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PubMed2003

Cardiovascular function in acromegaly.

Even with modern treatment, acromegaly is associated with a 2- to 3-fold increase in mortality, mainly from vascular disease, which is probably a result of the long exposure of tissues to excess GH before diagnosis and treatment. There is accumulating evidence that effective treatment to lower serum GH levels to less than 1-2 ng/ml (glucose suppressed or random, respectively) and normalize IGF-I improves long-term outcome and survival. In addition to recognized cardiovascular risk factors of hypertension, type 2 diabetes mellitus, and dyslipidemia, there is accumulating evidence of specific structural and functional changes in the heart in acromegaly. Along with endothelial dysfunction, these changes may contribute to the increased mortality in this disease. There are specific structural changes in the myocardium with increased myocyte size and interstitial fibrosis of both ventricles. Left ventricular hypertrophy is common even in young patients with short duration of disease. Some of these structural changes can be reversed by effective treatment. Functionally, the main consequence of these changes is impaired left ventricular diastolic function, particularly when exercising, such that exercise tolerance is reduced. Diastolic function improves with treatment, but the effect on exercise tolerance is more variable, and more longitudinal data are required to assess the benefits. What scant data there are on rhythm changes suggest an increase in complex ventricular arrhythmias, possibly as a result of the disordered left ventricular architecture. The functional consequences of these changes are unclear, but they may provide a useful early marker for the ventricular remodeling that occurs in the acromegalic heart. Endothelial dysfunction, especially flow-mediated dilatation, is an early marker of atherosclerosis, and limited data imply that this is impaired in active acromegaly and can be improved with treatment. Similarly, early arterial structural changes, such as thickened intima media layer, appear more common in acromegalics, and there are hints that this may diminish with effective treatment, although more studies are required for a definite conclusion on this topic. In conclusion, impaired cardiac and endothelial structure and function in acromegaly are risk factors for vascular mortality and should be regarded as legitimate therapeutic targets in the overall management of this condition.

Acromegaly↗
PubMed2003

High prevalence of cardiac valve disease in acromegaly: an observational, analytical, case-control study.

To characterize mitral and aortic valve abnormalities we performed M-mode, two-dimensional, and pulsed Doppler echocardiography in 42 patients with active acromegaly, 22 patients cured of acromegaly, and 64 controls pair-matched with the patients for sex and age. The overall prevalence of valve abnormalities was higher in both the active patients (86% vs. 24%; P < 0.0001) and the cured patients (73% vs. 9%; P < 0.0001) than in controls. Left ventricular hypertrophy was higher in active (81% vs. 29%; P < 0.0001), but not in cured (41% vs. 14%; P = 0.09) patients than in controls. Cardiac valve abnormalities were associated with left ventricular hypertrophy in both patients and controls, without any difference between them. Conversely, among subjects without left ventricular hypertrophy, mitral and aortic abnormalities were only present in the patients (75% of active and 54% of cured), but not in controls (3% of active controls and 0% of cured controls). In conclusion, patients with active acromegaly and those cured of the disease have a high prevalence of mitral and aortic abnormalities. The persistence of valve disease in patients with cured acromegaly is likely to be correlated with the persistence of left ventricular hypertrophy, which should be carefully and continuously monitored as an aspect of the risk of cardiac dysfunction in these patients.

Acromegaly↗
PubMed2004

Increased prevalence of regurgitant valvular heart disease in acromegaly.

Cardiac involvement is common in acromegaly, but the prevalence of valvular abnormalities in patients with acromegaly has not been documented and is the topic of this study. In a prospective study design, 40 consecutive patients with acromegaly and 120 control subjects (matched for age, sex, hypertension, and left ventricular systolic function) were studied. All patients and controls were evaluated using conventional two-dimensional and Doppler echocardiography. Significant valve disease was more prevalent in acromegalics compared with controls (22% vs. 6.7%, respectively; P = 0.005). Aortic valve regurgitation (>/=>trace severity) was present in 30% of patients vs. 7% of controls (P < 0.001), and mitral regurgitation (>/=moderate severity) was absent in controls but present in 5% of acromegalics (P = 0.014 vs. controls). Binary logistic regression analysis showed a significant impact only for disease duration on valvular disease, with an odds ratio of 1.19 (95% confidence interval, 1.028-1.376; P = 0.019). Acromegaly is associated with an increased prevalence of regurgitant valvular heart disease. This is dependent on the duration of exposure to increased GH concentrations, with a 19% increase in odds per year. This increased prevalence of occult valvular disease indicates that these patients require appropriate follow-up care and monitoring, especially patients with inadequate control of GH overproduction.

