Long-acting Somatostatin Analogue Octreotide Research Articles

The effectiveness of acromegaly treatment according to the Registry of patients with pituitary tumors in the Republic of Tatarstan

Background: Acromegaly is a severe progressive neuroendocrine disease caused by chronic elevated concentrations of growth hormone and insulin-like growth factor 1 in individuals with completed physiological growth and leading to early disability and mortality. The Acromegaly Registry with its regular updates makes it possible to merge and systematize all the available information on the diseases, to assess the efficacy of treatment algorithms and to choose an optimal diagnostic and treatment strategy in a given territory.Aim: To evaluate the efficacy of various treatments for acromegaly based on the analysis of the regional Registry of patients with pituitary tumors in the Republic of Tatarstan.Materials and methods: The study was based on data from 217 patients with somatotropin producing pituitary adenomas entered in the Registry of patients with pituitary tumors in the Republic of Tatarstan as per January 2021. One hundred and eighty one (181 patients) with sufficient data to assess the remission rates and the disease course were included into the analysis.Results: Endonasal endoscopic adenomectomy as a first-line treatment has been performed in 93% (169/181) of the patients, with 34% of the cases (57/169) being in the full postoperative remission. The efficacy of surgical treatment depended on the tumor size, invasion grade and aggressiveness. A 1st generation long-acting somatostatin analog (octreotide) has been prescribed to 50% (91/181) of the patients (11 patients as first-line therapy and 80 patients after adenomectomy), with biochemical remission rate of 56% (51/91). Radiological treatment has been completed in 11,6% (21/181) of the patients. The complete remission rate after all treatment modalities (surgical, medical, and radiation therapy) was 60% (108/181).Conclusion: The effectiveness of treatment for acromegaly in the Republic of Tatarstan is comparable to that in the all-Russian and international registries. Nevertheless, 40% of the patients with acromegaly in the region do not have their disease biochemically controlled indicating the need to optimize drug treatment.

Clinical characteristics and management of growth hormone excess in patients with McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a sporadic, postzygotic disease presenting with fibrous dysplasia, cafe-au-lait spots and multiple endocrinopathies. Growth hormone (GH) excess is an uncommon but potentially severe complication of MAS. This study aims to describe the clinical manifestations of GH excess in the context of MAS and analyze the responses of these patients to treatments. Retrospective clinical study. Clinical data from 52 MAS patients were analyzed. Serum GH and IGF1 levels, as well as nadir GH levels after an oral glucose tolerance test and alkaline phosphatase (ALP) levels were determined before and after the treatment. In total, 13 MAS patients (25%) had the complication of GH excess, including 10 males (76.9%). Among them, all had FD, and 6 patients had sphenoidal bone involvement. Visual deficits were present in 8 patients, and hearing deficits were present in 5. Olfactory dysfunction was observed in 3 patients. Evident pituitary adenomas were confirmed in 9 patients by MRI. These patients underwent surgery with or without pretreatment of long-acting somatostatin analogue octreotide, and 6 achieved complete remission. The serum ALP levels decreased significantly after treatment for GH excess. MAS with GH excess is more common in male patients. GH excess can lead to more severe skeletal lesions in MAS patients involving more of the craniofacial bones. Complete trans-sphenoidal complete tumor excision with neuronavigational guidance is effective and could lower ALP levels. LAR is recommended as a preoperative treatment and when patients fail to achieve complete remission after surgery.

