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Predictors and rates of treatment-resistant tumor growth in acromegaly.

BACKGROUND: Multimodal therapy for acromegaly affords adequate disease control for many patients; however, there remains a subset of individuals that exhibit treatment-resistant disease. The issue of treatment-resistant pituitary tumor growth remains relatively under-explored. METHODS: We assessed the literature for relevant data regarding the surgical, medical and radiotherapeutic treatment of acromegaly in order to identify the factors that were predictive of aggressive or treatment-resistant pituitary tumor behavior in acromegaly and undertook an assessment of the rates of failure to control tumor progression with available treatment modalities. RESULTS: Young age at diagnosis, large tumor size, high growth hormone secretion and certain histological markers are predictors of future aggressive tumor behavior in acromegaly. Significant tumor regrowth occurs in less than 10% of cases thought to be cured surgically, whereas failure to control tumor growth is seen in less than 1% of patients receiving radiotherapy. Somatostatin analogs induce a variable degree of tumor shrinkage in acromegaly but up to 2.2% of somatostatin analog-treated tumors continue to grow. Relative to other therapies, limited data are available for pegvisomant, but these indicate that persistent tumor growth occurs in 1.6-2.9% of cases followed up regularly with serial magnetic resonance imaging scans. CONCLUSIONS: Treatment-resistant tumor progression occurs in a small minority of patients with acromegaly, regardless of treatment modality. Young patients with large tumors or those with high pre-treatment levels of growth hormone particularly warrant close monitoring for continued tumor progression during treatment for acromegaly.

Acromegaly↗

Changing patterns of insulin-like growth factor-I and glucose-suppressed growth hormone levels after pituitary surgery in patients with acromegaly.

OBJECT: According to a recent consensus statement on the treatment of acromegaly, its biochemical cure is defined as the normalization of age- and sex-adjusted insulin-like growth factor (IGF)-I levels and the suppression of growth hormone (GH) by glucose to lower than 1 ng/ml. The present study was prompted by the clinical observation that many cases of acromegaly can be considered cured according to one criterion but not others at different moments in a patient's postoperative course. METHODS: Fifty-three patients with acromegaly (30 women and 23 men) harboring nine microadenomas and 44 macroadenomas were evaluated after surgery by assessing age- and sex-adjusted IGF-I levels as well as glucose-suppressed GH levels. Fifty of these patients were studied more than once during follow up. Acromegaly was categorized as cured if the patient's IGF-I level was normal and their glucose-suppressed GH level was lower than 1 ng/ml; the disease was considered to be active if the patient's IGF-I level was high and the GH nadir was higher than 1 ng/ml following administration of glucose. Discordant categories of the disease were found in patients with high IGF-I levels and a GH nadir lower than 1 ng/ml after glucose administration and in those with normal IGF-I levels and a GH nadir higher than 1 ng/ml after glucose intake. At the first postoperative biochemical evaluation (1-3 months), 34% of patients harboring macroadenomas were classified as having been cured of acromegaly, 39% as having the active disease, and 27% as having the discordant form of the disease. When last evaluated (> or = 12 months postoperatively), the percentage of patients with the discordant form dropped to 14% and the proportion of cases cured and active was 44% and 41%, respectively. Of the nine patients with microadenomas, 44.4% were cured of acromegaly, 33.2% had the active disease, and 22% had the discordant variety on first evaluation. Twelve months or longer after transsphenoidal surgery, 55.5% of cases were cured, 11.1% were active, and 33% were discordant. In most cases, the discordant variety developed because of a persistently elevated level of IGF-I, followed by an incompletely suppressed GH level. Nineteen patients (38%) modified their biochemical category. In 15 of these patients this change in category was due to a change in IGF-I levels, becoming normal in 12 patients and rising to above normal range in three. A tumor remnant was demonstrated on magnetic resonance images in only four of these 19 patients. CONCLUSIONS: The authors conclude that the discordance rate between the biochemical markers that define cure in acromegaly is higher than previously reported, and the biochemical status assigned to a patient early in the postoperative course is very likely to change later, particularly when initially discordant.

Acromegaly↗

Acromegaly as an endocrine form of myopathy: case report and review of literature.

