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[Echocardiographic changes in 91 patients with acromegaly].

Echocardiography was performed in 91 patients with acromegaly. Left ventricular internal diameter, wall thickness and left ventricular mass were measured and calculated. 76 patients with active acromegaly (GH greater than 5 ng/ml) were analysed. The result revealed that the incidence of acromegalic cardiomyopathy was 85.5% and the left ventricular mass of active acromegaly was 339.1 +/- 85.6 g and 188.8 +/- 46.7 g/m2. Most of them had left ventricular hypertrophy (LVH) or/and left ventricular dilation. Right ventricular hypertrophy was rarely detected. Most of LVH were symmetric and about a quarter of the patients with LVH was asymmetric (septum was thicker than LV posterior wall). LV mass in the active acromegaly group was larger than that in the normal group and the inactive acromegaly group. These indicate that acromegalic cardiomyopathy is related to growth hormone.

Acromegaly↗

[Carpal tunnel syndrome in acromegaly--4-case report and review of literature].

Four cases of carpal tunnel syndrome in acromegaly were reported. These 4 cases were found in 21 acromegalies (19%). Besides change of features, they complained bilateral sensory disturbances of their hands. After transsphenoidal removal of pituitary adenoma, GH levels returned to the normal range and sensory disturbances were improved in all cases. Mechanism of carpal tunnel syndrome in acromegaly is that edematous synovial tissues compress the median nerve because oversecretion of growth hormone causes increase of sodium and water retention in the extracellular fluid. The patient who showes high basal level of growth hormone and/or acromegalic pattern by various tolerance tests does not always have the carpal tunnel syndrome. But this syndrome is apt to be found in active acromegaly. So the detection of the symptom showed by this activity such as hypersudation in our cases leads to the early diagnosis of acromegaly.

Acromegaly↗

Renal handling of iodothyronines in acromegaly.

Measurement of the free serum concentration, the 24-h urinary excretion and the renal clearance of T4, T3, 3,3',5'-tri-iodothyronine (rT3), 3',5'-diiodothyronine (3',5'-T2) and 3,3'-di-iodothyronine (3,3'-T2) was performed in 13 patients with active acromegaly and in 18 healthy controls. The acromegalic patients had normal serum levels of the free iodothyronines, whereas the urinary excretion of T4 and T3 was increased approximately two-fold in the patients with acromegaly. The creatinine clearance, reflecting the glomerular filtration rate (GFR), was increased in the acromegalic patients, in median 133 ml/min versus 87 ml/min (p less than 0.01) in the controls. Compared to the creatinine clearance the clearance of T3 and 3,3'-T2 was higher (p less than 0.01) in acromegalics as well as in controls. The patients with acromegaly had higher renal clearance of T4 and T3 than controls, in median 81 ml/min versus 33 ml/min, and 269 ml/min versus 137 ml/min, respectively (p less than 0.01). These differences were not due to changes in creatinine clearance. The renal clearance of 3',5'-T2 tended to be enhanced in acromegalic patients (8.2 ml/min versus 3.9 ml/min, p less than 0.10), both before and after correction for creatinine clearance. The data suggest that in acromegaly, as in normal condition, iodothyronines are subject to both glomerular filtration and active tubular transport mechanisms. Further, active acromegaly results not only in increased GFR, but also in changes of the net tubular transport in favour of secretion of at least T4 and T3, and possibly also of 3',5'-T2.

Acromegaly↗

[Peripheral thyroid function and TRH-TSH test in patients with acromegaly].

In 11 patients with acromegaly the peripheral thyroid hormones were determined and a TRH-TSH-test was carried out. Depending on the result of the determination of the growth hormone the patients were classified into two groups (active and inactive acromegaly). The serum thyroxin level and the T3-binding capacity were normal. Only in a few patients decreased triiodotyronine levels were found. Independent of the degree of activity of the acromegaly positive as well as negative TRH-TSH-tests were found. The struma in patients with acromegaly which is frequently to be observed seems to be in a causal connection with this disease. The examination show altogether that the control of the function of the thyroid gland and the TRH-TSH-test do not deliver an essential contribution for the diagnostics of acromegaly itself.

Acromegaly↗

Diagnosis and treatment of acromegaly.

