion of growth hormone in 24-h urine. Normal excretion was obtained in 10 patients, while 1 patient showed no response. The plasma growth hormone response to O-GTT was improved, but not normalized, in 4 of 7 patients treated for more than 6 months, and marked glucosuria disappeared in two diabetics. While the secretion of TSH, LH and FSH was unchanged, the prolactin secretion was inhibited. The urine excretion of free cortisol showed a 30% decrease, possibly due to a direct effect of bromocriptine on the ACTH-secretion. Hypercalcaemia was never seen, but the initial hypercalcuria showed a modest decrease without measurable changes in the creatinine clearance. The subjective relief during long-term treatment was marked in 10 of 11 patients and the dominating symptoms disappeared in 40-67%, whereas heal-pad thickness, enlarged sellae, and visual fields remained unchanged. No serious side effects were observed. Treatment with bromocriptine seems effective and should be considered as a remedy amongst others, in suitable cases of acromegaly.     

High prevalence of biochemical acromegaly in primary care patients with elevated IGF-1 levels

Objective  The estimated prevalence of acromegaly is 40–125 per million. The diagnosis of acromegaly is often delayed due to deficits in recognizing the signs of the disease. It is not known how many subjects with increased IGF-1 levels have acromegaly. We aimed to assess the prevalence of acromegaly in primary care by screening for elevated IGF-1 levels.
Design  A cross-sectional, epidemiological study (the DETECT study).
Patients  A total of 6773 unselected adult primary care patients were included.
Measurements  We measured IGF-1 in all patients and recommended further endocrine evaluation in all patients with elevated IGF-1 levels (> 2 age-dependent SDS).
Results  Of 125 patients with elevated IGF-1 levels, 76 patients had indeterminate results and acromegaly could be excluded in 42 patients. One patient had known florid acromegaly. Two patients had newly diagnosed acromegaly and pituitary adenomas. Four patients had biochemical acromegaly but refused further diagnostics. This corresponds to a prevalence of 1034 per million patients.
Conclusions  Our study shows a high prevalence of undiagnosed acromegaly in primary care. These results imply that acromegaly is underdiagnosed and stress the importance of detecting acromegaly.     

Glucose status in patients with acromegaly receiving primary treatment with the somatostatin analog lanreotide

To describe glucose status changes in patients with acromegaly receiving somatostatin analog lanreotide as primary treatment. This retrospective, single-center study conducted during 1996-2008, included acromegalic patients receiving primary lanreotide treatment. Baseline and last follow-up visit assessments included glucose status (according to American Diabetes Association criteria), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) levels. Glucose control was considered improved when fasting plasma glucose or antidiabetic treatments were reduced, and deteriorated if fasting glucose was the same/higher but with increased antidiabetic treatments. 42 patients (median age 50?years; range 29-75?years) were included. At baseline, 26 (62%) were normoglycemic, eight (19%) had impaired glucose tolerance/fasting glycemia, and eight (19%) had diabetes mellitus; family history of diabetes mellitus was significantly associated with abnormal glucose status. At final visit, the mean (SE) lanreotide dose was 108 (21) mg/month. Median treatment duration was 23?months, range 3-138?months, and 74% of patients received the 120-mg dose. Median GH levels decreased significantly (baseline, 12 [5-20] μg/l; final visit, 2.1 [1.0-4.7] μg/l; P?相似文献   

Long-term treatment outcome in acromegaly.

A number of groups have developed guidelines to indicate whether an individual with acromegaly has been cured by treatment. However, studies to date do not provide a robust definition of biochemical remission of the disorder based on correlation with long-term outcome. Available data suggest that those with a random serum growth hormone (GH) level of <2.5 microg/l, or a glucose-suppressed GH level of <1 microg/l following treatment have mortality figures indistinguishable from the general population. However, the confidence limits for these mortality estimates are quite wide. It remains possible that growth hormone levels lower than 1 microg/l for random samples, or even lower when using ultrasensitive GH assays, may indicate superior outcome, but this remains to be confirmed. There are limited data relating serum insulin-like growth factor-I (IGF-I) levels to outcome, although normalisation of serum IGF-I clearly improves outcome compared with continued elevation of measurements after treatment. Current evidence suggests that a post-treatment random serum GH <2.5 microg/l and a normal serum IGF-I value defines biochemical cure. Available data suggest that achieving similar growth hormone levels after treatment also reduces the prevalence of chronic complications of the disorder, which is subsequently reflected in improved mortality.     

The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical 'cure'

BACKGROUND AND AIM: The aim of this study was to illustrate the present role of transsphenoidal surgery as primary therapy in GH-secreting adenomas, and to compare the results concerning control of disease with previous series using older criteria of cure. METHOD: We report on a consecutive series of 688 acromegalic patients treated over a time period of 19 years. Biochemical cure was defined as normalisation of basal GH level, suppression of GH levels to below 1 ng/ml during an oral glucose load and normalisation of IGF-I levels. Of the 506 patients undergoing primary transsphenoidal surgery, a total of 57.3% postoperatively fulfilled the criteria used. RESULTS: The rate of biochemical 'cure' correlated with the magnitude of the initial GH levels, the tumour size and invasion. The overall complication rate was below 2%. Mortality in this series was 0.1% (1 of 688). During a follow-up period of 10.7 years only two recurrences (0.4%) occurred. However, in the patients treated by transcranial surgery and by repeat surgery the cure rate was found to be relatively low (5.2 and 21.3% respectively). CONCLUSIONS: These data suggest that surgery remains with very few exceptions the primary treatment of acromegaly for (i) a high cure rate, (ii) low morbidity, (iii) low recurrence rate and (iv) immediate decline of GH. Based on current criteria of cure, recurrences are uncommon. However, cure by surgery alone is improbable in patients harbouring extended, invasive tumours with high secretory activity, in whom further adjuvant treatment is mandatory.     

