Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results.

PURPOSE: Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. METHODS: CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. RESULTS: Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. CONCLUSIONS: OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each. Trial registration NCT03252353 (August 2017), NCT01412424 (August 2011).

Circulating insulin-like growth factor binding protein-3 predicts one-year outcome after ischemic stroke.

BACKGROUND: Insulin-like Growth Factor-1 (IGF-1) and Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) have been ascribed neuroprotective effects. We sought to determine whether levels of IGF-1 and IGFBP-3 predict functional outcome after ischemic stroke. METHODS: IGF-1 and IGFBP-3 levels were measured in the first week after stroke in patients with first ischemic stroke who were enrolled in the Berlin Cream&Sugar Study. National Institutes of Health Stroke Scale (NIHSS) was collected at admission. Lesion volume was determined from acute MRI if available. Functional outcome according to the modified Rankin Scale (mRS) was assessed after one year. In multivariate analyses we identified parameters associated with unfavourable functional outcome (mRS>2). RESULTS: We included 100 patients. 21 patients had an unfavourable functional outcome. IGF-1 levels were<- 2 standard deviation score (SDS) in 7 patients, and>2 SDS in 12 patients. IGFBP-3 levels werethe 95(th) percentile. Low levels of IGFBP-3 (p=0.002), NIHSS at admission (p=0.043) and age (p=0.001) were associated with unfavourable functional outcome in the univariate analyses. In multivariate analysis including IGFBP-3, IGF-1, age, thrombolysis and NIHSS only low IGFBP-3 levels (OR 7.2, 95%CI 1.8-29.0, p=0.006) were associated with unfavourable functional outcome. If lesion volume was incuded (n=71), only IGFBP-3 levels (OR 7.2, 95%CI 1.5-35.5, p=0.015) were associated with unfavourable functional outcome. CONCLUSION: IGFBP-3 levels after ischemic stroke may independently predict functional outcome after one year.

Intraoperative indocyanine green videoangiography for identification of pituitary adenomas using a microscopic transsphenoidal approach.

PURPOSE: Initial successful surgical treatment of pituitary adenomas is crucial to reach long-term remission. Indocyanine green (ICG) videoangiography (VA) is well established in vascular neurosurgery nowadays and several reports described ICG application in brain tumor surgery. We designed this study to evaluate the feasibility of intravenous application of ICG and visualisation of a pituitary lesion via the fluorescence mode of the operation microscope. METHODS: 22 patients with pituitary adenomas were treated with transsphenoidal microsurgery and were included in this study. Intraoperatively 25 mg ICG was administered intravenously and visualized via the fluorescence mode of the operation microscope (Pentero/Zeiss). RESULTS: 22 patients qualified for transsphenoidal surgery presenting with different clinical symptoms (13 patients with acromegaly, 6 with M. Cushing and 3 with other symptoms like vision disorder or dizziness) and identification of a pituitary lesion (21 of 22 patients) in preoperative MR-imaging (mean diameter: 9 mm; SD 3.6; 6 macroadenomas, 15 microadenomas, 1 MR-negative). In all 22 patients ICG VA was performed during surgery. No technical failures or adverse events after drug administration occurred. Visualization was optimal approximately 2.4 min after intravenous application. In all patients the adenoma could be detected via two different types of visualization: direct visualization by fluorophore emission versus indirect detection of the adenoma by a lower ICG fluorescence compared to the surrounding tissue. CONCLUSION: Our data show that intraoperative ICG VA can be a useful and easily applicable additional diagnostic tool for visualization of pituitary lesions using the microscopic approach.

The role of human growth hormone's C-terminal disulfide bridge.