Acromegaly is a clinical syndrome that most typically is the manifestation of adenomatous hyperplasia of growth hormone-secreting cells in the pituitary gland. Although the primary process is benign, many disfiguring and potentially serious complications can develop. Because of the slow evolution of signs and symptoms, acromegaly can be a diagnostic challenge. Furthermore, many common diseases, such as hypertension, diabetes mellitus and hyperlipidemia, occur secondary to acromegaly but may initially be treated as isolated primary processes. Systematic evaluation should be performed if acromegaly is suspected. The diagnosis is based on clinical observation, hormonal assays and selective radiologic imaging. Acromegaly is most often treated surgically, but radiotherapy and drug therapy can be effective alternatives.

Acromegaly↗

Increased epithelial cell proliferation in the colon of patients with acromegaly.

To gain insight into the possible physiological mechanisms responsible for the increased incidence of colonic neoplasms in patients with acromegaly, a prospective cohort study was carried out in 30 patients with acromegaly, a prospective cohort study was carried out in 30 patients with acromegaly. Seven patients had newly diagnosed acromegaly and 23 were studied during follow-up. Serum growth hormone and insulin-like growth factor-1 (IGF-1) were determined on two separate occasions. During diagnostic endoscopy, mucosal biopsies were obtained for immunohistochemical determination of sigmoidal epithelial cell proliferation, expressed as labeling index (LI). Duodenal and fecal bile acid analyses were performed using gas-liquid chromatography. Results were compared with normal ranges of the laboratory. An increased overall LI was found in 54% of the patients. Increased LI of the luminal, middle, and basal crypt compartments was found in 11, 64, and 28%, respectively. Similarly, comparisons of the mean +/- SEM of the overall LI and the LI of the middle and basal compartments between acromegalic patients and a control group showed overall LI 10.0 +/- 0.8% versus 5.7 +/- 0.6% (P < 0.001), middle LI 12.1 +/- 1.2% versus 5.0 +/- 0.6% (P < 0.001), and basal LI 17.1 +/- 1.3% versus 10.8 +/- 1.3% (P < 0.01). Duodenal and fecal bile acid proportions were within the normal ranges of the laboratory. There was a positive correlation between growth hormone and overall LI (r = 0.55, P < 0.01) by least square regression analysis. There was no correlation between duodenal bile acid composition and hormone levels. The proportion of secondary bile acids in feces correlated with growth hormone (r = 0.55, P < 0.05) as well as with IGF-1 (r = 0.59, P < 0.05). With multiple regression analyses, only a relation between overall LI and IGF-1 (P = 0.007) remained to hold true. Increased epithelial cell proliferation, most probably due to a direct stimulatory effect of especially IGF-1, contributes to the increased risk of colonic neoplasms in acromegaly.

Acromegaly↗

The diagnosis and management of acromegaly: a Canadian consensus report.

OBJECTIVE: To reach a Canadian consensus on the diagnosis and management of acromegaly. OPTIONS DIAGNOSIS: documenting autonomous growth-hormone hypersecretion and imaging of the pituitary. TREATMENT: surgical resection, adjunctive therapy with bromocriptine or octreotide and radiation therapy. OUTCOMES: Reduction of the morbidity and mortality associated with acromegaly. EVIDENCE: Review of international literature. VALUES: Achievement of consensus among a panel of Canadian endocrinologists. BENEFITS, HARMS AND COSTS: Acromegaly is a chronic debilitating condition that is associated with morbidity and mortality. This consensus statement is designed to improve the diagnosis and management of this rare condition in order to minimize the negative outcomes. Costs were not considered. RECOMMENDATIONS: The diagnosis of acromegaly is established by documenting autonomous growth-hormone hypersecretion and by imaging the pituitary. Surgical resection is the cornerstone of treatment; however, adjunctive therapy is often needed. Although growth-hormone reduction is often associated with alleviation of symptoms, an attempt should also be made to normalize levels of growth hormone and its target growth factor, insulin-like growth factor-I (IGF-I). Persistent secretion of excess growth hormone and IGF-I may pose significant long-term health risks. A suggested therapeutic algorithm is provided. The ease of administration of bromocriptine should prompt a trial of therapy with this agent. The subcutaneous use of octreotide is of particular benefit to those patients with persistently high levels of growth hormone and IGF-I that cannot be suppressed by other means. Because acromegaly is relatively rare and complex, its diagnosis and treatment require the concerted efforts of an endocrinologist, an neurosurgeon and a radiation oncologist.

