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PubMed2005

Pharmacological options in the treatment of acromegaly.

The last decade has seen two major changes in the management of patients with growth hormone (GH)-secreting pituitary tumors. Firstly, evidence has revealed a common pattern of increased mortality in patients with elevated GH and/or the target growth factor insulin-like growth factor-I (IGF-I). Secondly, the availability of highly specific and selective pharmacological agents to lower GH and/or IGF-I levels has greatly facilitated a more aggressive approach to the treatment of patients with persistently active acromegaly. This review will summarize the current major classes of pharmacotherapeutic agents with special emphasis on their recognized benefits and risks.

Acromegaly↗
PubMed1992

Assessment of gall bladder dynamics, cholecystokinin release and the development of gallstones during octreotide therapy for acromegaly.

The development of gallstones is a well recognized complication of therapy with the long-acting somatostatin analogue, octreotide in patients with acromegaly. A group of nine acromegalic patients was treated with octreotide at doses of 300-600 micrograms daily for 8 months and the changes in fasting and post-prandial cholecystokinin release, and gall bladder motor function (determined by a radiosotopic technique) were assessed at regular intervals. In addition the development of any gallstones was determined by serial ultrasonography. Fasting cholecystokinin levels showed no significant change over 6 months, whereas the post-prandial levels demonstrated a significant decrease (p less than 0.01) during therapy, yet remained significantly higher than fasting levels. Twenty-four hours after commencing therapy gall bladder ejection fraction was decreased by 57 +/- 23 per cent and gall bladder ejection rate decreased by 63 +/- 19 per cent compared to the pretreatment values, whereas after 6 months' therapy a marked reduction in gall bladder ejection fraction (greater than 35 per cent) and gall bladder ejection rate (greater than 40 per cent) persisted in only four of nine patients. Three of these four patients with persistently impaired gall bladder motor function were subsequently shown to have developed either gallstones or biliary sludge during the course of therapy. We conclude that treatment with octreotide is associated with an impaired post-prandial release of cholecystokinin in all acromegalic patients, but gallstones only develop in those patients who, in addition, have evidence of a persistently impaired gall bladder motor response to cholecystokinin.

Acromegaly↗
PubMed2005

[Possibilities of medical treatment in acromegaly].

Active acromegaly deteriorates the quality of life and shortens the life expectancy. Surgery is the first-line therapy in the majority of patients, followed by radiotherapy in unsuccessful cases. The surgery cure rate is only one half in the case of macroadenomas and it takes years before radiotherapy normalizes GH and IGF-I levels. In the interim, medical therapy is necessary. Second-generation dopamine agonists (cabergoline) are successful in about one third of patients, especially in those with lower basal IGF-I levels and with adenomas co-secreting prolactin. Somatostatin analogues octreotide and lanreotide are the gold standard of medical treatment - both are available in a form applicable as once-monthly injections. They successfully control disease activity in the majority of patients and induce tumour shrinkage in part of adenomas. Surgical debunking of macroadenomas improves the results of therapy with somatostatin analogues and it is not necessary to discontinue this therapy before radiotherapy. The potential of higher efficiency represent new analogues, binding not only to somatostatin receptor subtype 2, but also to subtype 5 and "dopastatins" that are able to bind both to the somatostatin and the dopamine D2 receptors. The advent of the GH receptor antagonist pegvisomant provides the possibility to normalise IGF-I in virtually every patient. Combined treatment with somatostatin analogues probably enables reduction from daily to weekly injections.

Acromegaly↗
PubMed1991

Alpha-subunit immunoreactivity in plurihormonal pituitary adenomas of patients with acromegaly.

Twelve plurihormonal pituitary adenomas, removed surgically from 11 of 20 patients with acromegaly, were investigated. The mean age of the 11 patients was 45 yr. Seven patients with eight tumors were men. The tumors were immunostained for all known adenohypophysial hormones by the avidin-biotin-peroxidase complex (ABC) technique. All 12 adenomas were immunoreactive for growth hormone (GH) and alpha-subunit; prolactin (PRL) was detected in five tumors. Stains for the beta-subunits of glycoprotein hormones [thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)] revealed immunopositivity for specific beta-subunits in ten adenomas. The close association between GH and alpha-subunit in pituitary tumors of acromegalic patients remains to be explained.