OBJECTIVE: Human growth hormone (hGH), as well as the other members of the same polypeptide hormone family, have a four-helix bundle structure linked by two disulfide bridges, C53-C165 and C182-C189 in hGH. The C-terminal disulfide bridge of growth hormone is evolutionally conserved but its role is unknown. Our aim was to determine its importance for GH structure and/or function. DESIGN: We disrupted the highly conserved C-terminal disulfide bridge of hGH by substituting one or both of its cysteines by alanines. Mutant and wild type hGH genes were expressed in human embryonic kidney (HEK)-293 cells and the hGH analogs were characterized in vitro regarding biological activity, stability and binding to GH receptor (GHR) as well as GH binding protein (GHBP). RESULTS: Disrupting the hGH C-terminal disulfide bridge significantly reduces binding affinity to GHR and GHBP. If one of the cysteines is removed, the stability of the molecule is reduced but this feature is reversed when both cysteines are absent. However, despite decreased binding affinity and stability, biological activity is only modestly decreased when the disulfide bridge is removed. CONCLUSIONS: Our study reveals the importance of the C-terminal disulfide bridge of GH for receptor binding and the detrimental effect of its unpaired cysteines on stability as well as, to a lesser extent, biological activity. This improved knowledge of structure-function relationships helps better understand the biology of GH and related molecules. This could have an impact on diagnosis and treatment of patients with growth disorders.

A consensus on the diagnosis and treatment of acromegaly complications.

In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.

Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression.

CONTEXT: Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. OBJECTIVES: The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. DESIGN: Four single-dose studies were conducted in 75 healthy volunteers. INTERVENTION: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 µg octreotide were administered. MAIN OUTCOME MEASURE: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. RESULTS: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. CONCLUSIONS: The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.

Efficacy and acceptability of lanreotide Autogel® 120 mg at different dose intervals in patients with acromegaly previously treated with octreotide LAR.

OBJECTIVE: To assess the efficacy of different dosing intervals of lanreotide, Somatuline Autogel® (Lan-ATG) 120 mg in patients with acromegaly, previously treated with octreotide, long-acting release (Oct-LAR). PATIENTS AND STUDY DESIGN: Patients previously on Oct-LAR 10, 20, or 30 mg were switched to 6 repeated deep subcutaneous injections of Lan-ATG 120 mg at intervals of 56, 42, or 28 days, respectively. After the third injection, dose intervals were adjusted on the basis of insulin-like growth factor 1 (IGF-1) levels. RESULTS: The ITT (Intention To Treat) population comprised 35 patients who received at least one dose of study medication and at least one post-baseline efficacy assessment. Overall, 62.9% (n=22) of patients had normalised IGF-1 levels with Lan-ATG at study end (one injection interval after the 6 (th) injection of Lan-ATG), which was similar to the proportion at baseline (60.0% [n=21]). QoL did not change from baseline to study end. Patient preference for Lan-ATG was highest in the 56-day dosing interval group: 71%, 54% and 41% of the patients in the 56, 42 and 28 day groups, respectively, expressed a preference for treatment with Lan-ATG (preference for Oct-LAR: 29%, 9% and 35%, respectively, while the remainder had no preference). CONCLUSION: Lan-ATG 120 mg injected at intervals of 56, 42 and 28 days provided equivalent hormonal control and QoL to Oct-LAR 10, 20 and 30 mg injected every 28 days, respectively. The proportion of patients preferring Lan-ATG treatment was greater in the longer injection interval groups.

The German ACROSTUDY: past and present.