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Prevalence of thyroid diseases in patients with acromegaly: results of an Italian multi-center study.

Acromegaly is frequently associated with the presence of thyroid disorders, however the exact prevalence is still controversial. An Italian multicenter study was performed on 258 patients with active acromegaly (high levels of IGF-I and lack of suppression of serum GH levels below 2 microg/l after an OGTT). The control group was represented by 150 patients affected by non-functioning and PRL-secreting pituitary adenomas. Two hundred and two out of 258 acromegalic patients (78%) were affected by thyroid disorders with a significantly higher prevalence with respect to the control group (27%, p<0.0001). One hundred and three patients presented (39.9%) non-toxic nodular goiter, 46 (17.8%) non-toxic diffuse goiter, 37 (14.3%) toxic nodular goiter, 1 toxic diffuse goiter (0.4%), 12 (4.6%) Hashimoto's thyroiditis, 3 (1.2%) thyroid cancer. Two patients presented a co-secreting TSH pituitary adenoma. Thirty-six patients had been previously treated for various thyroid abnormalities. Among the 222 acromegalic patients never treated for thyroid disorders thyroid ultrasonography was performed on 194 subjects. Thyroid volume in patients with thyroid abnormalities was 28+/-17.5 ml (median 23) while it was 10.8+/-3.6 ml (median 10) in patients without thyroid disorders (p<0.0001). Thyroid volume was correlated with the estimated duration of acromegaly (r=0.7, p<000.1), but not with age or with serum GH, IGF-I and TSH concentrations. Thyroid volume was higher in acromegalic patients than in the above control population (23.5+/-16.9 ml vs 13.9+/-12.8 ml, p<0.0001). In 62 acromegalic patients 101 fine-needle biopsies of thyroid nodules were performed; 7 nodules were suspicious and the patients were submitted to thyroid surgery: papillary thyroid carcinoma was found in 3 patients. In conclusion, in a large series of acromegalic patients an increased prevalence of thyroid disorders (78%), particularly non-toxic nodular goiter, has been observed. Thyroid volume, evaluated by ultrasonography, was correlated to the estimated duration of acromegaly. Finally, the prevalence of thyroid carcinoma was slightly increased than in the general population.

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Empty sella syndrome. Sequela of the spontaneous remission of acromegaly.

Untreated acromegaly is usually a progressive disorder resulting in early death from cardiovascular or pulmonary complications. Although spontaneous remission of the metabolic features of acromegaly is not uncommon, its correlation with return to truly normal serum growth hormone concentrations is not routinely documented. This study reports a patient with the empty sella syndrome occurring as a sequel to the spontaneous remission of acromegaly. This association, as well as the preservation of normal anterior-pituitary function, suggests that selective tumor infarction resulted in the "empty sella" and cessation of active acromegaly.

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Macroglossia in acromegaly and hypothyroidism.

The tongues of two patients with macroglossia were examined at autopsy. One of the patients had acromegaly and the other had hypothyroidism. To evaluate the size of the enlarged tongues, the average weight of the tongue in the human adult was determined first in a series of 20 unselected autopsies, 10 males and 10 females (ages 44 to 85). The weight of the tongue was greater in males than in females and was directly correlated with the height of the subject. Cachexia had relatively little effect on the weight. In acromegaly (case 21) and myxedema (case 22) the tongue was enlarged by at least 50%. Histopathology showed enlargement of muscle fibers especially anteriorly in acromegaly and hypothyroidism, thickening of the epithelium and increased subepithelial and interstitial connective tissue. Incidental findings included venous thrombi and telangiectasia in the subepithelial connective tissue in both hypothyroidism and acromegaly and a corpus amylaceum and two islands of hyaline cartilage in the tongue of hypothyroidism.

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[Stimulation of growth hormone and prolactin secretion with TRH in acromegaly (author's transl)].