OBJECTIVE: To describe a case of muscle weakness in a patient with acromegaly and to review the pathophysiologic features of this disorder. METHODS: We present the clinical, laboratory, electromyographic, and muscle biopsy findings in our patient and review related reports in the literature. RESULTS: A 58-year-old woman with acromegaly presented with complaints of bilateral hip pain, weakness, and instability 8 months after transsphenoidal resection of a growth hormone (GH)-secreting pituitary macroadenoma. She had biochemically normal thyroid and adrenal function and no evidence of any neuropathy, inflammatory myopathy, or rheumatologic disorder to explain her symptoms. Investigations revealed increased levels of GH, insulin-like growth factor-I, serum creatine kinase (CK), and the MB fraction of CK, normal results of nerve conduction studies, and nonspecific findings on electromyography and muscle biopsy. A review of the literature revealed that although muscle weakness is a well-recognized feature of acromegaly, only a few cases similar to ours have been reported since acromegaly was first described in the late 1800s. Little is known about the natural history, best diagnostic approach, and optimal therapy for this debilitating complication. CONCLUSION: Muscle weakness in acromegaly is common and may result from a combination of the direct effect of GH excess on muscle and other metabolic derangements (hypothyroidism, hypoadrenalism, or diabetes). Mechanical factors may also contribute, such as joint laxity in conjunction with hypermobility. Affected patients may benefit from a reduction in GH levels and physiotherapy for adaptive training. Persistently increased serum CK levels in a patient with diabetes, for whom no other cause is found, should prompt an investigation for acromegaly. More research into this aspect of acromegaly is needed for enhancement of our understanding of, and therapy for, this debilitating condition.

Acromegaly↗

Homocysteine levels in acromegaly patients.

Acromegaly is associated with a two to three-fold increase in mortality related predominantly to cardiovascular disease. The excess mortality is associated most closely with higher levels of growth hormone (GH). Survival in acromegaly may be normalized to a control age-matched rate by controlling GH levels; in particular, GH levels less than 2.5 ng/mL are associated with survival rates equal to those of the general population. Hyperhomocysteinemia has also been recognized as a risk factor for cardiovascular disease, yet there are limited data on the prevalence of hyperhomocysteinemia in patients with acromegaly. Eighteen acromegaly patients (7 male, 11 female, mean age 42.8 +/- 11.0 years) in our endocrine clinic consented to having the following tests performed: complete blood count (CBC), thyroid hormones, folic acid, vitamin B12, plasma homocysteine levels, uric acid, fibrinogen, CRP, fasting glucose, insulin, C-peptide, total serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, GH, insulin-like growth factor-1 (IGF-1) and GH levels after an oral glucose tolerance test (OGTT). By history, fourteen had macroadenomas and four had microadenomas; eight had hypertension; two had glucose intolerance, and four had diabetes. Fifteen had had transsphenoidal or transfrontal surgery: two had been cured, but 13 others were taking long-acting octreotide. Five patients had undergone radiotherapy and the acromegaly in two was treated primarily with long-acting octreotide. CBC, thyroid hormone, folic acid, and vit B12 levels were normal in all patients. We divided the patients into two groups according to mean GH levels after an OGTT: Group 1 (GH<2.5 ng/mL, n=10), and Group 2 (GH<2.5 ng/mL, n=8). Comparison of the two groups using Mann-Whitney U testing revealed statistically significant lower levels in Group 1 of the following parameters: GH (1.91 +/- 0.90 vs. 8.58 +/- 5.55 ng/mL, p=0.002), IGF-1 (338.30 +/- 217.90 vs. 509.60 +/- 293.58 ng/dL, p=0.06), GH after an OGTT (1.42 +/- 0.81 vs. 9.01 +/- 4.53 ng/mL, p=0.001), plasma homocysteine (12.85 +/- 4.47 vs. 18.20 +/- 4.99 micromol/L, p=0.05), total cholesterol (164.0 +/- 20.81 vs. 188.0 +/- 22.26 mg/dL, p=0.05) and LDL cholesterol (81.0 +/- 9.64 vs. 116.70 +/- 13.03 mg/dl, p=0.01). Differences between the other parameters were not significantly different. Acromegaly patients with high GH levels after an OGTT have much higher levels of homocysteine than patients with lower GH levels. The role of elevated homocysteine levels as an independent cardiovascular risk factor in the mortality of acromegaly patients should be determined in future studies.

Acromegaly↗

Are there alternative tests for diagnosis of acromegaly?