Acromegaly↗
PubMed2004

Significance of "abnormal" nadir growth hormone levels after oral glucose in postoperative patients with acromegaly in remission with normal insulin-like growth factor-I levels.

Our initial study in postoperative patients with acromegaly identified a group of patients in remission, as defined by normal IGF-I levels, but who had a subtle abnormality of GH suppression after oral glucose. To investigate the significance of this abnormality, we have undertaken further detailed testing of GH secretion and a longitudinal follow-up of some of these patients. Of the 110 postoperative patients with acromegaly evaluated by oral glucose tolerance test, 76 were in remission (i.e. normal IGF-I level), and of these subjects with acromegaly in remission, 50 had normal nadir GH (<0.14 microg/ml) (group I), and 26 had abnormal nadir GH (>0.14 microg/ml) (group II). Fourteen subjects in remission, seven from remission group I and seven from remission group II, underwent additional testing consisting of both hourly GH sampling over 8 h and, on a separate day, arginine stimulation testing. The mean of hourly GH was higher in group II (0.47 +/- 0.04 microg/liter) than in group I (0.19 +/- 0.07 microg/liter; P = 0.002). GH response to arginine was greater in group II than in group I (P < 0.01). Of those patients in remission from the initial cohort studied, 49 (30 subjects from group I and 19 from group II) underwent serial longitudinal oral glucose tolerance testing every 1-2 yr over a 1- to 6.5-yr period (mean follow-up, 3.2 yr). The initial pattern of GH suppression persisted in most patients. IGF-I levels remained normal in all patients in group II, but five subjects from group II developed an elevated IGF-I level and, thus, a biochemical recurrence. The rate of disease recurrence was greater in group II than in group I (P = 0.003). We have found that some postoperative subjects with acromegaly in remission with normal IGF-I levels have persistently abnormal nadir GH levels after oral glucose that may be accompanied by other evidence of greater GH secretion than postoperative patients with normal GH suppression. This abnormal pattern of GH suppression may be associated with increased risk of disease recurrence in some patients.

Acromegaly↗
PubMed2004

Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly.

Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF-I remain uncertain. The West Midlands Pituitary database contains details of 419 patients (241 female) with acromegaly. Serum IGF-I data from the Regional Endocrine Laboratory were available for 360 patients (86%). At diagnosis, mean age was 47 yr (range, 12-84) and mean duration of follow-up was 13 yr (0.5-48). Sixty-one percent were treated by surgery and 39% by nonsurgical means. Radiotherapy was used alone or as adjuvant therapy in 50%. All patients were registered with the Office of National Statistics to obtain information on deaths. At the date of analysis (31 December 2001), 95 of the 419 patients had died (43 males), giving a standardized mortality ratio of 1.26 [confidence interval (CI), 1.03-1.54; P = 0.046]. After controlling for age and sex, data indicated that mortality was increased in subjects with posttreatment GH levels more than 2 micro g/liter, compared with those with levels less than 2 micro g/liter [ratio of mortality rates (RR), 1.55 (range, 0.97-2.50); P = 0.068]. By contrast, a much smaller increase was observed for subjects with elevated posttreatment IGF-I levels compared with those with normal levels [RR, 1.20 (range, 0.71-2.03); P = 0.50]. Treatment with radiotherapy was associated with increased mortality [RR, 1.67 (range, 1.09-2.56); P = 0.018], with cerebrovascular disease the predominant cause of death [standardized mortality ratio, 4.42 (range, 2.71-7.22); P = 0.005]. These results confirm the increased mortality in acromegaly and suggest that reduction of GH levels to less than 2 micro g/liter is beneficial in terms of improving long-term outcome. The sole use of IGF-I as a marker for effective treatment of acromegaly is not justified by this data. This study also highlights the potential deleterious effect of radiotherapy.