Inappropriate stimulation of growth hormone (hGH)-secretion with TRH in acromegalic subjects has been shown previously, whereas prolactin (hPRL) secretion was reported to be blunted in active acromegaly. In this study TRH induced hGH and hPRL secretion was investigated in 23 active (mean hGH level: 68.5 +/- 19.9 ng/ml; +/- SE) and 15 inactive acromegalics (mean hGH level: 2.3 +/- 0.4 ng/ml; +/- SE). Fourteen of the active acromegalics showed a significant increase up to more than double of the basal hGH level after 200 mug TRH while in only one of the inactive acromegalics an inappropriate rise of hGH was induced by TRH. Basal hPRL levels were elevated in 9 and within normal range in 14 of the patients with active acromegaly. Except in 3 patients who had normal basal hPRL levels and in one patient with excessively elevated hPRL and hGH levels due to an hPRL and hGH producing adenoma, all patients had normal hPRL responses to TRH. In those with inactive acromegaly, 9 had hPRL levels below normal and only , out of the 15 patients showed a normal rise of hPRL after TRH. The patients who showed no hPRL response to TRH demonstrated also other signs of pituitary insufficiency due to the operative procedure. In contrast to a previous report these findings demonstrate that normal or enhanced hPRL secretion is found in active acromegaly. The inappropriate rise of hGH after TRH is compatible with a loss of specificity of the receptor for GRH of the adenoma cell and can be found also in patients with normal basal hGH levels after treatment suggesting that remaining adenoma tissue is present in the pituitary fossa.

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Osteoporosis in longstanding acromegaly: characteristic changes of vertebral trabecular architecture and bone matrix composition.

Although it is now 60 years after Erdheim's (1931) detailed description of vertebral alterations in severe acromegaly, it is still unclear whether osteoporosis is a consistent feature of acromegalic bone disease or not. We studied the vertebral trabecular bone of a 44-year-old woman who had suffered active acromegaly for more than 20 years, and compared it with 17 normal as well as 2 osteoporotic controls. Histomorphometry revealed a very low trabecular bone volume and thus documented the presence of osteoporosis. The mean trabecular plate thickness was strikingly increased in acromegaly (possibly caused in part by a low-dose fluoride treatment), whereas it was normal or reduced in the osteoporotic controls. The meticulous analysis showed islands of cartilaginous tissue in the core of the acromegalic trabeculae which were not present in any other sample. In these areas collagen II was detected by immunohistochemistry. Biochemical analysis revealed that collagen II accounted for 7% of the total collagenous matrix. The degree of hydroxylation of lysyl residues of collagen I was close to the average value of all control samples studied. Our data show that osteoporosis can occur in acromegaly and that it is characterized by unusual architectural and compositional features. These findings challenge the prevailing view that the matrix of osteoporotic bone always shows a normal composition.

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Long-term treatment of acromegaly with the somatostatin analogue SR-lanreotide.

OBJECTIVE: To assess the efficacy and tolerability of SR-lanreotide in the treatment of active acromegaly. PATIENTS AND DESIGN: 30 patients (17 men and 13 women) were treated in whom active acromegaly was confirmed by clinical features, a mean GH level of >5 mlU/l and failure to suppress GH to <2 mlU/l after a 75 g glucose load. Patients were treated for a median period of 60 weeks (range 12-168) with im injections of SR-lanreotide 30 mg given every 7-14 days. MEASUREMENTS: Mean GH and IGF-I levels were measured at baseline and every 12-weeks together with symptom score assessment. MRI of the pituitary gland was performed at baseline and if an adenoma was identified at yearly intervals. Gall bladder ultrasound scans were performed at baseline and then every 24-weeks. RESULTS: Twenty-three patients were treated for at least 48-weeks and, in these, GH levels fell from 10.5 mlU/l (7.6-17.6) (median and interquartile range) at baseline to 3.2 mlU/l (2.4-3.9) (p<0.0001) and IGF-I levels ftom 88.9 nmol/L (71.4-137.1) to 56.8 nmol/l (39.3-75.4) (p=0.0002). GH response to treatment was better in elderly patients (age> or =65 years) compared to younger patients but neither sex, pre-treatment GH levels, previous surgery nor previous radiotherapy influenced the response. Treatment resulted in a significant improvement in the symptoms of active acromegaly in the majority of patients. A significant reduction in the size of the pituitary adenoma was documented in 6 of 10 patients who had a repeat MRI scan after one year. Treatment was well-tolerated by the majority of patients; side effects were mainly transient gastrointestinal symptoms. These were severe in only 2 patients necessitating discontinuation of the drug. Two patients developed new gall stones and 4 female patients had temporal hair loss necessitating stopping treatment in one of them. There were minor effects on glucose tolerance which were not of clinical importance. CONCLUSION: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients.