Pivotal studies have demonstrated that pharmacotherapy with pegvisomant (Somavert) is a highly effective treatment for acromegaly. Since clinical experience with the drug was very limited, the Pegvisomant Observational Study was launched in Germany immediately with the drug becoming commercially available to patients early in 2004. Its purpose was to record safety and efficacy data on as many patients as possible. As of 12th August 2008 a total of 371 patients (185 males, 186 females) had been included in the study. They were on pegvisomant therapy for an average of 118 weeks. Median and mean doses of pegvisomant were 15 and 16.4 mg/day respectively. Treatment efficacy was monitored by IGF1 levels and the patients symptoms were evaluated by completion of a questionnaire (patient-assessed acromegaly symptom questionnaire). Safety data included liver function tests, fasting glucose, HbA1c measurements, and tumor size monitoring by repeated magnetic resonance imaging. Normalization of IGF1 ranged from 55.7% of the 273 patients assessed after 6 months to 71.3% of 202 patients assessed after 24 months of treatment. It was 70.7% after 36 months (133 patients), 64.8% at 48 months (71 patients), and 58.4% after 60 months (24 patients). In 39 patients (10.9%) treatment was discontinued due to serious adverse events or adverse events with 25 (6.7%) of these patients having a potential causal relationship with the pegvisomant treatment. Liver function tests became abnormal in 20 patients and another three patients were recorded to have hepatobiliary disorders. Tumor size increase was reported in 20 patients, but only confirmed in nine patients by careful revision of all available images. Local injection site reactions were observed in 12 patients. In conclusion, in this large group of pegvisomant-treated patients, long-term data for up to 5 years of treatment are now available. In 71.3% of patients with previously not sufficiently treatable acromegaly, IGF1 levels were normalized by pegvisomant therapy. Elevated transaminases usually normalized after discontinuation but in half of the affected patients also despite continuation of treatment without dose alteration. Tumor progression was a rare event. It did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. As from this presently largest database of acromegalic patients treated with pegvisomant, long-term results are encouraging. The German data are now merged into the global ACROSTUDY and will constitute a major portion of the international ACROSTUDY project as a continuing global web-based observational study.

Pituitary tumor size in acromegaly during pegvisomant treatment: experience from MR re-evaluations of the German Pegvisomant Observational Study.

In treatment-resistant patients with acromegaly, pharmacotherapy with pegvisomant (Somavert) is a highly effective option. However, safety concerns have been raised related to a potential increase in tumor size during long-term pegvisomant treatment. Therefore, neuroradiological monitoring of tumor extension and volume was performed in the German Pegvisomant Observational Study, which covers 87% of patients treated with pegvisomant in Germany. As of 15 July 2007, a total of 307 patients (156 males and 151 females) had been included in the study and were on pegvisomant therapy for an average of 86.7 weeks. Median and mean doses of pegvisomant were 15 and 16.6 mg/day respectively. Out of these 307 patients, 18 were reported to have tumor-size increases as adverse events. From these 18 patients, all available serial magnetic resonance images were collected. Identical or similar sequences were chosen and the region of interest was magnified and compared across time after the best possible fit had been achieved by size and gray-scale correction. All available images were carefully re-evaluated according to this method. In 10 out of the 18 patients, there was no evidence of tumor-size increase, when the pre-treatment scans were compared with the most recent follow-up investigations. In two out of the remaining eight patients, there was a rebound effect observed after withdrawal of somatostatin analog treatment, but no further progression. In another three out of the eight patients, tumor-size increase had already been documented before pegvisomant treatment was commenced, during preceding somatostatin analog treatment and continued therapy. In the last three patients, tumor progression after the start of pegvisomant treatment was confirmed. All three patients had undergone pituitary surgery as primary treatment, but had not been pre-treated with radiotherapy. In all three cases, the tumor increase was not considered clinically significant and the investigators decided to continue pegvisomant treatment. In conclusion, in this large group of pegvisomant-treated patients, tumor progression was rare. It was reported in between 2 and 3% of patients treated, and did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. In over one-half of patients, reports of tumor increase could not be confirmed by re-evaluation. This was mostly due to non-identical gantry projections. Misjudgements mainly occurred when only images from two individual investigations, rather than the entire series of scans, were compared. Thus, we recommend a careful serial evaluation of all available images to avoid misinterpretations and erroneous alerts. As from this presently largest database of acromegalic patients treated with pegvisomant, tumor-growth rate appears not to be different from patients on other treatment modalities. Although these data are reassuring with regard to the concern of somatotroph adenoma growth under peripheral GH receptor blockade, further study is required.