Acromegaly↗
PubMed2004

Serum adiponectin is reduced in acromegaly and normalized after correction of growth hormone excess.

Adiponectin, an adipocyte-derived hormone, possesses insulin-sensitizing, antiinflammatory, and antiatherogenic properties. We hypothesized that hypoadiponectinemia was present in acromegaly, as in other conditions with increased insulin resistance and cardiovascular risk. Using an in-house RIA, serum adiponectin was determined in 35 patients with active acromegaly and 35 age-, sex-, and body mass index-matched healthy controls. Twenty-five patients were restudied after GH-lowering therapies. Serum adiponectin was significantly reduced in the acromegalic patients (4.3 +/- 1.8 vs. 6.7 +/- 1.8 microg/ml in controls; P < 0.001), but was increased after treatment with Sandostatin LAR, a long-acting somatostatin analog (5.8 +/- 2.6 vs. 3.8 +/- 1.6 microg/ml pretreatment; P < 0.001; n = 15) or transsphenoidal surgery (6.5 +/- 2.7 vs. 3.9 +/- 1.5 microg/ml preoperation; P < 0.01; n = 10). Fasting insulin was an independent determinant of serum adiponectin levels (P < 0.01) in control subjects, contributing to 11.7% of the variance in circulating adiponectin. In cultured 3T3-L1 adipocytes, adiponectin mRNA levels were decreased by insulin (1.5 microm; P < 0.005) or IGF-I (1 microg/ml; P < 0.05), but not by GH (1 microm) or somatostatin (1 microm). In conclusion, hypoadiponectinemia is present in active acromegaly, probably secondary to the inhibitory effect of high circulating insulin levels. Hypoadiponectinemia, reversible with GH-lowering therapies, may contribute to the increased insulin resistance and cardiovascular risk in patients with acromegaly.

3T3-L1 Cells↗
PubMed2005

Postoperative evaluation of patients with acromegaly: clinical significance and timing of oral glucose tolerance testing and measurement of (free) insulin-like growth factor I, acid-labile subunit, and growth hormone-binding protein levels.

CONTEXT: It is not exactly known when patients with acromegaly should be evaluated for cure after transsphenoidal adenomectomy (TA). OBJECTIVE: The objective of this study was to define the optimal time point of postoperative evaluation by serial measurements of glucose-suppressed GH levels [oral glucose tolerance test (OGTT)] and the GH-dependent parameters IGF-I, free IGF-I, acid labile subunit (ALS), and GH-binding protein (GHBP). DESIGN: We describe a prospective study with 1-yr follow-up. SETTING: The study was conducted at a university hospital. PATIENTS: Seventeen patients with acromegaly were included in the study. MAIN OUTCOME MEASURES: The main outcome measures were OGTT results at 1, 2, 3, 8, and 12 wk after TA; weekly measured GH, (free) IGF-I, ALS, and GHBP levels up to 12 wk; and total IGF-I levels measured at 52 wk. RESULTS: Postoperatively, nine patients were in remission with an OGTT GH nadir of less than 0.5 microg/liter and normalized IGF-I levels, whereas eight patients had persistent acromegaly. In both cured and noncured patients, OGTT results at 1 wk after TA were highly reproducible over time. In contrast, early postoperative IGF-I levels fluctuated and only stabilized at 12 wk. In all cured patients, free IGF-I levels rapidly normalized within 2 wk after TA (specificity, 100%). Preoperative ALS levels were elevated in all patients and normalized only in the cured patients after TA (specificity, 89%). Preoperative GHBP levels were low and increased from 2 wk after surgery. CONCLUSIONS: We show that in the postoperative evaluation of patients with acromegaly, already 1 wk after surgery, an OGTT using 0.5 microg as the GH nadir cutoff value has a high predictive value for cure, whereas early IGF-I levels show varying patterns toward stabilization. Therefore, IGF-I should be measured as a predictive parameter not within 3 months after surgery. Free IGF-I and ALS levels may have an additional value in the postoperative assessment of disease activity.