In acromegaly, clinical features are of the utmost importance, and biochemical confirmation is rarely difficult. However, some clinically manifest acromegalics have subtle abnormalities in GH secretion resulting in post-glucose GH nadir in the designated "normal" range with high IGF-I levels. Clinical decision may be based on the probability of the disease and elevated IGF-I levels. The TRH test or the frequent GH sampling test may help confirm acromegaly but on their own have no diagnostic advantage. A TRH-GH response is not specific to acromegaly, while frequent sampling is not practical. Other tests rarely add information beyond that obtained by usual investigations. Post-treatment assessment of the disease activity and definition of acromegaly cure, by measuring GH secretion, remain problematic. IGF-I levels seem to differentiate normality less clearly and discordance of GH and IGF-I results is frequent. Post-treatment probability for residual disease activity should include more clinical parameters such as insulin sensitivity, leptin and echocardiography. Furthermore, with efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, requiring stimulatory testing. Acromegaly is a disfiguring and disabling illness, in which by definition, the disorder is caused by a pituitary GH-secreting adenoma resulting in high circulating levels of GH and IGF-I. The clinical features of acromegaly include those of GH and IGF-I on tissues and the effects of the pituitary tumor itself. There is no single cut-off value for GH with perfect discrimination between acromegaly and normality. The recommended post-glucose GH nadir value of 1 microg/l is now considered to be inappropriately high, and measurement of IGF-I levels although extremely valuable has its limitations. Furthermore, some acromegalics may have subtle abnormalities in GH secretion, resulting in post-glucose GH nadir in the designated "normal" range with elevated IGF-I levels.

Acromegaly↗

Sleep apnea in active acromegaly.

Previous case reports have shown an association between acromegaly and the sleep apnea syndrome (SAS). Some of the patients described had central SAS, raising the possibility that an elevation of the growth hormone (GH) level may cause a defect in respiratory drive. We determined the prevalence of SAS in 21 patients with a history of acromegaly. We separated them into two groups based on serum GH concentrations. Ten patients had active acromegaly (mean GH concentration, 62.2 ng/mL; range, 12.6 to 148 ng/mL), while 11 patients had inactive acromegaly (mean GH, 3.2 ng/mL; range, 0.7 to 6.4 ng/mL). Four of the ten patients with active acromegaly had SAS; none of the 11 patients with inactive acromegaly had SAS. Three patients with SAS had the purely obstructive type, and one had the mixed central and obstructive type. The hypercapnic ventilatory response was normal in all patients tested and was not influenced by the GH level. We conclude that SAS is associated with active acromegaly and that the GH level does not affect the hypercapnic ventilatory response. The absence of SAS in successfully treated patients suggests that it may resolve after a normal GH level is restored.

Acromegaly↗

Impaired left ventricular diastolic filling in patients with acromegaly: assessment with radionuclide angiography.

UNLABELLED: Acromegaly is associated with increased cardiac morbidity and mortality, but it is not clear whether this is the result of a specific disease of heart muscle or of increased incidence of hypertension. METHODS: Twenty-six patients with acromegaly (11 male and 15 female, mean age 45 +/- 13 yr) and 15 and 12 age- and sex-matched normal controls underwent high temporal resolution radionuclide angiography and two-dimensional echocardiography at rest. RESULTS: Normal controls and patients with acromegaly did not differ with respect to heart rate, ejection fraction, time to end systole, peak ejection rate (PER) and time to PER. In contrast, peak filling rate (PFR), normalized to end diastolic volume (EDV), or stroke volume (SV), or expressed as the ratio of PFR-to-PER was reduced (p < 0.01), time to PFR (TPFR) was prolonged (p < 0.01), and echocardiographic left ventricular mass index was higher (p < 0.001) in patients with acromegaly compared to normals. Patients with acromegaly were divided in normotensives (group 1, n = 17) and hypertensives (group 2, n = 9). Although left ventricular mass index was significantly (p < 0.01) higher in group 2 compared to group 1, PFR and time to PFR were not different between the two groups of acromegalic patients. In the entire group of patients with acromegaly significant relationships between left ventricular mass index and EDV/s (r = -0.56, p < 0.01), SV/s (r = -0.73, p < 0.001), and PFR/PER (r = -0.61, p < 0.001) were observed. CONCLUSION: Patients with acromegaly have impaired left ventricular diastolic filling at rest related to greater left ventricular mass index even in the absence of systemic hypertension.

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[Relationship between fasting glycemia, serum peptide C, insulin, growth hormone and plasma glucagon in acromegaly].