Experience with the long-acting somatostatin analogue Octreotide in the treatment of castrate-resistant prostate cancer

Experience with the long-acting somatostatin analogue Octreotide in the treatment of castrate-resistant prostate cancer

Transsphenoidal endoscopic surgery for acromegaly: a clinical analysis of 210 cases

Objective To investigate the efficacy of transsphenoidal endoscopic surgery for acromegaly. Methods The clinical data of 210 consecutive patients with acromegaly operated with transsphenoidal endoscopic surgery from January 2007 to January 2014 were analyzed retrospectively. The patients with preoperative higher surgical risk used long-acting somatostatin analogue octreotide. Surgery was conducted in combination with intraoperative high field magnetic vesonance imaging and neuronavigation, postoperative head MRI and endocrine were followed up, including biochemical indicators, such as growth hormone and insulin-like growth factor-1. The patients with residual tumor and without remission of endocrine chose octreotide or radiosurgery according to the specific situation. Results There were 129 males and 81 females, their age ranged from 21 to 67 years old (mean 40.7 years). Preoperative MRI revealed that the maximum diameter of the tumors in 183 patients (87.1%) was >1 cm. Three patients were treated with octreotid before procedure. The tumors of 171 patients (81.4%) were resected completely, 22 (10.5%) were resected subtotally, and 17 (8.1%) were resected partially. There were no procedure-related deaths in this group. Postoperative achieved endocrine remission in 148 cases (70.5%). The average growth hormone level before procedure was decreased from 27 ng/mL (range 4 to 150 ng/mL) to 5 ng/mL (range 0 to 32 ng/mL) after procedure. A total of 184 patients were follow-up for 3 to 84 months (mean 27.5 months). During the follow-up period, the subjective symptoms of 161 patients (87.5%) were improved and returned to the daily work and study. In patients who had residual tumors and did not achieve endocrine remission after procedure, 34 were treated with octreotide after procedure and 29 accepted radiosurgery. Conclusion Transsphenoidal endoscopic surgery is the preferred treatment option for acromegaly. Patients should regularly examine the head MRI and endocrine after procedure. The treatments of octreotide and radiosurgery may control the residual tumors and improve endocrine. Key words: Pituitary neoplasms; Acromegaly; Endoscopic; Neurosurgical procedures

S-1/gemcitabine療法に加え持続性オクトレオチドの併用投与を施行した高度肝転移をともなう膵神経内分泌癌の1例

S-1/gemcitabine療法に加え持続性オクトレオチドの併用投与を施行した高度肝転移をともなう膵神経内分泌癌の1例

Successful treatment of protein-losing enteropathy due to AA amyloidosis with octreotide in a patient with rheumatoid arthritis

Protein-losing enteropathy (PLE) is a rare syndrome of gastrointestinal protein loss that may complicate a variety of diseases. This excessive protein loss across the gut epithelium can be explained by several mechanisms, such as augmentation of the intestinal mucosal capillary permeability, mucosal disruption, intestinal or mesenteric vasculitis, and lymphangiectasia. However, these pathophysiologic alterations of the gut are closely linked to the underlying cause, and primary treatment for PLE should be directed at the underlying condition. Here, we report a female patient with rheumatoid arthritis who developed severe PLE due to AA amyloidosis and was successfully treated with octreotide. She had been suffered from rheumatoid arthritis for 18 years, and her arthritic symptoms at the time of presentation were not definite but manifested as severe diarrhea and general edema with hypoalbuminemia. PLE due to gastrointestinal amyloidosis was confirmed by increased fecal α1-antitrypsin clearance and a colonoscopic biopsy that was positive for amyloid deposits. The diarrhea dissipated with conventional treatment, but the general edema resolved only after introducing a long-acting somatostatin analog (octreotide), along with a gradual recovery of the serum albumin level. This case teaches us that in the case of PLE due to AA amyloidosis that is refractory to conventional treatment, the administration of octreotide should be considered.