Acromegaly↗
PubMed1984

Stimulation of growth hormone by vasoactive intestinal polypeptide in acromegaly.

Vasoactive intestinal polypeptide (VIP) was administered as an iv bolus of 1 micrograms/kg BW to 8 acromegalic patients and in doses of 0.5 and 1 microgram/kg BW to 15 normal volunteers. Both systolic and diastolic blood pressures decreased, and pulse rate increased transiently after VIP injection. VIP stimulated PRL release from the anterior pituitary in normal subjects. Plasma PRL responses to VIP in women were dose dependent and larger than those in men. On the other hand, plasma GH levels rose markedly after VIP injection in all 6 patients with untreated acromegaly. In 2 patients studied after transsphenoidal microadenomectomy, there was no plasma GH response to VIP. In 2 other patients with inactive acromegaly as well as in normal subjects, VIP failed to affect plasma GH levels. In all 6 patients with active acromegaly, LRH (1-2 micrograms/kg BW, iv) did not increase plasma GH levels, but TRH (5-10 micrograms/kg BW, iv) caused significant increases in plasma GH, the magnitude of which was not similar to that of increases seen after VIP injection. Paradoxical GH responses to TRH were not observed in patients in the inactive phase after transsphenoidal surgery. These findings suggest that VIP stimulates GH release in vivo in acromegalic patients. A VIP test as well as a TRH test offer promise as simple and reliable techniques to evaluate the activity of acromegaly, particularly after transsphenoidal surgery.

Acromegaly↗
PubMed1985

Changes in calcium homeostasis in acromegaly treated by pituitary adenomectomy.

Patients with acromegaly have alterations in mineral metabolism. To determine the effect of correction of excess GH secretion on calcium metabolism, we studied 12 acromegalic patients before and 3-4 weeks after pituitary adenomectomy. Treatment of acromegaly resulted in significant decreases in both serum calcium [from 9.3 +/- 0.2 to 8.7 +/- 0.1 mg/dl (mean +/- SEM); P less than 0.01] and urinary calcium excretion (from 200 +/- 24 to 88 +/- 12 mg/24 h; P less than 0.0002). Serum phosphate also decreased significantly (P less than 0.01) from 4.8 +/- 0.2 to 4.3 +/- 0.2 mg/dl. Both serum immunoreactive PTH and calcitonin levels were normal initially and did not change after surgery. The mean serum 25-hydroxyvitamin D (25OHD) level was significantly (P less than 0.01) lower and the 1,25-dihydroxyvitamin D [1,25-(OH)2D] level was significantly (P less than 0.0001) higher in acromegaly compared with measurements in 25 normal subjects. After surgery, the serum 25OHD level did not change; however, the serum 1,25-(OH)2D concentration fell significantly (P less than 0.0001) from 60 +/- 4 to 43 +/- 2 pg/ml. A positive correlation was found between the decrements in urinary calcium excretion and the serum 1,25-(OH)2D level when the comparison was made between the decrements as percentages of pretreatment values (r = 0.64; P less than 0.05). The accumulated data suggest that the hypercalciuria in acromegaly might be due to intestinal calcium hyperabsorption, which could be attributed to the elevated circulating 1,25-(OH)2D level. Excessive GH secretion might stimulate the production of 1,25-(OH)2D and might also directly stimulate calcium absorption.

Acromegaly↗
PubMed1988

Medical management of acromegaly due to ectopic production of growth hormone-releasing hormone by a carcinoid tumor.