Sex-specific regulation of ENaC and androgen receptor in female rat kidney.

With the beginning of puberty blood pressure increases and is persistently higher in men than in premenopausal women. Sex steroids are known to have complex effects on the renal and cardiovascular system and are involved in blood pressure regulation. The epithelial sodium channel (ENaC) modulates sodium reabsorption in the kidney, but little is known about sex-specific regulation of ENaC subunit expression. Regulation of the androgen receptor (AR) is known to be tissue-specific and age-dependent, but not well studied in the kidney. We investigated the effects of sex steroids on ENaC subunits and renal AR expression in an in vivo rat model. Ovariectomized female Wistar rats were treated with placebo, testosterone, 5 alpha-dihydrotestosterone (DHT) or 17 beta-estradiol (E2) for 14 days, and quantitative PCR and Western immunoblots were performed. DHT significantly decreased expression of all ENaC subunits in female rats, whereas testosterone showed only a trend to lower ENaC expression. These results are in contrast to previous studies where stimulating effects of androgens on the alpha-subunit of ENaC were seen. AR mRNA expression showed a trend to lower levels in females after testosterone treatment in this study. However, estrogen treatment significantly downregulated AR mRNA expression. In male control animals we were able to show a significantly increased expression of AR mRNA upon testosterone treatment. Our data demonstrate that AR and ENaC are regulated by sex steroids. That way sex steroids might modulate renal sodium reabsorption and therefore provide a possible explanation for sex differences in blood pressure.

Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe GH deficiency (GHD).

OBJECTIVE: At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF-I within the reference range. It is unclear whether in such patients serum IGF-I levels are regulated by factors other than GH. DESIGN AND PATIENTS: We performed a double-blind, randomized, placebo-controlled, cross-over study to investigate the effect of the GH receptor antagonist - pegvisomant (20 mg daily for 14 days) on GH and IGF-I levels in three cohorts: patients with GHD and a normal IGF-I (NORMS); patients with GHD and a low IGF-I (LOWS) and healthy volunteers (CONS). RESULTS: Pegvisomant decreased IGF-I in CONS and NORMS [158.5 (101-206) vs. 103 (77-125) microg/l, P < 0.01; 124 (81-136) vs. 95 (51-113) microg/l, P < 0.01 respectively], but not in LOWS [31 (< 31-32) vs. 34.5 (< 31-38) microg/l], and this was associated with an increase in mean 24 h GH in CONS [0.49 (0.12-0.89) to 1.38 (0.22-2.45) microg/l (P = 0.03)] and in NORMS [69 (0-320)% from 0.1 (< 0.1-0.13) to 0.17 (0.11-0.42) microg/l (P = 0.03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6.1 (0.8-9) vs. 20.4 (13.1-28.8) microg/l, P = 0.03; 0.4 (0.1-0.5) vs. 0.5 (0.3-0.6) microg/l, respectively], but not in LOWS. CONCLUSIONS: These data indicate that patients with severe GHD with a normal IGF-I are able to increase GH secretion in response to a pegvisomant-induced fall in IGF-I, whereas those with low IGF-I levels are unable to increase GH secretion. Therefore circulating IGF-I appears to be GH-independent in GHD patients with a low IGF-I, but remains partially GH-dependent in GHD patients with a normal IGF-I.

[Growth hormone therapy in adults. Attempt to assess a decade of use]. / Wachstumshormontherapie beim Erwachsenen : Versuch einer Bilanz nach einer Dekade.

Patients with adult growth hormone deficiency apparently can develop a clinical picture with pronounced obesity, dyslipidemia, decreased bone density, and increased fracture rate as well as psychosocial limitations irrespective of the loss and replacement of further hypophyseal axes. The extent of these changes is strongly dependent on interindividual variations. Retrospective analyses have indicated a possibility of elevated morbidity and mortality among this patient cohort which can be due to the proatherogenic alterations (central obesity, dyslipidemia). Treatment with recombinant growth hormone in controlled trials resulted in evident improvement in quality of life, better body composition and lipid profile as well as an increase in bone density. Whether these improvements will also pay off in terms of reduction of endpoints (decline in fracture rates, decrease of cardiovascular morbidity and mortality) has not yet been confirmed by controlled studies. When administered at low doses, titrated according to the IGF-1 level, growth hormone replacement appears to be a safe and well-tolerated therapeutic regimen.