Meta-Analysis on the Effects of Octreotide on Tumor Mass in Acromegaly

BackgroundThe long-acting somatostatin analogue octreotide is used either as an adjuvant or primary therapy to lower growth hormone (GH) levels in patients with acromegaly and may also induce pituitary tumor shrinkage.ObjectiveWe performed a meta-analysis to accurately assess the effect of octreotide on pituitary tumor shrinkage.Data SourcesA computerized Medline and Embase search was undertaken to identify potentially eligible studies.Study Eligibility CriteriaEligibility criteria included treatment with octreotide, availability of numerical metrics on tumor shrinkage and clear definition of a clinically relevant reduction in tumor size. Primary endpoints included the proportion of patients with tumor shrinkage and mean percentage reduction in tumor volume.Data Extraction and AnalysisThe electronic search identified 2202 articles. Of these, 41 studies fulfilling the eligibility criteria were selected for data extraction and analysis. In total, 1685 patients were included, ranging from 6 to 189 patients per trial. For the analysis of the effect of octreotide on pituitary tumor shrinkage a random effect model was used to account for differences in both effect size and sampling error.ResultsOctreotide was shown to induce tumor shrinkage in 53.0% [95% CI: 45.0%–61.0%] of treated patients. In patients treated with the LAR formulation of octreotide, this increased to 66.0%, [95% CI: 57.0%–74.0%). In the nine studies in which tumor shrinkage was quantified, the overall weighted mean percentage reduction in tumor size was 37.4% [95% CI: 22.4%–52.4%], rising to 50.6% [95% CI: 42.7%–58.4%] with octreotide LAR.LimitationsMost trials examined were open-label and had no control group.ConclusionsOctreotide LAR induces clinically relevant tumor shrinkage in more than half of patients with acromegaly.

Non tumoral hyperserotoninaemia responsive to octreotide due to dual polymorphism in UGT1A1 and UGT1A6

Gilbert's syndrome is a common inherited metabolic disorder, caused by genetic aberration in the enzyme UDP-glucuronosyl-transferase 1A1 that leads to reduced glucuronidation of bilirubin. Recent advances in molecular genetics have frequently reported the concurrence of dual genetic polymorphisms in UDP glucuronosyl-transferases 1A6 and 1A1 in patients with Gilbert's syndrome, leading to defective glucuronidation of bilirubin, as well as several other endogenous and exogenous substrates, such as serotonin. We present a case of Gilbert's syndrome with severe persistent hyperserotoninaemia, mimicking carcinoid syndrome, due to dual polymorphisms in UDP-glucuronosyl-transferases 1A1 and 1A6. The patient was treated with a long-acting somatostatin analogue (octreotide) for 8 months, resulting in a significant reduction in serum serotonin levels and immediate relief of the symptomatology, followed by a long-term remission. The frequent occurrence of hyperserotoninaemia in Gilbert's syndrome may contribute, at least partly, to the nonspecific symptomatology commonly seen in these patients and should be promptly evaluated.

Acromegaly with Diabetes Insipidus after Pituitary Tumor Removal: Successful Pregnancy and Delivery

A 33-year-old woman visited our hospital because of oligomenorrhea. Acromegaly was diagnosed based on elevated insulin like growth factor-I (IGF-I) and paradoxical growth hormone (GH) rise in oral glucose tolerance test. Pituitary macroadenoma was detected on magnetic resonance imaging (MRI). The pituitary tumor was removed. Still, diabetes insipidus developed. We prescribed desmopressin and bromocriptine. Two months post-surgery, IGF-I was decreased and a combined pituitary function test was normal, except for the follicle stimulating hormone response. Residual tumor was detected on MRI. The bromocriptine dose was increased and treatment with the long-acting somatostatin analogue octreotide long acting release (LAR) was begun. After the fifth round of octreotide LAR, IGF-I was normalized. After the seventh round of octreotide LAR, the patient became pregnant. Bromocriptine and octreotide LAR were stopped, and desmopressin was continued. Successful delivery occurred at week 38 of pregnancy. The patient was discharged without any complications. Acromegaly is a disease caused by chronic GH hypersecretion, generally related to a somatotroph adenoma. Amenorrhea and menstrual irregularities are common in acromegaly. Pregnancy rarely occurs because chronic anovulation usually exists. When gonadotroph axis was preserved, the possibility of pregnancy in a woman of child-bearing age with acromegaly should be considered. (J Korean Endocr Soc