A 59-yr-old woman with a disseminated carcinoid tumor was evaluated for acromegaly. She had previously undergone a hypophysectomy for acromegaly and an enlarged pituitary, with a reduction in her serum GH levels from 100 to 4 micrograms/L. Recurrence of acromegalic symptoms 2 yr later was accompanied by elevated serum GH (16 micrograms/L) and insulin-like growth factor I (IGF-I; 528 micrograms/L) and plasma GHRH levels (12 micrograms/L; normal, less than 30 ng/L). Computed tomographic scan did not reveal pituitary enlargement. Metastatic carcinoid tissue in bone removed at biopsy contained GHRH (100 pg/mg tissue). High performance liquid chromatography of plasma GHRH revealed predominantly GHRH-(3-40)-OH, a biologically inactive GHRH metabolite, along with mature GHRH forms, while carcinoid tissue contained both GHRH-(1-40)-OH and GHRH-(1-44)-NH2. Treatment with pergolide initially resulted in reduction in serum GH and IGF-I levels and amelioration of symptoms of acromegaly. However, after 14 months of pergolide therapy, serum GH levels increased despite administration of up to 1000 micrograms pergolide/day. Plasma GHRH levels remained elevated throughout the treatment period. Subsequent treatment with SMS 201-995, a long-acting somatostatin analog, for over 1 yr resulted in sustained reductions of ectopic GHRH secretion, GH hypersecretion, and IGF-I levels. Plasma GHRH levels correlated with simultaneously measured serum GH levels in response to acute SMS 201-995 administration. SMS 201-995 was an effective medical treatment for acromegaly caused by ectopic GHRH production in this patient.

Acromegaly↗
PubMed1990

Pulsatile growth hormone secretion in patients with acromegaly and normal men: the effects of growth hormone-releasing hormone infusion.

Twenty-four GH secretory patterns were studied before and during continuous infusions of GHRH in six patients with active acromegaly and in six normal adult men. GH release was episodic in both groups. Control subjects showed a normal diurnal variation in GH release, with the majority of GH released at night (2200-0800 h); mean levels were 1.5 +/- 0.4 (SE) ng/mL (day) and 4.2 +/- 0.8 ng/mL (night). Acromegalics had no diurnal variation in GH; levels were 45.3 +/- 13.7 ng/mL (day) and 39.8 +/- 12.2 ng/mL (night). Acromegalics demonstrated an increased frequency of GH pulses compared to normals (11.8 +/- 0.8 vs. 2.2 +/- 0.3/24 h). During continuous 24-h infusions of GHRH, the normal subjects continued to show a diurnal variation in GH release, but GH pulse frequency increased to a rate (11.7 +/- 1.4 pulses/24 h) very similar to that of the patients with acromegaly. In contrast, GHRH infusion did not alter the GH pulse frequency in the acromegalics. GHRH increased the mean levels of GH in both groups (patients 80.2 +/- 20.3 vs. 41.0 +/- 12.1 ng/mL, x +/- SE. P less than 0.05; controls 10.2 +/- 2.0 vs. 3.33 +/- 0.5 ng/mL, P less than 0.01). Some of the patients with acromegaly showed a progressive decline in GH levels during the infusion period, suggesting desensitization or exhaustion of releaseable stores; however, GH levels remained above basal values in all patients. After the 24-h GHRH infusions, the GH response to a bolus of GHRH was diminished in the normal subjects (2.1 +/- 0.9 vs. 16.8 +/- 5 ng/mL, x +/- SE; P less than 0.01) but not in the acromegalic patients (30.2 +/- 8.9 vs. 35.5 +/- 12.5 ng/mL; NS). These results indicate that GH release is episodic under basal conditions and during continuous GHRH infusion in both acromegalic and normal subjects, indicating the importance of other modulators of GH release, such as somatostatin, which may remain pulsatile even in acromegaly.

Acromegaly↗
PubMed1992

Regulation of pulsatile growth hormone secretion by fasting in normal subjects and patients with acromegaly.

