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PubMed1997

Heart valve operation in acromegaly.

BACKGROUND: Intractable congestive heart failure is known as a serious complication of acromegaly, but valvular heart disease rarely occurs in acromegalic patients. We experienced 5 surgical cases of valvular heart disease associated with acromegaly. We describe the features of those cases in this report. METHODS: The patient characteristics and operative and pathologic findings were retrospectively studied. RESULTS: There were 4 men and 1 women. Age at operation was 59 +/- 5.5 years. Cardiac lesions consisted of 1 case of aortic regurgitation associated with mitral regurgitation, 1 of aortic regurgitation, and 3 of mitral regurgitation. Operative procedures consisted of 1 double valve replacement (aortic and mitral valve replacement), 1 aortic valve replacement, and 3 mitral valve replacements. The causes of aortic valvular regurgitation were aortic valvular degeneration and aortic annular dilatation. The causes of mitral regurgitation were chordal rupture and mitral valvular degeneration. Histopathologic examination of the excised valves showed mucopolysaccharide deposits and myxomatous degeneration of the leaflets. The myocardium showed fibrosis of interstitial spaces and endocardium, and disarrangement of muscle fibers. CONCLUSIONS: We report 5 successful surgical cases of valvular heart disease associated with acromegaly. Earlier operation is recommended for such cases because of acromegalic cardiomyopathy.

Acromegaly↗
PubMed1997

LDL subfractions in acromegaly: relation to growth hormone and insulin-like growth factor-I.

Acromegaly is associated with changes in lipoprotein metabolism and an excess in cardiovascular mortality. We have examined low density lipoprotein (LDL) subfraction distribution in 24 patients with active acromegaly and in controls matched for age, sex and body mass index. LDL was subfractionated by density gradient ultracentrifugation. The concentration of small dense LDL-III was significantly higher in the acromegalic patients compared to the controls (94.2 +/- 44.9 versus 67.2 +/- 30.4 mg/dl, P < 0.05) and there was a concomitant reduction in the intermediate subfraction LDL-II (124.8 +/- 31.3 versus 149.9 +/- 30.0 mg/dl, P < 0.05). Univariate analysis showed that both growth hormone (GH) and insulin-like growth factor (IGF)-I correlated with LDL-III and inversely with LDL-II. Acromegalic patients were found to have lower hepatic lipase (HL) and lipoprotein lipase (LPL) activities than controls (HL: 13.29 +/- 6.56 versus 21.58 +/- 7.27 micromol FFA released/ml/h, P < 0.001: LPL: 7.22 +/- 3.04 versus 11.53 +/- 7.85 micromol FFA released/ml/h, P < 0.05) whereas plasma cholesteryl ester transfer protein (CETP) activity was significantly increased (8.15 +/- 1.81 versus 5.54 +/- 1.86 pmol/microl/h, P < 0.001). Both GH and IGF-I were significantly associated with HL, LPL and CETP activities. Multivariate analysis on this relatively small sample size showed that in normal subjects, triglyceride and HL activity were the major determinants of LDL-III. In contrast, GH and HDL were the main determinants in acromegaly, accounting for 32 and 24% in the variability of LDL-III respectively. In conclusion, GH excess has a direct effect on LDL subfraction distribution.

Acromegaly↗
PubMed1996

Treatment options for acromegaly.