UNLABELLED: The aim of this study was to investigate interrelations among fasting glycaemia, serum C-peptide, insulin, growth hormone and plasma glucagon concentration in people with acromegaly. 22 patients with active acromegaly, 11 women and 11 men (group A) and 19 healthy people (group K) participated in the study. The oral glucose tolerance test was carried out in all participants. Blood glucose, serum C-peptide, growth hormone and plasma glucagon concentration was measured. 13 patients with acromegaly had normal glucose tolerance (group AT) and 9 had impaired glucose tolerance (group AN). Statistical analysis was performed using Student's test and regression analysis. The comparison of patients from group A and K showed, that serum growth hormone, C-peptide, insulin, blood glucose concentration in fasting state was higher in acromegaly. There were no differences in fasting plasma glucagon concentration between both groups. Fasting glycaemia was similar in patients AT and controls, but there were also higher fasting serum C-peptide and insulin concentrations in the AT group. Fasting blood glucose, serum C-peptide and insulin concentration was higher in AN group than in controls. There were no significant differences in the above parameters between AT and AN group. Analysis of regression showed the negative correlation of fasting serum growth hormone and blood glucose concentration in the group A and AT. However there was no correlation between other parameters and fasting glycaemia, in particular between fasting glycaemia and insulin concentration. Fasting glycaemia positively correlated with fasting serum insulin concentration in healthy men. The comparison of glycaemia and fasting concentration of some hormones in patients with acromegaly regarding their glucose tolerance, did not answer the question, which hormonal abnormality is the most specific for disturbances of carbohydrate metabolism in acromegaly. Therefore groups of patients with markedly high of hormones in fasting state concentrations were distinguished. There was no difference in fasting glycaemia in this people compared to patients with normal or moderately elevated concentrations of hormones studied. CONCLUSIONS: There is higher fasting glycaemia in patients with acromegaly compared to healthy men. Among them one can see subjects with normal glucose tolerance that is accompanied with high serum C-peptide and insulin concentration. Disturbances of glucose-insulin interregulation occur in these people.

Acromegaly↗

[The prevalence of hypertension in acromegaly].

AIM: To estimate the prevalence of hypertension (HT) in a group of patients with acromegaly at the moment of diagnosis and after treatment. PATIENTS AND METHODS: Fifty-seven patients, 43 females and 14 males with a mean age of 45.19 +/- 11.9 years were studied retrospectively. In the last visit 9 patients (15.7%) were in remission and 47 (84.2%) had active acromegaly. We considered hypertensive the patients with systolic BP > or = 140 and/or diastolic BP > or = 90 mmHg. Hypertension was classified in four stages:- mild, moderate, severe and very severe. RESULTS: The prevalence of hypertension at the moment of diagnosis was 35%. The hypertensive patients had a mean age of 51.75 +/- 9.3 years and normotensive patients 41.65 +/- 11.6 years (p < 0.001). In females the prevalence of HT was 27.9% and in males it was 57% (p = NS). In hypertensive patients (n = 20), the mean BP was 159 +/- 15 (syst.)/97.2 +/- 9.8 (diast.), 16 patients (80%) had mild to moderate HT and the remainder had severe (n = 2) and very severe (n=1) HT. In the last visit, 22.2% of patients were cured and 46.8% of those with active acromegaly were hypertensive. None of the patients cured and initially normotensive developed HT; among those that were hypertensive (n = 3), 2 remained hypertensive and 1 became normotensive. Among patients with active acromegaly and initially normotensive, 7 developed HT 4.85 +/- 2.03 years later; of those hypertensive at diagnosis (n = 16), only one became normotensive. The last case was 27 years old. The patients that remained hypertensive had a mean age of 53.8 +/- 6.85 years (41-62 years). CONCLUSIONS: The prevalence of hypertension at the moment of diagnosis was 35%, similar to the majority of studies published and higher than the general population. The hypertensive patients were significantly older the normotensive patients and most of them had mild to moderate HT. We observed an increase in the prevalence of HT over the years in the cases that maintained active acromegaly. In our series only one of the three patients cured became normotensive, therefore, we concluded that HT in acromegaly is frequently irreversible. The chances of normalization seems higher in younger patients and probably with a shorter duration of acromegaly.

Acromegaly↗

One-year follow-up of patients with acromegaly treated with fixed or titrated doses of lanreotide Autogel.