In acromegaly, GH hypersecretion occurs despite elevated insulin-like growth factor-I (IGF-I) levels, implying defective IGF-I feedback. To study the possible mechanisms of defective IGF-I negative feedback in acromegaly, we assessed parameters of pulsatile GH secretion during fasting-induced decrease in plasma IGF-I. Seven patients with active acromegaly and six normal controls were fasted for 6 days and GH secretory profiles were obtained by frequent (every 10 min) blood sampling for 24 h and analyzed by Cluster. Fasting resulted in similar decreases in IGF-I, body weight, and blood glucose levels, and increases in free fatty acid and beta-hydroxybutyrate in all subjects. Normal subjects showed increases in 24-h total and pulsatile GH production, GH pulse frequency, maximal pulse amplitude, interpulse and nadir levels, implying suppression of hypothalamic somatostatin secretion and increase in GH-releasing hormone (GHRH) pulse frequency. In acromegalic patients, GH (and, by inference, GHRH) pulse frequency was unchanged. Three patients had increases in GH production, interpulse, and nadir levels similar to the normals while the other four had no change or paradoxical decreases in these parameters. Percentage change in GH production was highly correlated with percentage change in interpulse and nadir levels in both normals and patients. Mean GH response to GHRH (0.33 micrograms/kg iv) did not change significantly in any group as a result of fasting. Our data suggest that in healthy humans IGF-I negative feedback on GH secretion involves suppression of GHRH pulse frequency. GH (and, by inference, GHRH) pulse frequency is resistant to decrease in IGF-I in acromegaly, suggesting that lowered sensitivity of GHRH neurons to IGF-I may be the mechanism of high GH pulse frequency in this disease.

Acromegaly↗
PubMed1995

The prevalence of colonic polyps in acromegaly: a colonoscopic and pathological study in 103 patients.

Patients with acromegaly are reported to be at risk of developing adenomatous colonic polyps, which are considered to be preneoplastic lesions. This assumption is, however, usually drawn from results obtained in rather small series of patients or without a control group. We, therefore, undertook a prospective colonoscopic and pathological study comprising 103 acromegalic patients and 138 nonacromegalic control subjects referred for irritable bowel syndrome. The prevalence of adenomatous colonic polyps was significantly increased in acromegalic patients compared to that in control subjects (22.3% vs. 8.0%; P = 0.0024). The significance was similarly present in male acromegalic patients (28.6% vs. 5.5% in male control subjects; P = 0.0026), but was absent in female acromegalic patients. The prevalence of colonic polyps was also significantly increased in the group of acromegalic patients under 55 yr of age (20.0% vs. 3.0% in the control group of the same age; P = 0.0026). Other characteristics of adenomatous colonic polyps in acromegaly were the multiplicity and the presence proximal to the splenic flexure. No difference in the duration of acromegaly was found between patients with or without adenomatous polyps. The prevalence of hyperplastic colonic polyps was also significantly increased to 24.3% in acromegalic patients vs 4.4% in control subjects (P < 0.001). In conclusion, in view of the increased incidence of adenomatous colonic polyps, colonoscopy should be part of the follow-up examination in acromegaly.

Acromegaly↗
PubMed1995

Characterization of the paradoxical growth hormone inhibitory effect of galanin in acromegaly.

