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Medical treatment of acromegaly with long-acting somatostatin analogs (LA-SMSA) and the GH receptor antagonist, pegvisomant (PEGV), has made it possible to achieve normal serum IGF1 concentrations in a majority of patients with acromegaly. These two compounds, however, impact the GH-IGF1 axis differently, which challenges the traditional biochemical assessment of the therapeutic response. We postulate that LA-SMSA in certain patients normalizes serum IGF1 levels in the presence of elevated GH actions in extra-hepatic tissues. This may result in persistent disease activity for which we propose the term extra-hepatic acromegaly. PEGV, on the other hand, blocks systemic GH actions, which are not necessarily reliably reflected by serum IGF1 levels, and this treatment causes a further elevation of serum GH levels. Medical treatment is therefore difficult to monitor with the traditional biomarkers. Moreover, the different modes of actions of LA-SMSA and PEGV make it attractive to use the two drugs in combination. We believe that it is time to challenge the existing concepts of treatment and monitoring of patients with acromegaly.

Objective: To investigate whether early intervention with recombinant human growth hormone (hGH) after hip fracture improves functional recovery and long-term outcome. Subjects and methods: Functional recovery after hip fracture is often incomplete. The catabolic situation that develops after the hip fracture accident, and a state of malnutrition either pre-existing or developing after surgery, are main contributing factors for the poor clinical outcome. hGH has been used to promote anabolism in a variety of clinical catabolic situations. The study design was randomized, double-blind and placebo-controlled. A total of 111 patients older than 60 years with an accidental hip fracture (mean age 78X5^9X1 (S.D.) years) were randomized to receive either hGH (20 mg/kg per day) or placebo for a period of 6 weeks, starting within 24 h after the hip fracture accident. Thereafter patients were followed up for an additional period of 18 weeks. Efficacy was assessed by comparing the changes in the Barthel Index score of activities of daily living and in a patient's living situation between the hGH-and the placebo-treated subjects. Results: Eighty-five (78.5%) patients completed the first 8 weeks of the study and 76 (68.5%) the entire study period of 24 weeks. When split according to age, a trend was found that for patients older than 75 years the changes in Barthel Index score from baseline were less in the hGH group than in the placebo group 218X6^18 vs 228X1^26 at 6 weeks after surgery P , 0X075X There was an overall trend to a higher rate of return to the pre-fracture independent living situation in the hGH group than in the placebo group. Analysis by age revealed a significantly higher proportion of hGHthan placebo-treated patients returning to the pre-fracture living situation for subjects older than 75 years (93.8 vs 75.0%, P 0X034X hGH treatment increased IGF-I values to levels in the range of those of normal subjects of 50±60 years of age. Conclusions: A 6 week treatment with hGH (20 mg/kg per day) of otherwise healthy patients after an accidental hip fracture may be of benefit if given to subjects older than 75 years of age. The rate of return to the pre-fracture living situation in subjects of this age treated with hGH was significantly increased when compared with the placebo-treated group. The treatment intervention was well tolerated and no safety issues were recorded.

Ghrelin is a metabolically regulated hormone that activates the G protein-coupled receptor GH secretagogue receptor type 1a (GHSR) not only in the pituitary gland but also in peripheral tissues such as the pancreas, stomach, and T cells in the circulation. We have investigated the effects of lipids and altered plasma membrane composition on GHSR activation. Oligounsaturated fatty acids (OFAs) disrupt the structure of membranes and make them more fluid. Prolonged (96 h), but not acute, treatment of the GHSR cells with the 18C OFAs oleic and linoleic acid caused a significant increase in sensitivity of the receptor to ghrelin (EC50 reduced by a factor of 2.4 and 2.9 at 60 and 120 M OFAs, respectively). OFAs were found to block the inhibitory effects of ghrelin pretreatment on subsequent ghrelin responsiveness, suggesting that OFAs suppress desensitization of GHSR. Radioligand displacement studies did not show a significant shift in receptor binding after incubation with OFAs. However, it was found that OFA treatment suppressed GHSR internalization, likely explaining OFA-induced refractoriness to ligand-induced desensitization. The involvement of lipid rafts in this process was indicated by the altered responsiveness of GHSR under conditions that alter membrane cholesterol. In conclusion, our findings demonstrate the importance of membrane composition for GHSR activation and desensitization and indicate at least part of the mechanism through which OFAs and cholesterol could affect ghrelin's activity in vivo.

Introduction: In an animal model of acromegaly (PEPCK-hGH transgenic mice), low systemic levels of ghrelin have been observed compared with normal mice. We hypothesized that systemic circulating ghrelin levels are also decreased in humans with active acromegaly and that the contribution of central ghrelin production to systemic ghrelin levels is minimal. Objectives: The aim of the present study was to investigate, in two subjects with active acromegaly, whether there are differences between systemic ghrelin levels and ghrelin concentrations in the petrosal sinus. Design: We measured systemic and central ghrelin levels in these two acromegalic patients by bilateral simultaneous inferior petrosal sinus sampling. Central and systemic blood samples were drawn before and 1, 5, 10, 15 and 20 min after stimulation with GH-releasing hormone (GHRH). Ghrelin was measured with a commercially available radioimmunoassay. Results: In one acromegalic subject, the baseline systemic and central ghrelin levels were within the same range as in two non-acromegalic obese subjects. No gradient could be observed between central and systemic ghrelin concentrations. Stimulation with GHRH did not change the ghrelin concentrations in this patient. In the other acromegalic subject, the systemic ghrelin levels were also in the same range as in two non-acromegalic obese subjects. However, in this subject, baseline ghrelin concentrations in the right inferior petrosal vein were considerably lower than the systemic ghrelin concentrations, indicating a peripheral over central gradient. Administration of GHRH induced a significant rise in central ghrelin concentrations in the right inferior petrosal vein. Ghrelin levels in the left inferior petrosal vein and systemic ghrelin levels were in the normal range and GHRH stimulation did not change these concentrations. Conclusions: The absence of a central over peripheral ghrelin gradient in these two acromegalics indicated that circulating ghrelin is mainly produced peripherally. Circulating systemic ghrelin levels were not decreased in these two subjects with active acromegaly.

principal components analysis and descending hierarchical classification. Results:Steps 1-3: Development and adaptation of a self-reported 44-item questionnaire on a 0-10 scale of fears and beliefs. 5 domains established a priori: origin of the disease, flares, treatments, disease progression and consequences of disease.Step 4: In the study of 226 patients (161 RA, 65 axSpA), all dimensions were ≥ 0.79 and ≤ 0.93, apart from the domain "origin of the disease" (0.67). Principal component analysis identified 6 axes (63.7% of variance explained) and the descending hierarchical analysis identified 9 clusters (63.7% of variance). 2 clusters were highly correlated (r2= 0.80) and combined into a single cluster. Based on the psychometric validation, the following domains were identified: fears of the disease progression/consequences (18 items) and fears about treatment (5); beliefs related to: psychological influence (2), genetic influence (2), physical influence (4), diet influence (4), lifestyle (3) and diverse opinions (4). ConClusions: This analysis confirms the internal consistency of the questionnaire developed. The scoring results should help physicians to understand their patients' perceptions of their disease better and eventually lead to improved adherence to treatment.

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