Acromegaly↗
PubMedDate not supplied

[Pharmacological treatment of acromegaly].

Acromegaly is an endocrine disorder usually due to a growth hormone (GH)-secreting pituitary adenoma. This deforming disease is associated with several metabolic abnormalities and results in an elevated cardiovascular mortality. Pituitary transsesphenoidal surgery has been considered the treatment of choice, however, even in the most experienced hands this procedure succeeds in curing only 50 to 60% of the patients. Therefore, close to 50% of patients require an adjunctive form of treatment such as radiation therapy or the use of diverse medications that modulate GH secretion (somatostatin analogues) or action (GH receptor antagonists). The present review summarizes the clinical experience with these novel medications.

Acromegaly↗
PubMed1991

Insulin-like growth factor binding proteins (IGFBPs) in acromegaly.

Hypersecretion of growth hormone (GH) is the principal feature of acromegaly and is accompanied by an excess of IGF-I production which mediates some of the actions of GH. The activity of IGF-I is modulated by a number of specific binding proteins (IGFBPs) which form complexes with IGF-I in the circulation. In this study, the technique of Western Ligand Blotting followed by 2-dimensional radioactive scanning was employed to investigate the correlations between relative levels of the IGFBPs and the main factors implicated in their regulation: IGF-I, GH and insulin, in a group of acromegalics with varying disease activity. The two glycosylated forms of IGFBP-3 correlated with increased levels of IGF-I (40.5 kD, r = 0.468, p < or = 0.01 and 36.5 kD, r = 0.809, p < or = 0.001), but did not relate to mean GH levels. Quantification of IGFBP-2 on the ligand blot showed an association with RIA levels of IGFBP-1 (r = 0.35, p < or = 0.05). IGFBP-1 RIA levels did not relate to the radioactivity in the assumed IGFBP-1 region of the ligand blot. This may be explained by fragments of IGFBP-3 running in this region and could account for the correlation seen between radioactivity in the 29 kD band with both forms of IGFBP-3 as well as with IGFBP-4. IGFBP-3 levels were normal in biochemically cured acromegalics with normal GH levels, although fasting insulin levels remained higher than normal (mean 16 +/- 4 vs normal 7.4 +/- 0.4 mU/L).(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1991

[Active acromegaly and gigantism: some clinical characteristics of 50 patients].

50 patients with autonomous growth hormone excess (48 with adult acromegaly and 2 with gigantism) were studied between 1966 to 1986 (2.38 pts/year). Characteristic clinical presentation, an increase in growth hormone (GH) uninhibited by glucose, and/or hyperphosphemia and hyperhydroxiprolinuria were present in all patients. No cases of hypercalcemia were recorded. Phosphemia was increased in 55.8%, alkaline phosphatases in 61.7%, calciuria in 26.9% and hydroxyprolinuria in 74.2% of the patients. Basal GH was over 5 ng/ml (89.9 DS +/- 170.9) in 42 pts, and in 37 was not suppressed after glucose administration, 38% had an increased (paradoxical response) and 62% a flat response (less than 50% change of basal values). TRH test was performed in 14 patients, 8 presented an increase in GH titer. Hyperprolactinemia was seen in 4 of 12 patients in whom this hormone was measured. The size of the sella turcica was increased in 93%, and although the larger sellar size correlated to higher levels of GH, correlation was not significant. 20% of the pts had rheumatological disease, 14% goiter, 12% cardiac disease, 26.5% had diastolic hypertension and 4% renal lithiasis (hypercalciuric pts). 38% had hyperglycemia with a diabetic glucose tolerance test and 18% had non-diabetic abnormal glucose tolerance test.

Acromegaly↗
PubMed1991

Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group.