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Acromegaly and end-stage renal disease: a diagnostic challenge.

Chronic renal failure is associated with an impairment of the GH/IGF-I axis. We report the diagnostic challenges in a 72-yr-old female suffering from end-stage renal disease and presenting with clinical findings suggestive of acromegaly. GH was not suppressed during an oral glucose tolerance test, but rose paradoxically. However, serum IGF-I levels were within the normal range. IGF-binding proteins (IGFBP)-2 and -3 were markedly elevated and GH-binding protein (GHBP) was diminished. Clinical findings suspicious of acromegaly could be ascribed to pre-existing characteristics and consequences of end-stage renal disease. This suggested that the disturbances of the GH/IGF-I axis in our patient were due to chronic renal disease, rather than acromegaly. In the work-up for acromegaly, clinicians should be alerted to GH resistance in chronic renal failure.

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Acromegaly due to ectopic secretion of GHRH by bronchial carcinoid in a patient with empty sella.

GH hyperproduction due to ectopic secretion of GHRH is a rare cause of acromegaly. Since 1959, approximately 50 cases of ectopic GHRH production from extrapituitary tumors have been described. Here we report the clinical and biochemical features of a 47-yr-old Caucasian woman with ectopic GHRH syndrome sustained by a bronchial carcinoid. The criteria for the diagnosis of acromegaly due to ectopic GHRH secretion were satisfied in our patient (i.e. confirmation of active GH hypersecretion, unequivocal demonstration of GHRH production and secretion from an extrapituitary tumor and cure of acromegaly after neoplasm removal). The tumor was an atypical carcinoid and there was a familial history of lung and colorectal cancer. Acromegaly was slightly active (mean GH value: 7.4 ng/ml, IGF-I: 436 ng/ml) and after tumor removal there was a progressive decline of GH levels, consistent with remission of pituitary somatotroph hyperplasia. Pituitary radiology showed an empty sella demonstrating for the first time its association with ectopic GHRH syndrome.

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Gender- and age-related differences in the endocrine parameters of acromegaly.

Acromegaly is a severe slow-developing disease associated with a poor prognosis for cardiovascular disease. To evaluate the impact of age and gender on the severity of the disease, 151 de novo patients with acromegaly (79 women, 72 men, age range 19-77 yr) were included in this open retrospective multi-center cohort study. Basal GH and IGF-I levels, GH response after glucose load and maximal tumor diameter at MRI were measured in all patients at diagnosis. Fasting GH levels and maximal tumor diameter were similar in women and men, while serum IGF-I levels were lower (664.9+/-24.9 vs 755.9+/-32 microg/l; p=0.02) and GH nadir after glucose load was higher (27.5+/-3.7 vs 18.5+/-2.2 microg/l; p=0.04) in women than in men. In both sexes, patients' age was negatively correlated with basal and nadir GH, IGF-I levels and tumor size; fasting GH levels were positively correlated with IGF-I levels and nadir GH after glucose. No interaction between age and gender was found on biochemical and morphological parameters. At diagnosis, elderly patients with acromegaly have lower GH and IGF-I levels, lower GH nadir after glucose load and smaller adenomas than young patients. Women have lower IGF-I levels but higher GH nadir after glucose load than men. These age and gender differences should be considered to appropriately evaluate the activity of acromegaly throughout a life-span.

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Doppler echocardiographic patterns in patients with acromegaly.