Evaluation of health-related quality of life in patients with Cushing's syndrome with a new questionnaire.

UNLABELLED: Chronic exposure to hypercortisolism has significant impact on patient's health and health-related quality of life (HRQoL), as demonstrated with generic questionnaires. We have developed a disease-generated questionnaire to evaluate HRQoL in patients with Cushing's syndrome (CS; CushingQoL). OBJECTIVE: Validate the CushingQoL questionnaire in patients with CS in clinical practice conditions. DESIGN: Observational, international, cross-sectional study. METHODS: A total of 125 patients were recruited by 14 investigators from Spain, France, Germany, The Netherlands, and Italy over a 2-month period. Clinical and hormonal data were collected and correlated with results of the generic short form 36 (SF-36) questionnaire, a question on self-perceived general health status and the CushingQoL score. RESULTS: A total of 107 patients were pituitary-dependent and 18 adrenal-dependent CS; 104 (83%) were females, mean age 45 years (range 20-73 years); 39 (31%) were currently hypercortisolemic; and 47 (38%) adrenal insufficient. In clinical practice, CushingQoL was feasible (117; 94% of patients fully responded to the questionnaire in a mean time of 4 min), reliable (Crohnbach's alpha=0.87), and valid (factorial analysis demonstrated unidimensionality and Rasch analysis lead to a final version with 12 items). A significant (P<0.001) correlation was observed between CushingQoL score and patients self-perceived general health status and dimensions of SF-36 (Pearson's correlation coefficient > or =0.597). Patients with current hypercortisolism scored worse (lower) than those without (44+/-22 vs 56+/-21, P=0.004). Linear regression analysis identified female gender and hypercortisolism as significant predictors for worse QoL. CONCLUSION: CushingQoL is useful to evaluate HRQoL in patients with CS and correlates with clinical parameters.

Assessment of suspected insulinoma by 48-hour fasting test: a retrospective monocentric study of 23 cases.

OBJECTIVE: Insulinoma causes fasting hypoglycaemia due to inappropriate insulin secretion. The diagnosis of insulinoma is based on Whipple's triad during a supervised fasting test. The aim of our study was to evaluate retrospectively the percentage of positive 48-hour fasting tests in a large series of patients with insulinoma. DESIGN, PATIENTS AND METHODS: In a retrospective study, we identified 39 patients (24 females, 15 men; average age 47 years [range 12-78 years]) with insulinoma. Sixteen patients were diagnosed by spontaneous hypoglycaemia. Twenty-three patients with insulinoma were tested with a 48-hour fasting test and compared to 31 healthy controls who had a negative fasting test and were followed up for at least two years. RESULTS: The fast was terminated due to neuroglycopenic symptoms in 4 patients (17.4%) at the 12th hour, in 17 patients (73.9%) at the 24th hour, and in 22 patients (95.7%) at the 48th hour. One patient with insulinoma had no neuroglycopenic symptoms, but was diagnosed by glucose and insulin levels during the 48-hour fast. Healthy controls had significantly higher blood glucose and lower insulin levels, and a lower insulin-glucose ratio than patients with insulinoma at the end of the fast. CONCLUSIONS: In conclusion, the 48-hour fasting test was successful in the diagnosis of insulinoma in 95.7% of patients. In this series we did not observe a need for fasting beyond 48 hours.

Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma.