Treatment options for acromegaly include surgical removal of the adenoma, radiotherapy, or pharmacological reduction of growth hormone (GH) levels by dopamine agonists or somatostatin analogs. Whether such treatment can truly cure acromegaly is debatable. A problem with evaluating efficacy of treatment is the lack of consensus of what constitutes a cure. Despite modern neurosurgical techniques for resecting GH-secreting pituitary adenomas, more than 50% of patients may have persistent GH hypersecretion; radiotherapy may take years to produce an effect. There is thus interest in pharmacological relief of symptoms and reduction in GH secretion. We report on eight patients with a biochemical diagnosis of acromegaly (failure of suppression of GH levels to < 2.5 micrograms/L following a glucose tolerance test [GTT]). The use of Sandostatin-LAR (Sandoz Pharma Ltd, Basel, Switzerland) in doses of 20 to 30 mg intramuscularly at 4 week intervals produced consistent and therapeutic serum octreotide concentrations, suppressed GH secretion to 5 micrograms/L in all eight subjects, lowered insulin-like growth factor-1 (IGF-1) levels in all and normalized values in seven of eight, improved or led to disappearance of symptoms and signs, and was not associated with an increase in adverse events as compared with subcutaneous treatment.

Acromegaly↗
PubMed1996

Acromegaly--the place of the neurosurgeon.

Over 12 years, we performed 498 operations for growth hormone (GH)-secreting pituitary adenomas (489 in acromegaly and nine for gigantism), with 479 by the trans-sphenoidal and 19 by the transcranial route. A consecutive series of 224 patients had an overall cure rate of 56%, with normalization in 71% when the criterion was only basal GH. Endocrine remission occurred in 72% of microadenomas, 50% of macroadenomas, and only 17% of giant adenomas. Seventy-three percent of the patients with preoperative GH levels less than 10 ng/mL were cured, but only 33% with GH greater than 100 ng/mL. Our cure rate for invasive adenomas was 38%. Surgical reexploration can lead to a 50% cure rate. Overall morbidity was low. Pretreatment of large adenomas with octreotide may soften them and facilitate their removal, and one third shrink. It also relieves the symptoms of acromegaly and improves the patient's general condition for surgery. Octreotide as first-line therapy is indicated in patients with risk factors for surgery, and it is becoming an alternative to radiotherapy after surgery. It is more potent than dopamine agonists in lowering GH levels. We recommend postoperative radiotherapy (+/- octreotide) if GH levels are fairly high after surgery or if the adenoma shows major invasiveness. Surgery is still the initial therapy of choice in acromegaly due to its high cure rate and low morbidity.

Acromegaly↗
PubMed2001

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.

BACKGROUND: Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS: Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS: Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION: Pegvisomant is an effective medical treatment for acromegaly.

Acromegaly↗
PubMedDate not supplied

Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly.

Pegvisomant monotherapy once daily returns concentrations of insulin-like growth factor I (IGF-I) to normal in most patients with acromegaly, but is very costly. In a 42-week dose-finding study, we assessed the efficacy of the combination of long-acting somatostatin analogues once monthly and pegvisomant once weekly in 26 patients with active acromegaly. Dose of pegvisomant was increased until IGF-I concentration became normal or until a weekly dose of 80 mg was reached. IGF-I reached normal concentrations in 18 of 19 (95%) patients who completed 42 weeks of treatment, with a median weekly dose of 60 mg pegvisomant (range 40-80). No signs of pituitary tumour growth were noted, but mild increases in liver enzymes were observed in ten patients (38%). This combined treatment is effective, might increase compliance, and could greatly reduce the costs of medical treatment for acromegaly in some patients.

Acromegaly↗
PubMed1997

Stimulatory and inhibitory effects of neuropeptide Y on growth hormone secretion in acromegaly in vivo.

It has been reported that neuropeptide Y (NPY) affects growth hormone (GH) secretion in several animal species. With respect to the role of NPY in regulating GH release in humans, one previous study has reported that NPY inhibited GH secretion from cultured GH-secreting pituitary adenoma cells in vitro. However, since it has yet to be explored whether NPY affects GH secretion in acromegaly in vivo, in this study we attempted to examine the effect of intravenous (i.v.) bolus injection of 100 microg of human NPY on plasma GH levels in 15 patients with active acromegaly, trying to find a possible correlation among GH responses to NPY, thyrotropin-releasing hormone (TRH;500 microg, i.v.), luteinizing hormone-releasing hormone (LHRH;100 microg, i.v.), and bromocriptine (Br;2.5 mg, per os). NPY significantly increased GH secretion (more than twice the basal level) in 4 (27%) patients, and all of them were responsive to LHRH and non-responsive to Br. In contrast, 3 (20%) acromegalics showed a significant decrease in GH levels (less than half the baseline) after NPY, and all these patients were responsive to both TRH and Br. From these results, we hypothesize that the NPY-induced increase in GH release may be a feature of somatotroph-like pituitary adenoma causing acromegaly, whereas the NPY-induced decrease in GH secretion may be a feature of lactotroph-like adenoma.