Galanin is a 29-amino acid straight-chain biologically active peptide which has been found to decrease circulating GH levels in some acromegalic patients, whereas is able to increase GH secretion in normal subjects. The aim of our study was to ascertain the incidence, entity and mechanism of the paradoxical GH inhibitory effect of galanin in acromegaly also looking at possible correlations between the GH responses to galanin and the main clinical and biochemical features of the patients. Finally, the effects of either successful or unsuccessful neurosurgical intervention on the GH inhibitory effect of galanin in acromegaly were investigated. A series of 23 consecutive patients with active acromegaly seen at the Endocrine Section of the Department of Internal Medicine of the University of Brescia (Italy) between 1991 and 1994 was examined. The acromegalic patients were subdivided in group 1 (i.e. patients who were 1) untreated, 2) evaluated before surgery, and 3) not cured after surgery and radiotherapy) and group 2 (i.e. surgically cured). All patients were submitted at least once to the following biochemical and radiological evaluations: 1) baseline serum insulin-like growth factor-I and PRL samples, 2) iv infusion of synthetic porcine galanin (500 micrograms in 100 mL saline) from -10 to 30 min, 3) iv bolus injection of TRH (200 micrograms) at time zero, 4) oral glucose tolerance test (75 g glucose, orally) at time zero, and 5) magnetic resonance of the pituitary sella. Adenomatous tissue obtained during neurosurgery in four patients was cultured in vitro, and the effect of the addition of galanin in the culture medium on GH secretion was tested. During galanin infusion in 19 of 21 group 1 patients, serum GH levels were lower with respect to baseline (range of GH decrease, -6.2 to -85.4% with respect to basal levels). During galanin infusion, no reductions in GH levels were observed in the acromegalic patients cured after neurosurgery (group 2); on the contrary, 6 of 7 patients displayed a normal stimulatory response to galanin (range of GH increase, +120-1533.3% of the basal level). A significant correlation between the percent decrease in GH levels after galanin treatment and the percent increase after TRH was found in group 1 patients (r = -0.783; P < 0.05). In three of the four adenomas examined, galanin determined a clear decrease in GH secretion (mean nadir, 63.3 +/- 12% of the baseline secretion rate). In conclusion, we demonstrated that the large majority of numerous patients with active acromegaly show a decrease in serum GH levels after galanin administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Acromegaly↗
PubMed1998

Octreotide as primary therapy for acromegaly.

The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB

Acromegaly↗
PubMed2000

Octreotide may act as a radioprotective agent in acromegaly.

Clinical experience shows that an increasing number of patients undergoing radiation treatment for recurring acromegaly or acromegaly persisting after surgery are treated with octreotide. We, therefore, performed a follow-up study of patients undergoing stereotactic radiosurgery (Gamma Knife) to determine whether this medication has an influence on the ultimate result of radiation therapy in either a positive or negative sense. It has been suggested that the combination of radiation with antisecretory drugs may increase the effectiveness of radiation. A follow-up study of 31 patients suffering from recurrent acromegaly and acromegaly persisting after surgery, and who had been treated with stereotactic radiosurgery, showed that patients treated with octreotide at the time of radiation application simultaneously reached a normal level of growth hormone and insulin-like growth factor-I only after a significantly longer interval than patients who did not receive the drug. The two groups of patients did not demonstrate significant differences in the main clinical findings (age, sex, target volume, radiation dose, baseline growth hormone, and baseline insulin-like growth factor-I).

Acromegaly↗
PubMed2000

Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure.

Radiation therapy (RT) has traditionally been considered a useful additional therapy for patients with acromegaly not achieving biochemical remission after surgery. However, recent evidence has suggested that RT is not curative in most patients with acromegaly when normalization of the serum insulin-like growth factor I (IGF-I) level is used to define remission. Therefore, we evaluated the success of RT based on IGF-I level in the 47 patients who received RT as part of their treatment from the cohort of 161 patients with acromegaly seen by us between 1981 and 1999. Four patients in whom no post-RT IGF-I level was available were excluded from the analysis. Of the remaining 43 patients, 32 patients received external beam RT, 6 received fractionated stereotactic radiosurgery, 4 received gamma-knife RT, and 1 received proton beam RT. The most recent IGF-I levels in these 43 patients, obtained a mean of 5.2 yr post-RT (range, 0.8-13.2 yr), were compared to age-adjusted normal ranges. IGF-I levels were normal in 17 patients (39.5%) without the addition of medical therapy. The percentage of patients with a normal IGF-I level generally increased with time post-RT; 27% of patients less than 6 yr post-RT, but 69.2% of patients 6 yr or more post-RT had normal IGF-I levels. Using the more traditional criterion for cure, a random GH measurement, 74% of patients had a GH level below 5 ng/mL, and 44% had a GH level below 2.5 ng/mL and would have been considered in remission based on these criteria. We conclude that with time RT remains a useful adjunctive treatment for many patients with acromegaly. RT should be considered along with appropriate medical therapy in selected patients who do not achieve normalization of IGF-I level after surgery or for those resistant to medical therapy.