BACKGROUND: We wanted to determine the clinical and biochemical effects of long-term therapy with the somatostatin analog octreotide in 189 acromegalic patients. METHODS: Patients were treated at 23 medical centers for 6 days to 231 weeks (median, 24.2 weeks) with varying octreotide dosages (100 to 1500 micrograms/d; median, 300 micrograms/d). Serum growth hormone and insulin-like growth factor I (IGF-I) concentrations before and at the end of the study were compared, and correlations between the response to treatment with total daily dosage and duration of treatment were sought. RESULTS: The clinical response rate was 88%, irrespective of dosage or treatment duration. Serum growth hormone levels decreased in 172 (94%) of 182 patients and IGF-I levels decreased in 91 (92%) of 99. The mean pretreatment growth hormone level was 39.4 +/- 4.4 micrograms/L and decreased to 12.2 +/- 1.5 micrograms/L. Growth hormone levels decreased to less than 5 micrograms/L in 82 (45%) of 182 patients. The pretreatment IGF-I level was 5.62 +/- 0.41 U/mL and decreased to 2.64 +/- 0.19 U/mL; suppression to 2 U/mL or lower occurred in 46 (46%) of 99 patients. The degree of growth hormone suppression was associated with longer treatment duration but not with the total octreotide dosage per day. In 34 patients studied prospectively, pituitary tumor size decreased by greater than 20% in 15 (44%). Side effects occurred in 37% of patients and were most commonly transient loose alcoholic stools, pain at the injection site, and abdominal discomfort; severity was mild to moderate. Glucose tolerance was unchanged or improved in 52% and declined in 48% of 25 patients evaluated. CONCLUSIONS: Octreotide is an effective treatment for acromegaly that may be used as primary therapy or after surgery and/or pituitary irradiation.

Acromegaly↗
PubMed1991

Upper airflow obstruction and pulmonary function in acromegaly: relationship to disease activity.

Pulmonary function and disease activity were assessed in a large series of patients with acromegaly (19 men and 16 women). Large lungs, defined as a vital capacity greater than 120 per cent of predicted normal occurred in six of 19 males and six of 16 females. Ten of the 12 patients with elevated vital capacity had active disease (growth hormone greater than 5 mU/l during a glucose tolerance test). There was no association with duration of disease. Diffusing capacity was normal overall but DLCO greater than 120 per cent occurred in six of 14 females and one of 18 males. Significant intrathoracic airflow obstruction occurred in eight of 35 patients, six of whom were nonsmokers. Upper (extrathoracic) airflow obstruction was the most common pulmonary function abnormality. A maximal expiratory/inspiratory flow ratio greater than 1.0 at 50 per cent vital capacity occurred in 13 of 18 males and four of 16 female patients, and there was an association with disease activity (17 of 25 subjects with active disease had upper airflow obstruction compared to one of nine in remission; p = 0.01). Nocturnal hypoxaemia occurred in three of 13 patients studied: six of this group had upper airways obstruction. They were all male with elevated growth hormone levels and upper airflow obstruction. In summary, in 35 acromegalics (26 with active disease), large lungs occurred in 12 patients (34 per cent) and upper airflow obstruction in 17 patients (50 per cent). The latter may develop nocturnal hypoxaemia--this was seen in three of six patients with upper airflow obstruction. Upper airways obstruction was more common in males (13 of 18 compared to four of 16 females; p = 0.04) and its presence in males should arouse suspicion of nocturnal hypoxaemia.

Acromegaly↗
PubMed1990

Albright's syndrome with acromegaly and Hashimoto's thyroiditis: report of a case.

The case of a 35-year-old woman with Albright's syndrome, acromegaly and Hashimoto's thyroiditis is presented. She had noted deformity of the left mandible and chest from childhood. She developed persistent galactorrhea and amenorrhea after the delivery of her second child. X ray of the skull, and a head CT, revealed a pituitary tumor and fibrous dysplasia of the left mandible, sphenoid, zygomatic bone and pteryoid plate. Serum GH and PRL levels were markedly elevated. She received recontouring surgery of the left mandible, and a pathological examination confirmed the diagnosis of fibrous dysplasia. Chest X ray also showed fibrous dysplastic change of the left 4th, 5th, 6th and 7th ribs and left clavicle. Because of poor response to bromocriptine, she received a craniotomy to remove the pituitary macroadenoma. Pathological examination of the tumor revealed an acidophilic tumor. Postoperative radiotherapy was given for residual active tumor. She developed adrenal crisis two months after radiotherapy when she discontinued replacement therapy. The diagnosis of Hashimoto's thyroiditis was arrived at by palpation of the goiter, elevated thyroid antibodies, ultrasound pictures of the thyroid, fine needle aspiration cytology and hypothyroidism. To our knowledge, this is the first report of Albright's syndrome with Hashimoto's thyroiditis. The hypothesis of autoimmune disease is proposed to explain the hypofunction of the endocrine glands associated with Albright's syndrome.