Acromegaly↗
PubMed2003

Pegvisomant in the treatment of acromegaly.

Epidemiological studies have highlighted the need for tight control of growth hormone (GH) and insulin-like growth factor I (IGF-I) in patients with acromegaly. Studies highlighting the events involved in GH receptor signaling have allowed the development of a pegylated GH receptor antagonist (pegvisomant) for use in humans, which has been designed to outcompete GH for the GH receptor, but which contains a position 120 amino acid substitution that prevents recruitment of a second GH receptor. This process of receptor dimerisation is crucial for signal transduction and IGF-I generation. Clinical trials of pegvisomant suggest it is the most effective treatment for acromegaly to date, as this therapy is capable of normalising serum IGF-I in up to 97% of patients when doses of 40 mg per day are used. This paper reviews the development of pegvisomant and the clinical experience in patients with acromegaly to date.

Acromegaly↗
PubMedDate not supplied

Usefulness of insulin-like growth factor binding protein-3 levels to determine acromegaly activity and effectiveness of transsphenoidal pituitary surgery.

BACKGROUND: Several series reported in the literature concerning the results of the treatment of acromegaly have been difficult to evaluate because the indicators are inaccurate. METHODS: We investigated the usefulness of insulin-like growth factor binding protein-3 (IGFBP) levels to determine disease activity after surgical treatment of acromegaly in 13 patients with confirmed somatotroph adenoma. RESULTS: Before surgery, all 13 non-treated patients had elevated serum levels of IGFBP-3 as well as total and free IGF-I. In addition, there was no overlap with the normal controls (p < 0.001). IGFBP-3 levels correlated significantly (0.91, p < 0.001) with GH suppressibility by glucose after surgery. CONCLUSIONS: These data confirm that IGFBP-3 is a better indicator of acromegalic activity than either total or free IGF-I. There was a high correlation with GH suppressibility by glucose after surgery; both free and total IGF-I could be considered sensitive markers only for diagnosis of active acromegaly but not for efficacy of surgery.

Acromegaly↗
PubMed1999

Effect of pituitary microsurgery on acromegaly complicated nephrotic syndrome with focal segmental glomerulosclerosis: report of a rare clinical case.

A case of nephrotic syndrome complicated by acromegaly is presented. The first renal biopsy specimen showed minor glomerular abnormalities with glomerular hypertrophy, corresponding with minimal change nephrotic syndrome. Corticosteroid therapy led to a partial remission, followed by frequent relapses after reduction of the drug. A diagnosis of atypical focal segmental glomerulosclerosis (FSGS) was made based on the second renal biopsy results 6 months after the first. We combined steroid therapy with the administration of an anticoagulant, cytotoxic agents, angiotensin-converting enzyme inhibitor, and low-density lipoprotein adsorption. Except for the angiotensin-converting enzyme inhibitor, these medications were not effective in terms of allowing a reduction in the high dosage of steroid, which in turn threatened progressive osteoporosis and lumbar vertebrae fracture. Administering the steroid at a moderate dosage, treatment was focused on the complicating acromegaly from pituitary microadenoma. Subcutaneous injections of octreotide acetate, a somatostatin analogue, reduced proteinuria and increased urine volume. Subsequent transsphenoidal microsurgery of the adenoma resulted in the normalization of the elevated creatinine clearance and the further reduction in steroid dosage while maintaining a remission state. This is the first reported clinical case with acromegaly followed by FSGS, and it is suggested that hypersecretion of growth hormone participates in the development and progression of glomerular disease.