Effectiveness of self- or partner-administration of an extended-release aqueous-gel formulation of lanreotide in lanreotide-naïve patients with acromegaly

Surgical resection is often not curative in patients with acromegaly and long-acting somatostatin analogues (lanreotide or octreotide) are often needed. This study assessed the efficacy and safety of self- or partner-administration of lanreotide in patients with acromegaly. This was a six-month, single-arm, open-label study conducted at 13 endocrinology clinics. Fifty-nine patients received deep subcutaneous lanreotide injections every 28 days. Twelve patients started on 120 mg lanreotide and forty-seven started on 90 mg lanreotide. At week 16, the dose was adjusted to 60, 90 or 120 mg based on insulin-like growth factor-1 (IGF-1) levels at week 12. Fifty-nine patients with acromegaly either switched from long-acting octreotide (switch; n = 33) or were somatostatin analogue treatment-naïve or not currently taking long-acting octreotide (“other”; n = 26). The key endpoints included the percentage of patients/partners able to self- or partner-inject lanreotide and those with normal IGF-1 or growth hormone (GH) levels at week 24/early termination. 100% of patients/partners correctly self- (n = 41) or partner-injected (n = 18) lanreotide by week 4. By week 24/early termination, IGF-1 levels were controlled in 93.7% of switch and 46.2% of “other” patients, while GH levels were controlled in 76.9% and 39.1% of patients, respectively. Both IGF-1 and GH were controlled in 73.1% of switch and 30.4% of “other” patients. Most switch patients (81%) reported they preferred lanreotide over long-acting octreotide for future use (P = 0.0001). Self- or partner-administration of lanreotide is generally well tolerated and associated with IGF-1 and GH control in many lanreotide-naïve patients with acromegaly.

Refractory neuroendocrine tumor—response to liposomal doxorubicin and capecitabine

A 61-year-old patient with no relevant medical or family history presented with a 2 month history of refractory dry cough that led to the diagnosis of typical carcinoid tumor of the lung metastatic to the mediastinal lymph nodes and liver. She initially received a long-acting somatostatin analog (octreotide) and chemotherapy with cisplatin and etoposide, which was ineffective. Physical examination, laboratory test, chromogranin A test, CT scan, (111)In-diethylenetriaminepentaacetic acid (DTPA)-octreotide scan, (18)F-FDG-PET scan, fine-needle and tissue core liver biopsies. Pulmonary spindle-cell carcinoid tumor with metastases to mediastinal lymph nodes and liver. Systemic treatment with oral capecitabine (1,500 mg/m(2) daily from day 1 to day 21) and intravenous liposomal doxorubicin (10 mg/m(2) on days 1, 8 and 15), both repeated every 4 weeks, administered concomitantly with long-acting octreotide 30 mg every 3 weeks. The patient achieved a significant and long-lasting response with the combination of capecitabine and liposomal doxorubicin. She reported no severe adverse effects.

Somatostatin receptors: clinical implications for endocrinology and oncology.

Somatostatin receptors are present on most hormone-secreting tumours. They are the pathophysiological basis for the successful control of hormonal hypersecretion by pituitary adenomas, metastatic islet cell tumours and carcinoids during treatment with the long-acting somatostatin analogue octreotide. There is also evidence for inhibition of tumour growth in some of these patients. Visualization of somatostatin receptor-positive tumours is possible in vivo after the administration of ([111In]diethylenetriaminepentaacetic acid)octreotide. Primary tumours are detected and often metastases that were previously unrecognized. Tumours that secrete growth hormone or thyroid-stimulating hormone and non-functioning pituitary adenomas, islet cell tumours, carcinoids, paragangliomas, phaeochromocytomas, medullary thyroid carcinomas and small-cell lung cancers are visualized in 70-100% of cases. Meningiomas, renal cell cancers, breast cancers and malignant lymphomas are often somatostatin receptor positive, allowing their localization with this scanning procedure. In some of these tumours discrepancies have been noted between binding studies with somatostatin-14, somatostatin-28 and octreotide, which suggests the presence of somatostatin receptor subtypes on some tumours. Most hormone-secreting tumours react in vitro to octreotide with an inhibition of hormone release and growth. Cultured meningioma cells react to octreotide with a stimulation in growth, possibly by interference with the autocrine inhibitory growth control by interleukin 6. This suggests that the presence of somatostatin receptors on human tumours does not automatically imply a beneficial effect of somatostatin analogue therapy.