OBJECTIVE: Somatostatin analogue treatment is first-line medical therapy for acromegaly. This study compared the efficacy and tolerability of titrated doses of the long-acting somatostatin analogue preparation lanreotide Autogel with fixed doses and with lanreotide prolonged release (PR) 30 mg microparticles. PATIENTS: Patients entering the initial study had received a diagnosis of active acromegaly within the previous 5 years. DESIGN: This open, comparative, multicentre study was a 1-year extension of a previous trial during which patients with acromegaly had switched from lanreotide PR 30 mg microparticles injected intramuscularly every 7, 10 or 14 days, for at least 3 months, to one of three fixed doses of lanreotide Autogel (120, 90, or 60 mg every 28 days, respectively). In this extension study, patients continued to receive 60, 90, or 120 mg of lanreotide Autogel by deep subcutaneous injection every 28 days for 1 year. Doses could be titrated at entry or after four or eight injections, according to the GH/IGF-I response (dose increased if GH > 2.5 micro g/l, or decreased if GH < 1 micro g/l with normal IGF-I). MEASUREMENTS: Mean +/- SEM GH and IGF-I concentrations were analysed and gallbladder echography performed at weeks 0, 16, 32, and 48. Acromegaly symptoms were recorded monthly and tolerance and side-effects were monitored throughout the study. RESULTS: In total, 130 patients entered this extension phase. After 1 year of treatment with titrated doses of lanreotide Autogel, mean GH (2.4 +/- 0.2 micro g/l) and IGF-I (287 +/- 12 micro g/l) concentrations were significantly lower than with lanreotide microparticles (GH, 2.8 +/- 0.2 micro g/l, P < 0.001; IGF-I, 332 +/- 15 micro g/l, P < 0.01) or with fixed-dose lanreotide Autogel (GH, 3.0 +/- 0.2 micro g/l, P < 0.001; IGF-I, 310 +/- 14 micro g/l, P = 0.02). GH hypersecretion was reduced to </= 2.5 micro g/l in 68% of patients with titrated-dose lanreotide Autogel compared with 49% with microparticles (P < 0.001) and 56% with fixed-dose lanreotide Autogel (P </= 0.005). In the 65 patients who did not require any dose titration, there was no substantial change in serum lanreotide concentration, GH or IGF-I levels over the 12-month study duration. Acromegaly was effectively controlled (GH </= 2.5 micro g/l and normalized IGF-I) in significantly more patients (43%) compared with microparticles (32%; P < 0.05). There was a trend for improved control of acromegalic symptoms with dose titration, whereas the incidence of gastrointestinal symptoms and local tolerance was similar with lanreotide Autogel and lanreotide microparticles. Gallbladder echographies showed new lithiasis in 8% of lanreotide Autogel patients. CONCLUSION: Dose titration of lanreotide Autogel improved GH and IGF-I control in patients with acromegaly beyond that achieved using fixed doses of lanreotide Autogel or lanreotide microparticles. Titrated long-term lanreotide Autogel treatment is well tolerated.

Acromegaly↗

Gonadotrophin and free alpha-subunit secretion in patients with acromegaly and clinically non-functioning pituitary tumors: anterior pituitary function and the effect of thyrotrophin-releasing hormone.

The effect of the tumor size on the anterior pituitary hypofunction is analyzed in 29 patients with acromegaly and 34 patients with clinically non-functioning pituitary tumor (NFPA). Gonadotrophin and free alpha-subunit (SU) concentrations during daytime variations (samples were taken hourly for 24 h) and after stimulation with TRH were measured as well. Patients with NFPA had a higher prevalence of isolated secondary hypogonadism (20.6% vs 10.3%) and more severe pituitary failure (52.9% vs 6.9%) in comparison with acromegalic patients (p < 0.0001). However, there was no association between the tumor size and the anterior pituitary hypofunction (p = 0.1 and p = 0.9) in patients with NFPA and acromegaly respectively. In premenopausal women and in men with normal/low gonadotrophin levels, mean daytime levels of LH (0.75 +/- 0.6 vs 1.5 +/- 1.9 mlU/ml; p = 0.002) and FSH (2.1 +/- 2.7 vs 4.1 +/- 4.9 mlU/ml; p = 0.009) were higher in patients with acromegaly. There was no difference in the alpha-SU level (p = 0.9). Women with gonadotrophin levels compatible with menopause and men with elevated gonadotrophin levels had the same degree of gonadotrophin and alpha-SU elevation regardless of the tumor type. TRH induced significant rise of LH in 8 (23.5%), FSH in 5 (14.7%) and alpha-SU in 10 (29.4%) patients with NFPA. Among 29 patients with acromegaly LH rose in 6 (20.7%), FSH in 5 (17.2%) and alpha-SU in 3 (10.3%) patients. In conclusion, the anterior pituitary function is better preserved in patients with acromegaly than in patients with NFPA. It seems that the size of pituitary tumor is not the major factor in the pathogenesis of hypopituitarism in patients with macroadenomas. Gonadotrophin and possibly alpha-SU response to TRH exists not only in some patients with clinically non functioning pituitary tumors but also in some patients with acromegaly. Further investigations are need to explain if it represents a biochemical marker of a plurihormonal pituitary tumor in these patients.