Associations of remission status and lanreotide treatment with quality of life in patients with treated acromegaly

OBJECTIVE: Acromegaly has an important impact on quality of life (QOL). The aim of this study was to evaluate the associations of remission status and lanreotide treatment with QOL in patients with treated acromegaly, by the newly developed disease-generated acromegaly QOL questionnaire (ACROQOL). DESIGN: Cross-sectional study. METHODS: Fifty-two patients with treated acromegaly were recruited to complete the Chinese version of the ACROQOL translated and validated from the English version. These patients were divided into controlled and uncontrolled groups based on the latest remission criteria and further subdivided into four groups according to the present treatment with lanreotide or not. Comparisons between groups were analyzed. RESULTS: There was no difference between controlled and uncontrolled groups in the ACROQOL scores of total score, both scales and psychological subscales. However, in the controlled group, present treatment with lanreotide, in comparison with no treatment, showed worse ACROQOL scores in total score (P = 0.021), psychological scale (P = 0.011), psychological subscale 'appearance' (P = 0.032) and 'personal relations' (P = 0.010). CONCLUSIONS: The lanreotide treatment was negatively associated with QOL in biochemically controlled acromegalic patients, especially in the psychological aspect.     

Ghrelin test for the assessment of GH status in successfully treated patients with acromegaly

OBJECTIVE: Posttreatment assessment of disease activity and definition of cure of acromegaly, using measurement of GH secretion, remains problematic. Furthermore, with our efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, thus requiring testing for GH deficiency. The aim of our study was to evaluate residual GH secretion in cured patients with acromegaly. DESIGN AND METHODS: At baseline, circulating GH, IGF-I, IGFBP-3, leptin and lipid (cholesterol and tri-glycerides) levels were measured in 33 acromegalic patients nine years after treatment with surgery of whom 6 were additionally irradiated. Two tests were performed: the GH suppression test--oral glucose tolerance test (OGTT) and the GH provocation test--ghrelin test (1 microg/kg i.v. bolus) and the results were compared with 11 age- and sex-matched control subjects. RESULTS: According to the consensus criteria (normal IGF-I levels and post-OGTT GH nadir <1 microg/l), 21 treated acromegalic patients were cured, 6 had discordant IGF-I and GH nadir values during OGTT, while 6 had persistent acromegaly. After the GH provocative test with ghrelin (cut-off for severe GH deficiency is GH <3 microg/l), we detected 9 severely GH deficient patients (GHD) among 21 cured acromegalic patients. Mean GH peak (+/-s.e.m.) response to the ghrelin test in GHD acromegalics was significantly lower compared with acromegalics with sufficient GH secretory capacity and control subjects (1.2 +/- 0.2 microg/l vs 20.1 +/- 2.4 microg/l vs 31.1 +/- 2.5 microg/l respectively, P<0.0001). Mean IGF-I and IGFBP-3 levels were not different between GHD and GH-sufficient cured acromegalics. Leptin levels and body mass index (BMI) were significantly higher in GHD male acromegalics compared with GH-sufficient male acromegalics. GHD female acromegalics tended to have higher BMIs while leptin levels were not different. CONCLUSIONS: The assessment of residual GH secretory capacity by the GH provocation test is necessary in the long-term follow-up of successfully treated acromegalics since a large proportion of these patients are rendered GH deficient.     

Psychosocial morbidity in acromegaly: a study from India

To study the psychosocial profile of patients of acromegaly in a developing country setting. Seventeen patients with acromegaly underwent a cross-sectional assessment regarding their socio-demographic and clinical profile, life events, social support, coping, dysfunction, quality of life and psychiatric morbidity. Seventeen demographically matched healthy participants (free from psychological morbidity) acted as the control group. The acromegaly group had predominance of urban married males (64.7%) with mean age 36.05 +/- 17.06 years (range = 15-61), and mean duration of illness of 36.05 +/- 42.5 (range = 4-240) months. Six subjects (i.e., GHQ-positive group) scored positive (indicating presence of psychiatric morbidity) on the General Health Questionnaire-12 giving a psychiatric morbidity rate of 33.33%, with five fulfilling an ICD-10 diagnosis. Compared to the GHQ-negative group, the GHQ-positive group had more number of life events in the entire lifetime, used significantly more number of emotional coping strategies, had more dysfunction, and poorer quality of life (in domains of physical health, social relationship, and general well-being). Psychiatric morbidity occurs in a significant percentage of patients with acromegaly. Presence of psychiatric morbidity is associated with dysfunction and poorer quality of life.