Pituitary tumor enlargement in two patients with acromegaly during pegvisomant therapy

Several classes of pharmacological agents are approved for the medical therapy of acromegaly, including dopamine agonists, somatostatin analogs and a growth hormone receptor antagonist. Pegvisomant, a growth hormone receptor antagonist, suppresses IGF-1 levels into the normal range in over ninety percent of patients. However, increased tumor volume was reported in patients receiving pegvisomant who had not received prior radiotherapy. To describe two patients with acromegaly who developed significant tumor enlargement on pegvisomant and discuss the potential mechanisms involved. Both patients received long-acting somatostatin analog (octreotide) therapy subsequent to incomplete transsphenoidal tumor resection. Octreotide did not normalize GH/IGF-1 levels in either patient but did control tumor mass size. Pegvisomant therapy was initiated after discontinuing octreotide. Both patients exhibited suppression of IGF-1 into the normal range during pegvisomant therapy. However, significant tumor enlargement occurred in both. Potential mechanisms for tumor enlargement include the natural tendency of the tumor to grow with time, discontinuation of tumor suppressive effects of the somatostatin analog, or a direct effect of pegvisomant. The presumed mechanism of tumor enlargement is by loss of the inhibitory effect on tumor growth when IGF-1 levels are reduced. This could also explain the increase in circulating GH levels in patients with acromegaly receiving pegvisomant; patient 1 demonstrated an 18-fold increase in circulating GH levels while receiving the drug. The mechanisms of tumor enlargement in patients with acromegaly on pegvisomant are likely multifactorial. Patients, especially those who have not received prior radiotherapy, should be closely monitored for tumor enlargement.

A review of the current clinical trials for gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours of the gastroenteropancreatic axis include carcinoid tumours and islet cell tumours of the pancreas (pancreatic endocrine tumours). Standard medical therapies prescribed for these malignancies include long-acting somatostatin analogues (octreotide and lanreotide) for the palliation of hormonal syndromes; cytotoxic agents (streptozocin, dacarbazine, adriamycin and 5-fluorouracil), which are primarily for the management of advanced islet cell tumours; and hepatic artery embolisation or chemoembolisation for the treatment of liver metastases. Clinical research promises to expand this therapeutic armamentarium. Most of the experimental treatments that are being evaluated in human clinical trials fall into the following categories: angiogenesis inhibitors, novel somatostatin analogues, radiolabelled somatostatin analogues, mTOR inhibitors and novel cytotoxic agents. This review summarises the present scope of clinical research in this field.

Drug-induced hepatitis in an acromegalic patient during combined treatment with pegvisomant and octreotide long-acting repeatable attributed to the use of pegvisomant

We report on a patient with acromegaly who developed severe drug-induced hepatitis during combined treatment with the long-acting somatostatin-analog octreotide and the GH receptor antagonist pegvisomant. The hepatic enzyme disturbances normalized after discontinuation of pegvisomant. After rechallenge with monotherapy pegvisomant, however, the hepatic enzyme disturbances reappeared within a few weeks, indicating that most likely pegvisomant alone and not the long-acting somatostatin analog or the combination of these two drugs was responsible for this case of drug-induced hepatitis. Clinicians should be aware of this potential severe adverse drug reaction and therefore frequent control of hepatic enzymes is mandatory during treatment with pegvisomant.