Acromegaly↗

Quantitative ultrasound of the heel and some parameters of bone turnover in patients with acromegaly.

Acromegaly caused by growth hormone (GH) hypersecretion is characterized by enhanced skeletal growth and soft tissue enlargement. Insulin-like growth factor-1 (IGF-1) is the main peripheral mediator of GH action and it has a crucial role in the maintenance of a normal bone mass. However, in some patients with acromegaly, secondary osteoporosis is observed, despite the strong anabolic effect of GH and IGF-1 in bones. It is thought to be due to hypogonadism. The bone changes are accompanied by increased turnover. The aim of this study was to assess bone properties by ultrasound and turnover in patients with acromegaly. The study was carried out in 26 patients (13 men, 13 women): 14 with active acromegaly and 12 cured by surgery who had non-active disease. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and their combination Stiffness Index (SI) by quantitative ultrasound (QUS) of the heel, hormonal status, serum osteocalcin (OC) concentration and the urinary excretion of pyridinoline collagen crosslinks (PYR) were all studied. Controls were 20 age- and sex-matched healthy persons. We observed statistically significantly lower QUS values in patients with active disease than in those whose disease was cured. The differences were more pronounced in men. QUS values were lower in the entire group of patients compared with the controls; however, the differences were not statistically significant. Serum OC concentrations and urinary PYR excretion were higher in active disease. Statistically significant inverse correlations between serum GH levels and SOS (r = -0.58, p = 0.002); BUA (r = -0.66; p = 0.0001); T-score (r = -0,65, p = 0.0001) and Z-score (r = -0.66, p = 0.0001) were found only in male patients. No correlations between IGF-1, duration of the disease, OC, PYR and other data studied were observed. In conclusion, we have shown decreased QUS parameters suggesting impaired bone properties and quality in terms of density and elasticity in men, but not in women, with active acromegaly. This finding suggests osteoporosis with increased bone turnover. The above-mentioned changes might be caused by the action of GH on trabecular bone and its metabolism, since no hypogonadism in male patients was shown. Moreover, the influence of acromegaly on heel geometry and soft tissue swelling should also be considered.

Acromegaly↗

Measuring tongue volumes and visualizing the chewing and swallowing process using real-time TrueFISP imaging--initial clinical experience in healthy volunteers and patients with acromegaly.

This study assessed both two-dimensional (2D) TrueFISP imaging for quantifying tongue volume and real-time TrueFISP imaging for evaluating chewing and swallowing in healthy volunteers and patients with acromegaly. In 50 healthy volunteers, tongue volumes were measured using a 2D TrueFISP sequence. Chewing and swallowing were visualized using a real-time TrueFISP sequence. Ten patients with acromegaly were examined twice with the same magnetic resonance imaging protocol: once prior to therapy and a second time 6 months after therapy. Prior to therapy, healthy volunteers had an average tongue volume of 140 ml for men and 90 ml for women, and patients with acromegaly had an average tongue volume of 180 ml for men and 145 ml for women. However, 6 months after therapy the mean tongue volumes in patients with acromegaly had decreased to 154 ml in the men and to 125 ml in the women. The chewing and swallowing process was normal in all volunteers. Prior to therapy, just two patients showed a chewing and swallowing pathology, which disappeared after therapy. Patients with acromegaly had larger tongue volumes than healthy volunteers, and TrueFISP imaging proved feasible for visualizing chewing and swallowing in real time and is capable of detecting possible pathologies. Furthermore, TrueFISP imaging can be used to monitor therapeutic approaches in patients with acromegaly.

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Cardiovascular aspects in acromegaly: effects of treatment.

Patients with acromegaly have significant morbidity and mortality, associated with cardiovascular disease. Acromegaly is often complicated by other diseases such as diabetes mellitus, hypertension, and coronary artery disease, so the existence of acromegalic cardiomyopathy remains uncertain. Cardiac performance was investigated in patients with uncomplicated acromegaly. A subgroup of hypertensive acromegalics was also studied. In addition, the effects of chronic octreotide therapy or surgery on cardiac structure and function in acromegaly were studied. Twenty-six patients and 15 healthy controls underwent gated blood-pool cardiac scintigraphy and echocardiography at rest and during exercise. Echocardiography was repeated after 6 months of octreotide therapy (n = 11). Cardiac scintigraphy was repeated after 12 and 24 months of octreotide therapy (n = 10) or 12 to 24 months after surgery (n = 8). ECG, blood pressure, and heart rate were monitored during cardiac scintigraphy. Left ventricular mass (LVM) was calculated from the findings of the echocardiography. Serum growth hormone (GH) levels and plasma insulin-like growth factor-1 (IGF-1) levels were monitored. LVM index was significantly higher (P < .003) in acromegalics than controls and in hypertensive acromegalics than normotensives, but all other indices of cardiac function were similar. Chronic octreotide decreased GH and IGF-1 levels and improved the structural abnormalities as measured by echocardiography. Chronic octreotide or surgery did not alter cardiac function parameters. Thus, important changes in cardiac structure and function occur in uncomplicated acromegaly, and improvements can be demonstrated after chronic octreotide therapy. Heart disease in acromegaly appears to be secondary to high circulating GH levels.