Acromegaly↗
PubMed1991

[Evaluation of myocardial blood flow and cardiac functional change in acromegaly].

We studied 201Tl myocardial scintigraphy and 99mTc-HSA gated blood pool scan to evaluate the influence of growth hormone on myocardial blood flow and hemodynamics in 16 patients with acromegalies. Contraction properties were almost within normal limit, but cardiac output was in high output state, because left ventricular ejection fraction (LVEF), right ventricular ejection fraction (RVEF) and cardiac output were 47.8 +/- 17.1%, 37.3 +/- 14.9%, and 6.4 +/- 1.7 L/min, respectively. Otherwise, 201Tl myocardial images revealed 62.5% no redistributed hypoperfusion, 18.8% redistributed hypoperfusion, 56.3% myocardial hypertrophy and 25.0% left ventricular enlargement. These data suggested the high incidence of acromegalic cardiomyopathy due to primary or secondary growth hormone effect.

Acromegaly↗
PubMed1990

[The McCune-Albright syndrome with hyperthyroidism, acromegaly and hypophosphatemic-hyperphosphaturic rickets].

A girl was described with an unusual combination of McCune-Albright's syndrome (polyostotic fibrotic dysplasia, hyperpigmentations on the skin and precocious puberty) with hyperthyroidism, hypophosphatemic-hyperphosphaturic rickets and acromegaly. Although the pathogenetic mechanism involved in the development of this endocrinopathy in this syndrome is not quite clear, the achieved results, as well as data of other researchers, suggest that the endocrinological disorders in this syndrome are the result of either an increased sensitivity of periphery endocrine organs or/and of an autonomous hyperfunction (similar to multiple endocrine adenomatosis).

Acromegaly↗
PubMed1990

[Increase of circulating levels of thymulin in hyperprolactinemia and acromegaly].

The production of thymulin by the thymic epithelium is under complex control involving the endocrine system. Experimental models have suggested that prolactin (PRL) and growth hormone (GH) participate in this regulation but this has not been documented in humans. Using a bioassay we measured circulating thymulin levels in patients with hyperprolactinemia (n = 21), acromegaly (n = 15), or both (n = 6). Thymulin was elevated in these three groups of patients compared with normal subjects or with patients with pituitary disease but no excess in PRL or GH. Contrasting with observations in control groups, thymulin did not decrease as a function of age in patients. No correlation between thymulin and PRL or GH levels was observed while thymulin and insulin-like growth factor 1 levels were correlated. A new radioimmunoassay used in some patients for thymulin determination yielded similar results. Overall these data demonstrate that PRL and GH are involved in the hormonal control of thymulin production by the thymic epithelium in the human.

Acromegaly↗
PubMed1990

Long-term treatment of acromegaly with a long-acting analogue of somatostatin, octreotide.

We have treated 16 acromegalic patients for up to 44 months with octreotide in varying doses. Growth hormone levels were suppressed in 14 patients with associated clinical improvement. IGF-1 levels were measured in 12 and fell into the normal range in 10. Prolactin was suppressed in six hyperprolactinaemic patients but was unaltered in normoprolactinaemic acromegalic patients. Post-prandial hyperglycaemia with impaired insulin secretion was noted in all patients, and one patient required oral hypoglycaemic agents. Octreotide did not affect thyroid function. CT scans from before and after six months of treatment demonstrated minimal tumour shrinkage in only two patients. Octreotide was well tolerated with no serious haematological or biochemical disturbance and no evidence of malabsorption. Two patients developed gallstones. Octreotide is effective in acromegaly. The development of gallstones is the only serious adverse event we have encountered.

Acromegaly↗
PubMedDate not supplied

[Morphologic and functional evaluation of the left ventricle in patients with acromegaly. An echocardiographic study].