Acromegaly↗
PubMed2001

The relationship between 24-hour growth hormone secretion and insulin-like growth factor I in patients with successfully treated acromegaly: impact of surgery or radiotherapy.

In patients with treated acromegaly, improved survival is associated with serum GH concentrations below 2 microgram/L (5 mU/L). A principal aim of therapy in acromegaly is to achieve a GH level less than 2 microgram/L, as such levels are thought to be "safe." However, such GH levels do not always equate with normalization of plasma insulin-like growth factor I (IGF-I), although epidemiological data linking survival or morbidity to IGF-I levels are at present lacking. The aims of this study were 1) to further define the nature of GH release in those acromegalic patients who achieve mean GH concentrations below 2 microgram/L post therapy, 2) to examine the effect of different therapeutic interventions on the 24-h GH profile (surgery alone or radiotherapy), and 3) to determine the relationship between the various characteristics of the 24-h GH profile and IGF-I production in acromegalic subjects who have achieved GH below 2 microgram/L. Spontaneous 24-h GH secretion was measured using both a conventional immunoradiometric assay (limit of detection, 0.4 microgram/L) and an ultrasensitive assay (limit of detection, 0.002 microgram/L). The GH data have been analyzed by several methods: 1) the pulse detection algorithm Cluster, 2) a distribution method for detection of peak [the observed concentration 95%, i.e. the threshold at or below which GH concentrations are assessed to be 95% of the time, as calculated by probability analysis (OC 95%)] and trough (OC, 5%) GH activity, 3) deconvolution analysis, and 4) approximate entropy analysis. GH was sampled every 20 min for 24 h, along with basal IGF-I and IGF-binding protein-3, in 21 treated acromegalic patients with a mean GH below 2 microgram/L [ACR; 9 women and 12 men; median age (range), 49 (31-76) yr] and 16 healthy controls [C; 6 women and 10 men; age, 50 (30-75) yr]. Mean 24-h serum GH concentrations were [median (range)]: ACR, 1.1 (0.04-1.5) microgram/L; C, 0.4 (0.02-3.3) microgram/L (P = 0.28). GH pulse frequency was: ACR, 11 (1-14)/24 h; C, 10 (8-18)/24 h (P = 0.41). In the GH profiles the mean heights of the GH peaks were: ACR, 1.2 (0.05-2.8) microgram/L; C, 0.8 (0.02-5.1) microgram/L (P = 0.91), and the mean GH valley nadirs were: ACR, 0.65 (0.03-1.1) microgram/L; C, 0.09 (0.01-1.8) microgram/L (P < 0.02). The OC 95% was: ACR, 1.0 (0.04-3.8) microgram/L; C, 1.0 (0.02-10) microgram/L (P = 0.65), and the OC 5% was: ACR, 0.09 (0.01-0.6) microgram/L; C, 0.01 (0.001-0.4) microgram/L (P < 0.001). The median IGF-I was: ACR, 227 (100-853) microgram/L; C, 156 (89-342) microgram/L (P < 0.005). Approximate entrophy values were: ACR, 1.06 (0.35-1.45); and C, 0.57 (0.27-1.19); P < 0.05. In the acromegaly group a significant positive correlation was found between IGF-I and the calculated GH secretory burst amplitude in the radiotherapy subset (r = 0.85; P < 0.0005) as well as between IGF-I and both the mean GH valley nadir (r = 0.60; P < 0.004) and the trough (OC 5%) GH activity for the acromegalic patients as a whole (r = 0.55; P < 0.02). We conclude that in treated acromegaly (GH, <2 microgram/L), 1) IGF-I (by approximately 50%) and basal GH secretion (by 5-fold) remain significantly elevated compared with control values despite similar mean 24-h GH concentrations; 2) the calculated GH secretory pulse amplitude, mean GH valley nadir, and OC 5% correlate positively with IGF-I; 3) the greater mean GH valley nadir and OC 5% in acromegalic patients compared with controls may account for the raised IGF-I; and 4) radiotherapy is unlikely to normalize the GH secretory pattern, which underlies the persisting elevated IGF-I levels.

Acromegaly↗