Acromegaly↗

Current concepts in the biochemical assessment of the patient with acromegaly.

Biochemical assessment of a patient for acromegaly aims to definitively establish or exclude the presence of growth hormone excess. Whether applied to a newly recognized patient or to detect residual disease after therapy, this assessment is best accomplished by measurement of both the degree of GH suppression after oral glucose administration (OGTT) and levels of the GH dependent peptide, insulin-like growth factor I (IGF-I). When measured properly and compared to a well-characterized, age-adjusted normative database, elevation of the serum IGF-I level is a sensitive and specific indicator for the presence of acromegaly or persistent disease after therapy. The diagnosis of acromegaly can be confirmed by documenting an elevated IGF-I level in combination with failure of GH to suppress after oral glucose to below 0.3 microg/l, when GH is measured with a highly sensitive and specific assay. Persistently, normal IGF-I levels along with a nadir GH <0.3 microg/l should exclude the diagnosis. In assessing disease status during or after treatment, normalization of IGF-I is an essential criterion for biochemical control. It is important to recognize that nadir GH levels are >0.3 microg/l in some healthy subjects, so this criterion alone is not diagnostic of acromegaly. Also, because of heterogeneity of clinically available GH assays, this GH criterion, which was developed with a research assay, may not be applicable to use with all other assays. A nadir GH cut off of 1 microg/l has been found to be reliable for use with some standard immunoassays. It is recommended that glucose-suppressed GH levels be interpreted in conjunction with those of IGF-I and with consideration of conditions other than acromegaly that can alter them. With greater assay standardization and the use of IGF-I levels along with new rigorous criteria for interpretation of GH suppression during a OGTT we can improve our identification of patients with acromegaly in earlier stages of the disease as well as better recognize residual disease during therapy.

Acromegaly↗

Pathogenesis and prevalence of hypertension in acromegaly.

Hypertension is an important complication of acromegaly, contributing to the increased morbidity and mortality of this condition. Prevalence of hypertension in acromegalic patients is about 35%, ranging from 18 to 60% in different clinical series, and the incidence is higher than in the general population. The lowering of blood pressure observed concomitantly with the reduction in GH levels after successful therapy for acromegaly suggests a relationship between GH and/or IGF-I excess and hypertension. The exact mechanisms underlying the development of hypertension in acromegaly are still not clear but may include several factors depending on the chronic exposure to GH and/or IGF-I excess. Experimental and clinical studies suggest that the anti-natriuretic action of GH (due to direct renal action of GH or IGF-I and/or to indirect, systemic GH or IGF-I-mediated mechanisms) may play a role in the pathogenesis of hypertension. Acromegaly is frequently associated with insulin resistance and hyperinsulinaemia which may induce hypertension by stimulating renal sodium absorption and sympathetic nervous activity. Whether sympathetic tone is altered in acromegalic hypertensive patients remains a matter of debate. Recent studies indicate that an increased sympathetic tone and/or abnormalities in the circadian activity of sympathetic system could play an important role in development and/or maintenance of elevated blood pressure in acromegaly, and may partially account for the increased risk of cardiovascular complications. Acromegalic cardiomiopathy may also concur to elevate blood pressure and can be aggravated by the coexistence of hypertension. Finally, a role of GH and IGF-I as vascular growth factors cannot be excluded. In conclusion, acromegaly is associated with hypertension, but there is still no real consensus in the literature on the mechanisms behind the development of the high blood pressure.

Acromegaly↗

The effect of a new slow-release, long-acting somatostatin analogue, lanreotide, in acromegaly.