Acromegaly↗
PubMed1991

Somatotropic adenomas without acromegaly.

Seventeen somatotropic adenomas removed from patients without acromegaly were studied. Thirteen of them presented as a prolactinoma with amenorrhea and/or galactorrhea and elevated serum PRL levels. According to basal serum GH levels, the patients were divided into two groups, namely Group I: GH slightly elevated (n = 4) and group II: GH less than or equal to 5 micrograms/l (n = 13). The tumoral GH secretion was proved by immunocytochemistry in all cases and by intratumoral RIA, in vitro study and/or in situ hybridization in five of them. Pathological, clinical and biochemical relationships suggested two anatomoclinical aspects. In group I, the tumors were small, well-differentiated somatotropic adenomas with clinically silent GH hypersecretion. It is probably an early stage of the disease. In group II, the tumors were large with normal GH serum levels. They were poorly differentiated and secreted very low amounts of GH. In nine of them, PRL and/or PRL mRNA expression were also detected. These tumors do not secrete enough GH to increase serum levels and cause acromegaly. The somatotropic adenomas without acromegaly correspond to two anatomoclinical aspects of the disease.

Acromegaly↗
PubMed1989

[Long-term effects of treatment with SMS 201-995 on sleep apnea syndrome associated with acromegaly].

A 60-year-old woman with acromegaly associated with sleep apnea was treated with the somatostatin analogue SMS 201-995 (Sandoz) for several months. Growth hormone levels were normalized and a rapid improvement in sleep apnea was controlled with polygraphic nocturnal monitoring. Hypophysectomy seems to have variable effects on sleep apnea in acromegaly. The origin of obstructive apnea in acromegaly is therefore unclear.

Acromegaly↗
PubMedDate not supplied

Current therapy for acromegaly.

Acromegaly is a disabling disease that is associated with reduced life expectancy. Lowering growth hormone (GH) concentrations rapidly improves patient wellbeing. Recent data also indicate that GH concentrations < 2.5 micrograms l-1 are associated with improved mortality, providing a therapeutic goal in the majority of patients. In most cases, initial therapy should be surgical via the transsphenoidal route and conducted by an experienced operator. In such centres of excellence, approximately 60 out of every 100 acromegalic patients should be 'cured' (GH < 2.5 micrograms l-1) by surgery alone. Effective medical therapies have been introduced in the form of long-acting somatostatin analogues--octreotide and lanreotide--and depot preparations of these drugs result in lowering of GH to < 2.5 micrograms l-1 and normalization of IGF-I concentrations in 55-65% of cases. Preliminary results are also emerging on Pegvisomant, a genetically engineered GH receptor antagonist, which is clinically and biochemically very effective. It is likely that this drug will be licensed for use in patients with acromegaly in the near future. These effective medical therapies will undoubtedly raise the issue of their use as primary therapy for acromegaly but at present they should be used as an adjunct to surgery and/or radiotherapy.

Acromegaly↗
PubMed2001

Clinical use of a growth hormone receptor antagonist in the treatment of acromegaly.

The elucidation of the mechanisms by which growth hormone (GH) interacts with its receptor has facilitated the design of compounds that function as GH-receptor antagonists. One such compound, B2036, has been conjugated to polyethylene glycol to produce a drug, pegvisomant, that has a powerful ability to lower circulating concentrations of insulin-like growth factor I (IGF-I), the principal mediator of GH action, in patients with acromegaly and to improve the symptoms and signs associated with GH excess. This article describes the mechanism of action of GH-receptor antagonists, reviews the preclinical and clinical data on the use of pegvisomant and discusses some of the challenges that lie ahead in judging the efficacy of a treatment that, unlike established therapies for acromegaly, does not aim to modify the underlying cause of acromegaly, namely excess GH secretion, but aims to lower serum IGF-I levels to normal.