BACKGROUND: Gigantism is rare with the majority of cases caused by a growth hormone (GH)-secreting pituitary adenoma. Treatment options for GH-secreting pituitary adenomas have been widened with the availability of long-acting dopamine agonists, depot preparations of somatostatin analogues, and recently the GH receptor antagonist pegvisomant. CASE REPORT: A 23-year-old male patient presented with continuous increase in height during the past 6 years due to a GH-secreting giant pituitary adenoma. Because of major intracranial extension and failure of octreotide treatment to shrink the tumour, the tumour was partially resected by a trans-frontal surgical approach. At immunohistochemistry, the tumour showed a marked expression of GH and a sparsely focal expression of prolactin. Somatostatin receptors (sst) 1-5 were not detected. Tumour tissue weakly expressed dopamine receptor type 2. The Gs alpha subunit was intact. Conversion from somatostatin analogue to pegvisomant normalized insulin-like-growth-factor-I (IGF-I) levels and markedly improved glucose tolerance. CONCLUSION: Pegvisomant is a potent treatment option in patients with pituitary gigantism. In patients who do not respond to somatostatin analogues, knowledge of the SST receptor status may shorten the time to initiation of pegvisomant treatment.

Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study.

OBJECTIVE: The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice. DESIGN: GPOS is an observational, multi-center, surveillance study, which comprises non-interventional data collection. METHODS: Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement. RESULTS: IGF-I levels decreased from 1.75+/-0.91-fold the upper limit of normal at baseline to 1.05+/- 0.62 at the 6-month visit, 0.96+/-0.60 at the 12-month visit, and to 0.89+/-0.41-fold after 24 months (P<0.0001). Mean duration of pegvisomant therapy was 51.8+/-35.8 weeks (median=51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4+/-45.9 to 101.5+/- 42.8 mg/dl after 6 months (P<0.01) and to 100.6+/-33.2 mg/ml after 12 months (P<0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in >1% were injection site reactions in 7.4%, elevated liver enzymes (>3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%. CONCLUSIONS: Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy.

Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologically proven chronic mild active hepatitis.

OBJECTIVE: The new GH receptor antagonist pegvisomant is the most effective medical therapy to normalize IGF-I levels in patients with acromegaly. Based on currently available data pegvisomant is well tolerated; however, treatment-induced elevation of transaminases has been reported and led to the necessity for drug discontinuation in some patients in the pivotal studies. The aim of this study was to evaluate and characterize the prevalence of elevated transaminases and to describe in detail the findings in a single case who required drug discontinuation because of elevation of transaminases which emerged during treatment and who underwent liver biopsy. DESIGN AND METHODS: Retrospective safety analyses were carried out on 142 patients with acromegaly receiving pegvisomant treatment in Germany between March 2003 and the end of 2004. Of these patients, 123 were documented in a post-marketing surveillance study, one case of elevated transaminases was reported spontaneously and the other patients were treated in a clinical study. RESULTS: Mean treatment duration with pegvisomant in the ongoing observational study at the end of 2004 was 28.3 +/- 19.9 (S.D.) weeks. Twelve out of the 142 patients had elevated transaminases above three times the upper limit of normal, likely caused by biliary obstruction in five of the patients. All patients but one affected by elevated transaminases had been previously treated with somatostatin analogues. In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases. The same number of patients showed a transient increase of transaminases with either spontaneous remission without dose modification (n = 4) or no re-increase of transaminases after temporary discontinuation and re-exposure (n = 2). The liver biopsy of one patient who was permanently withdrawn showed a chronic mild hepatitis with a mixed portal inflammation including eosinophilic granulocytes. CONCLUSIONS: Liver function tests should be regularly followed on pegvisomant treatment. Biliary complications, which may arise from restitution of normal gall bladder motility after cessation of somatostatin analogue treatment, need to be differentiated from pegvisomant-induced abnormalities. The histological pattern of the liver biopsy performed in one of the patients showed a mild chronic active hepatitis. The lack of dose dependency and rather low frequency of elevated transaminases in those cases where a biliary disorder was excluded render this reaction an idiosyncratic drug toxicity.