OBJECTIVE: Previous studies have shown that somatostatin analogues such as octreotide and lanreotide are effective in suppressing GH and IGF-I levels in acromegaly, but the mode of administration and the frequency of injections were inconvenient for the patients. We have evaluated the effects of a new slow-release (SR), long-acting formulation of lanreotide, a somatostatin analogue, on clinical, biochemical and safety responses in acromegaly. DESIGN: We studied the effects of SR-lanreotide 30 mg administered intramuscularly twice or three times monthly for 6 months. Ten patients were studied, in whom acromegaly was confirmed by clinical features,mean GH > 5 mU/l, and failure to suppress GH to < 2 mU/l after a 75-g oral glucose load. MEASUREMENTS: Subjective improvement in clinical symptoms of acromegaly was graded and recorded. Any adverse reactions were noted. Plasma GH levels were measured every 10 min for one hour from 08300930h; fasting IGF-I levels were determined at 0830h; GH, glucose and insulin responses to oral glucose loading were measured at 0,30,60,90 and 120 minutes from 0930 to 1130h. Baseline measurements were carried out and repeated at 3 and 6 months. Biliary ultrasonography was performed at baseline and 6 months. RESULTS: GH levels in the 10 patients decreased from 26.8 12.0 (mean SEM) to 12.7 7.0 mU/l at 3 months (P = 0.04) and 9.8 5.0 mU/l at 6 months (P = 0.06). Fasting IGF-I levels decreased from 123.2 27.0 to 73.5 13.0 nmol/l at 3 months (P = 0.01), and increased slightly to 97.4 31.0 nmol/l (P = 0.05) but remained below baseline levels at 6 months. Five patients achieved good control (GH < 5 mU/l) at 3 months. In the remaining 5 patients the dose frequency was increased to every 10 days and one achieved good control. IGF-I levels normalized in 3 and 5 patients at 3 and 6 months, respectively. Fasting insulin levels and peak insulin after an oral glucose load did not change significantly at 3 months but decreased from 11.7 2.0 to 7.8 3.3 mU/l (P = 0.05) and 106.2 24.6 to 53.3 14.3 mU/l (P = 0.04) at 6 months, respectively. There was no significant change in fasting glucose at 3 or 6 months. Most patients reported clinical improvement in acromegalic symptoms. No major adverse events were reported, but mild to moderate gastrointestinal symptoms were recorded after the initial injections. One patient developed asymptomatic gallstones at 6 months. CONCLUSIONS: This slow-release formulation of lanreotide given either twice or thrice monthly was well tolerated, more convenient for patients, effective in controlling and alleviating the symptoms of acromegaly, as well as suppressing GH and IGF-I levels, and had no detrimental effects on carbohydrate tolerance in acromegaly.

Acromegaly↗

Elevated fibrinogen levels decrease following treatment of acromegaly.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality from cardiovascular disease and from stroke in particular. Fibrinogen is an established risk factor for stroke and myocardial infarction and high levels of plasminogen activator inhibitor-1 (PAI-1) activity were predictive of a recurrent myocardial infarction. The aim of this study was to analyse fibrinogen and PAI-1 activity in patients with acromegaly before and after treatment. PATIENTS: Twenty patients with acromegaly were compared with healthy controls matched for sex (12 men, 8 women), age (mean 53 +/- 7 years), body mass index (mean 26.5 +/- 2.5 kg/m2) and smoking. Fibrinogen was also compared with a random population sample of men and women (n = 392), aged 25-64 years, from the WHO's MONICA Project, Göteborg, Sweden. RESULTS: The acromegalic patients had a higher lean body mass of 65 +/- 11 vs 59 +/- 11 kg (P < 0.05), lower body fat of 17 +/- 8 vs 25 +/- 10 kg (P < 0.01), higher plasma fibrinogen of 4.0 +/- 0.9 vs 2.4 +/- 0.5 g/l (P < 0.001) and plasma insulin of 15 +/- 14 vs 7 +/- 2 mU/l (P < 0.01), serum triglycerides of 1.5 +/- 0.5 vs 1.2 +/- 0.5 mmol/l (P < 0.05), as well as serum insulin-like growth factor-I (IGF-I) levels of 742 +/- 271 vs 168 +/- 51 micrograms/l (P < 0.001) compared with the matched controls. PAI-1 activity was similar, as was total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood glucose and blood pressure for acromegalic patients compared with controls. All the acromegalic patients had higher fibrinogen levels (p < 0.001) than the population mean. Plasma fibrinogen correlated positively with serum IGF-I in acromegaly (r = 0.55, P < 0.05). Fibrinogen decreased to a mean value of 3.2 +/- 0.3 g/l on treatment. CONCLUSION: Acromegaly is associated with high fibrinogen levels which may be one explanation for the increased risk of cardiovascular events, and stroke in particular, in this disease. Fibrinogen levels decreased following treatment of acromegaly.

Acromegaly↗