Systematic dose-extension of octreotide LAR: the importance of individual tailoring of treatment in patients with acromegaly.

The depot long-acting somatostatin analogue octreotide LAR (LAR) provides effective and well-tolerated treatment for acromegaly. Despite a 4-weekly recommended injection frequency, prolonged duration of GH suppression has been observed in some patients following treatment with long-acting somatostatin analogues. The aim of our study was to perform a prospective systematic study to determine whether extending the interval between doses of LAR allows maintenance of 'safe' GH in selected patients with acromegaly. Twenty-two patients (15 men, seven women), mean age 58.9 years (35-81 years) with active acromegaly (mGH > 5 mU/l), requiring treatment were selected to receive treatment with LAR. Eleven patients had received previous treatment with both transsphenoidal surgery and radiotherapy, while six had received surgery alone. All patients were commenced on treatment with 20 mg LAR intramuscularly (i.m.) every 4 weeks. Mean GH (mGH) was measured after three consecutive injections immediately prior to the fourth injection. The dose frequency was systematically reduced after every four injections if mGH < 5 mU/l. Once mGH > 5 mU/l, the dose frequency was increased and mGH reassessed. The dosing interval was successfully increased to greater than 4 weeks in 20/22 patients (90.9%). Six of 22 (27.3%) were receiving injections every 8 weeks and 3/22 (13.6%) every 12 weeks. GH and IGF-I were lower on treatment compared with baseline (P < 0.01). There was no difference in individual mGH and IGF-I between the values on 4-weekly dosing and those at final dose frequency. There was no relationship between final dose frequency and either mean GH or IGF-I prior to LAR, patient age, or previous treatment. The percentage suppression following 100 micro g octreotide subcutaneously did not predict subsequent dose frequency of LAR. The drug cost if patients had continued at 4-weekly intervals would be UK pound 187 850, compared with UK pound 101 065 for the individually titrated dose frequency (P < 0.01). This represents a final cost of 53.8% of the 4-weekly injection price. Individual tailoring of LAR administration maintains control of acromegaly, with reduced injection frequency and improved cost-effectiveness.

Chromogranin A as a determinant of midgut carcinoid tumour volume

Neuroendocrine (NE) tumours are characterized by their capacity to synthesize, store and release hormonal products. These substances are stored in neurosecretory vesicles together with chromogranin A (CgA). The concentration of plasma CgA in patients with NE tumours is thought to reflect the degree of NE differentiation, total tumour burden and effect of medical treatment. The aim of this study was to analyse the correlation between tumour weight and plasma CgA levels as well as the influence of treatment with a long-acting somatostatin analogue (octreotide) using nude mice with xenografted human ileal carcinoid tumours. There was a correlation between tumour weight and plasma CgA levels in all animals ( p<0.00001). In octreotide-treated mice, plasma CgA levels were significantly reduced versus untreated animals ( p=0.037). In conclusion, this study demonstrates that plasma CgA levels are closely correlated to tumour burden, and that plasma CgA is well suited for monitoring the clinical course and outcome of treatment in patients with NE tumours.

Doxorubicin and octreotide induce a 40 kDa breakdown product of p53 in human hepatoma and tumoral colon cell lines.

The chemotherapeutic drug doxorubicin and the anti-proliferative long-acting somatostatin analogue octreotide, both used in cancer treatment, have been shown to increase the expression of the p53 tumour suppressor protein. In the present study, we demonstrate by Western-blot analysis that, in addition to the p53 protein, these molecules were able to induce the expression of a shorter protein with an apparent molecular mass of 40 kDa (p40), recognized by antibodies raised against the N-terminus of p53. This induction was present in tumoral and non-tumoral cells and did not depend on the status of the endogenous p53 protein. The p40 protein was significantly induced after 3 h of cell treatment with doxorubicin or octreotide, remained stable until 24 h and was located in the nuclear extract. Using reverse primers corresponding to each exon of the p53 gene, only one transcript was amplified by reverse transcriptase-PCR. This suggested that p40 was issued from a post-translational modification and not from an alternative splicing. This protein was not recognized by the PAb421 antibody, suggesting that it was issued from a cleavage of the p53 C-terminal region (p40deltaC). Furthermore, this cleavage was not dependent on caspase activity. In conclusion, these results support the hypothesis that this post-translational modification plays a significant role in the regulation of multiple p53 signalling pathways. These results also suggest that octreotide, a molecule with different signalling pathways, was able as doxorubicin to generate a p53 breakdown product.