The aim of our study is to detect morphological and functional aspects of left ventricle with noninvasive M-B-Mode echocardiography in acromegalic patients (pz) with and without high blood pressure. We studied 19 acromegalic pz (group A) and 19 normal pz (group N). All subjects were evaluated for the following parameters: left ventricular mass index (MI); end diastolic volume index (EDVI); end systolic volume index (ESVI); ejection fraction (EF); end systolic stress (ESS). Group A vs group N shows an increase of cardiac mass (p less than 0.01), of EDVI (p less than 0.05) and of ESS (p less than 0.05). We found the asymmetrical septal hypertrophy, considered from other Authors one of the more evident markers of acromegaly, in only one patient. In conclusion, the acromegalic pz show an increase of cardiac mass and preload and a reduced capacity of adaptation to afterload variation independently of blood pressure values and of the duration of disease, even if they have normal indexes of global systolic function.

Acromegaly↗
PubMed1990

Insulin secretion and sensitivity in acromegaly.

To examine the effect of excess growth hormones on carbohydrate metabolism, we studied glucose-stimulated insulin secretion and glucose utilization in 6 patients with acromegaly and 6 age-, sex- and weight-matched normal subjects. The levels of plasma glucose and serum insulin were determined during fasting and every 30 min up to 180 min after 75 g of oral glucose loading. In addition, plasma glucose, serum insulin and serum C-peptide were measured during euglycemic glucose clamp with insulin infusion of 40 mU/m2,min-1. The acromegalic patients had significantly higher mean levels of fasting plasma glucose (p less than 0.05) and insulin (p less than 0.01). After glucose loading for 3 h, the acromegalic patients also had a higher incremental area under the curve of plasma glucose (p less than 0.05) and serum insulin (p less than 0.05). However, no significant difference in the fasting molar ratio of C-peptide/IRI was noted between these two groups. During euglycemic clamp studies, the steady-state serum insulin levels were identical between the two groups. The glucose disposal rate was lower in acromegalics than in normal subjects (p less than 0.01). The results demonstrated that glucose intolerance, hyperinsulinemia and insulin resistance are present in acromegalic patients.

Acromegaly↗
PubMed1990

Is the endogenous digitalis-like factor the link between hypertension and metabolic disorders as diabetes mellitus, obesity and acromegaly?

Endogenous factors cross-reacting with antidigoxin antibodies have been found in several tissues and body fluids of animals and humans, using commercially available digoxin radioimmunoassay or enzyme immunoassay methods. The chemical characteristics of these endogenous factors are, at present, unknown, although it has been suggested that they could be substances with low molecular weight. Experimental studies and theoretical considerations indicate that endogenous digitalis-like factors (DDLFs), in addition to the ability to react with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K(+)-ATPase (sodium pump). Therefore, EDLF can be an endogenous modulator of the membrane sodium-potassium pump and several authors have suggested that EDLF could play a role in the regulation of fluids and electrolytes, muscular tone of myocardial and also in the pathogenesis of arterial hypertension. In this review, the authors discuss the hypothesis that, in metabolic diseases such as diabetes mellitus, obesity and acromegaly, the sodium retention and volume expansion, possibly due to exaggerated sodium intake, and/or exogenously induced peripheral hyperinsulinemia and high levels of growth hormone, could trigger a sustained release of EDLF, which in turn increases the blood pressure.

Acromegaly↗
PubMed1990

[Calcium-phosphorus metabolism and calcitrophic hormones in patients with active acromegaly with and without osteoporosis].

Calcium-phosphor metabolism was studied in patients with active acromegaly with or without osteoporosis, mean age 45.2 +/- 11.4 years and mean duration of the basic disease 5.52 +/- 3.6 years. No significant deviations and no direct relation with the high serum growth hormone and prolactin levels were found. The normal basic secretion of the calcitrophic hormones--parathyroid hormone and calcitonin and their normal response to the hypercalcemia after intravenous calcium load of the patients with and without osteoporosis reject their direct participation in the pathogenesis of osteopenia. The changed skeletal sensitivity to calcitrophic hormones closely connected with the patients' age and the duration of the basic disease in combination with many other factors probably plays a major role in the pathogenesis of osteopenia.

Acromegaly↗