Acromegaly↗
PubMed2000

Axial bone mineral density in patients with acromegaly.

RATIONALE AND OBJECTIVES: The purpose of this study was to assess the influence of long-term elevated levels of growth hormone and insulin-like growth factor I on bone mineral density (BMD) of the spine in patients with acromegaly. MATERIALS AND METHODS: The spinal BMD in 40 patients with acromegaly was measured with quantitative computed tomography. The result was expressed as the mean of six measurements of consecutive vertebral bodies and as a z score. Twenty age- and sex-matched healthy persons also underwent spinal BMD measurement and served as controls. RESULTS: In 36 of the 40 patients, the BMD z score ranged within 2 standard deviations (SDs) above or below the mean. Only two patients (one man and one woman) had enhanced BMD loss (below 2 SD). Two other female patients had BMD values of more than 2 SD above the mean. Differences between patient subgroups were not statistically significant, but a statistically significant (P < .05) positive correlation was found between basal serum concentration of growth hormone and spinal BMD for the entire patient group. No correlation between BMD and basal serum concentration of insulin-like growth factor I was found. CONCLUSION: Hypersecretion of growth hormone in patients with acromegaly, regardless of other factors, has no evident effect on BMD of the lumbar spine.

Acromegaly↗
PubMed2000

Assessment of growth hormone status in acromegaly: what biochemical markers to measure and how?

Various studies have evaluated the usefulness of measuring insulin-like growth factor I (IGF-I) and IGF-binding proteins, compared with growth hormone (GH), in the diagnosis and follow-up of patients with acromegaly. The clinical use of recently developed, highly sensitive GH assays has improved our understanding of the secretion of GH at very low concentrations. Studies examining the GH nadir after oral glucose administration in healthy adults suggest that GH values should be suppressed to no more than 0.14 microg/l after oral glucose administration. The highly sensitive GH assays are now being used in the diagnosis of patients with acromegaly and in post-treatment follow-up. In addition, the use of IGF-I immunoassays has confirmed that serum IGF-I level is a reliable and useful biochemical marker for determining GH excess. The widespread use of highly sensitive, carefully validated assays offers accurate and reproducible biochemical information that will help in the overall clinical management of patients with acromegaly, including the monitoring of disease remission, disease cure and treatment titration regimen, as well as the early recognition of patients with residual disease.

Acromegaly↗
PubMed2001

Findings and theoretical considerations on the usefulness of the acid-labile subunit in the monitoring of acromegaly.

Growth hormone (GH) action induces a variety of biochemical factors of which insulin-like growth factor I (IGF-I) is conventionally measured for the diagnosis and monitoring of GH-related disorders such as GH deficiency or acromegaly. IGF-I circulates predominantly as a ternary complex with IGF-binding protein 3 (IGFBP-3) and the acid labile subunit (ALS). In the treatment of active acromegaly with the GH receptor antagonist pegvisomant, ALS showed a closer correlation with the change in ring size, measured as a clinical indicator of disease activity, than did IGF-I or IGFBP-3. ALS thus seems to be a clinically useful marker of disease activity in acromegaly.

Acromegaly↗
PubMed2001

Experience with pegvisomant in the treatment of acromegaly.

Established modalities of therapy for acromegaly (surgical adenomectomy, external beam pituitary irradiation, oral dopamine agonists, and injectable somatostatin analogues) have as their common goal the lowering of circulating growth hormone (GH) levels, with a consequent reduction in serum insulin-like growth factor I (IGF-I). Pegvisomant is a GH receptor antagonist that inhibits GH receptor dimerization and has a powerful ability to lower serum IGF-I levels in patients with active acromegaly. Currently available data suggest that pegvisomant is an effective treatment for acromegaly that is safe, well tolerated, and not associated with expansion of residual pituitary tumour over the time period studied.

Acromegaly↗