Use of somatostatin receptor ligands in obesity and diabetic complications

Somatostatin (SMS) is a potent inhibitory molecule. It inhibits both exocrine and endocrine secretory functions of the pancreas, suppresses growth hormone secretion and reduces the level of insulin-like growth factor-1. Long-acting somatostatin analogues were currently investigated for potential clinical benefits in two settings: (a) control of hyperinsulinaemia in obesity and (b) control of an excess of pro-angiogenic factors in diabetes-associated retinal complications. In two randomized, controlled trials the long-acting somatostatin analogue octreotide retarded progression of the microvascular complications in pre-proliferative and advanced stages of diabetic retinopathy. Inhibition of the early phase of insulin secretion by use of octreotide in patients with hypothalamic obesity resulted in weight loss and improved quality of life. Efficacy of octreotide correlated to residual β-cell activity prior to the treatment. Obesity and diabetes mellitus are the most common chronic metabolic disorders in the world. The use of somatostatin analogues addressing the various hormonal imbalances of these disorders may provide a novel concept for their pharmacological treatment.

Ventilation threshold as a measure of impaired physical performance in adults with growth hormone excess.

Fatigue is a prominent symptom among patients with GH excess and acromegaly. Identifying the physiological basis of such complaints and obtaining objective measures to quantify their severity remains an ongoing challenge. We investigated whether submaximal measures of aerobic performance can be used to assess GH excess-associated fatigue objectively. To investigate this possibility we examined the relation between physical function and physical capacity in 12 patients with active acromegaly and persistent fatigue before and after 3 and 6 months of treatment with the long-acting somatostatin analogue octreotide (LAR(R)). Heart rate (HR) and rating of perceived exertion (RPE using Borg's 10-point scale) were measured during a 160-metre self-paced walk test (SPW). Maximum oxygen uptake (VO2max) and ventilation threshold (VeT: a measure of work rate when breathlessness develops) were measured during a progressive treadmill test to fatigue or symptom-limited maximum. The Profile Of Mood States questionnaire (POMS) was used to quantify subjective feelings of fatigue and vigour. Morning fasting levels of GH and IGF-I were measured using immunoassay of serum samples. SPW speed at a fast pace of 1.69 +/- 0.18 m/s was achieved with higher than normal HR (112 +/- 15/min; normal = 102) and RPE (2.4 +/- 1.2). Similar to GH-deficient adults, VO2max (22.6 +/- 6.4 ml.kg-1.min-1; normal approximately 30 ml.kg-1.min-1) and VeT (13.1 +/- 2.9 ml.kg-1.min-1; predicted normal approximately 16 ml.kg-1(min-1) were low. However, VeT occurred at a normal fraction of VO2max (VeT/VO2max = 0.58). VeT was significantly increased and plasma IGF-I levels reduced following 3 and 6 months of octreotide LAR(R) treatment. Reduction in circulating IGF-I levels was correlated with improvement in reported vigour (r = 0.85) and VeT (r = 0.65) (P < 0.05). Our findings demonstrate impairment in physical function and physical capacity consistent with the perception of increased fatigue among acromegalic patients. These objective measures of compromised physical function are similar to the changes that we have reported previously in adults with GH deficiency. Taken together, these data suggest that a narrow window for GH/IGF-I levels is required to maintain optimal physical function.