Cardiovascular problems have long been recognized as responsible for an increased morbidity and mortality in patients with acromegaly. The aim of the present study was to evaluate echocardiographically the prevalence of cardiomyopathy in a cohort of acromegalic patients and to analyze the results in relation to demographic, clinical and hormonal data. This study, a retrospective controlled clinical trial, was performed in 25 acromegalic patients, 12 men and 13 women aged 26-66 years (mean: 52.6). Fifteen patients had an active disease, 10 were cured by previous pituitary surgery. The same echocardiographic parameters were analyzed in 50 healthy subjects aged 30-70 years (mean: 51.4). Serum GH was determined on at least 4 samples drawn over 24 hours and plasma IGF-I on a single point. Standardized parameters of diastolic and systolic function were evaluated by real-time Doppler echocardiography. Twelve patients with active acromegaly underwent also 48-hour ECG registering. Left ventricular (LV) hypertrophy was found in 14/25 patients (56%). No difference was found between patients with active disease (53%) and patients with cured acromegaly (60%). LV mass index was significantly increased in acromegalics in comparison with healthy subjects (137 +/- 43 g/m2 vs 96 +/- 16 g/m2, p < 0.01) and also the indices of LV diastolic function were significantly impaired. Asymmetric septal hypertrophy was found only in one patient. Hypertension was detected in 9/25 patients (36%) without difference between patients with active or cured disease (40% vs 30%, NS). No significant correlation was found between hormonal or clinical data and echocardiographic findings. During Holter monitoring, heart rate of acromegalics was not significantly different from that of controls (78 +/- 12 bpm vs 72 +/- 10 bpm, NS) and only isolated supraventricular or ventricular premature complexes (Lown class 1) were detected. In conclusion, this study provides evidence of subclinical LV dysfunction in acromegaly in the absence of other known causes of heart disease and no significant difference in echocardiographic pattern was apparent between active or cured acromegalics.

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Acromegaly.

Acromegaly is a slowly progressive disease characterized by 30% increase of mortality rate for cardiovascular disease, respiratory complications and malignancies. The estimated prevalence of the disease is 40 cases/1000000 population with 3-4 new cases/1000000 population per year. The biochemical diagnosis is based upon the demonstration of high circulating levels of GH and IGF-I. A random GH level lower than 0.4 microg/l and an IGF-I value in the age- and sex-matched normal range makes the diagnosis of acromegaly unlikely. In doubtful cases, the lack of GH suppressibility below 1 microg/l (0.3 microg/l according to recent reports) after an oral glucose load will confirm the diagnosis. A pituitary adenoma is demonstrated in most cases by CT scan or MRI. A negative X-ray finding or the presence of empty sella do not exclude the diagnosis. Cardiovascular complications (acromegalic cardiomyopathy and arterial hypertension) should be looked for and, if present, followed-up by echocardiography and 24h-electrocardiogram. Sleep apnoea, when clinically suspicious, should be confirmed by polisomnography. At the moment of diagnosis all patients should undergo colonscopy. Lipid profile should be obtained and glucose tolerance evaluated. Surgery, radiotherapy and medical treatment represent the therapeutic options for acromegaly. The outcome of transsphenoidal surgery is far better for microadenomas (80-90%) than for macroadenomas (less than 50%), which unluckily represent more than 70% of all GH-secreting pituitary tumours. Therefore, pituitary surgery is the first line treatment for microadenomas. Medical therapy is based on GH-lowering drugs (somatostatin receptor agonists and, in some cases, dopaminergic agents) and GH receptor antagonists (pegvisomant). The former are traditionally indicated after unsuccessful surgery and while awaiting the effectiveness of radiation therapy. However, GH-lowering drugs are also used as primary therapy when surgery is contraindicated or in the case of large GH-secreting macroadenomas which are not likely to be completely removed by surgery. These compounds may also be indicated in the preoperative management of some acromegalic patients in order to lower the risk of surgical and anaesthetic complications. For the moment pegvisomant is indicated for patients resistant to the GH-lowering drugs and there is no evidence for drug-induced enlargement of the pituitary tumour. In order to avoid this possibility, however, a combination of pegvisomant and GH-lowering compound can also be conceived. With pegvisomant, IGF-I plasma levels are the marker of therapeutic efficacy and normalize in 97% of patients. Radiotherapy is employed sparingly due to the number of side effects (80% of hypopituitarism). It is indicated after unsuccessful surgical and/or medical treatment and allows the control of hormonal secretion and tumour growth in approx. 40% and 100% of cases, respectively. Acromegaly is defined as controlled when, in the absence of clinical activity, IGF-I levels are in the age- and sex-matched normal range and GH is normally suppressible by the oral glucose load.

Acromegaly↗