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Human growth hormone (hGH) is a pituitary-derived endocrine protein that regulates several critical postnatal physiologic processes including growth, organ development, and metabolism. Following adulthood, GH is also a regulator of multiple pathologies like fibrosis, cancer, and diabetes. Therefore, there is a significant pharmaceutical interest in developing antagonists of hGH action. Currently, there is a single FDA-approved antagonist of the hGH receptor (hGHR) prescribed for treating patients with acromegaly and discovered in our laboratory almost 3 decades ago. Here, we present the first data on the structure and function of a new set of protein antagonists with the full range of hGH actions-dual antagonists of hGH binding to the GHR as well as that of hGH binding to the prolactin receptor. We describe the site-specific PEG conjugation, purification, and subsequent characterization using MALDI-TOF, size-exclusion chromatography, thermostability, and biochemical activity in terms of ELISA-based binding affinities with GHR and prolactin receptor. Moreover, these novel hGHR antagonists display distinct antagonism of GH-induced GHR intracellular signaling in vitro and marked reduction in hepatic insulin-like growth factor 1 output in vivo. Lastly, we observed potent anticancer biological efficacies of these novel hGHR antagonists against human cancer cell lines. In conclusion, we propose that these new GHR antagonists have potential for development towards multiple clinical applications related to GH-associated pathologies., Competing Interests: Conflict of interest R. Ba., R. Br., U. S., and J. J. K. hold patent rights to the novel pegylated GHR antagonists designed and discussed in this manuscript. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Growth hormone (GH) is a peptide hormone that mediates actions through binding to a cell surface GH receptor (GHR). The GHR antagonist, B2036, combines an amino acid substitution at 120 that confers GHR antagonist activity, with eight additional amino acid substitutions. Conjugation to polyethylene glycol (PEG) increases the serum half-life of these proteins due to reduced renal clearance. Recombinant forms of GH and its antagonists are mainly produced in prokaryotic expression systems, such as E. coli . However, efficient production in E. coli is problematic, as these proteins form aggregates as inclusion bodies resulting in poor solubility. In the present study, we demonstrate that N-terminal fusion to a thioredoxin (Trx) fusion partner improves soluble expression of codon-optimized B2036 in E. coli when expressed at 18 °C. Expression, purification and PEGylation protocols were established for three GHR antagonists: B2036, B20, and G120Rv. Following purification, these antagonists inhibited the proliferation of Ba/F3-GHR cells in a concentration-dependent manner. PEGylation with amine-reactive 5 kDa methoxy PEG succinimidyl propionate yielded a heterogeneous mixture of conjugates containing four to seven PEG moieties. PEGylation significantly reduced in vitro bioactivity of the conjugates. However, substitution of lysine to arginine at amino acid residue 120 in B2036 improved the in vitro activity of the PEGylated protein when compared to unmodified PEGylated B2036. Pharmacokinetic analysis demonstrated that the circulating half-life of PEGylated B20 was 15.2 h in mice. Taken together, we describe an effective strategy to produce biologically active PEGylated human GHR antagonists.

Current guidelines recommend the use of long-acting somatostatin receptor ligands (SRLs) first when surgery fails to correct GH/IGF-I hypersecretion in patients with acromegaly. In this issue of the journal, a pro- and contra debate will outline which arguments are in favour and which are against positioning pegvisomant (PEGV), a GH receptor antagonist, as the first-line treatment modality of acromegaly. The task of the pros was to promote a paradigm shift towards repositioning PEGV as first-line treatment as PEGV is safe and more effective than the first- and second-generation of SRLs. SRLs, when prescribed together with PEGV can still reduce tumour size when necessary, while they decrease the necessary dose of PEGV by around 50% in the average patient. They conclude that PEGV must move up towards the first-line treatment. For the cons, SRLs remain the first-line medical treatment. Indeed, even if, in recent studies, the remission rate is lower than initially claimed, SRLs are still effective not only for normalizing GH/IGF-I levels in half of the patients but also for inducing tumour shrinkage, improving comorbidities and headaches and reversing excess mortality. They are more convenient for use with their monthly administration and have a remarkable safety profile as demonstrated by the very prolonged experience acquired by more than 30 years of use. Finally, the cost-effectiveness of first-generation SRLs is better than that of PEGV. For all these reasons, cons consider that SRLs remain the best first medical treatment in patients requiring medical therapy.

Objectives: Lipoprotein lipase (LPL) catalyzes the hydrolysis of circulating triglycerides into free fatty acids (FFA) and thereby promotes FFA uptake in peripheral tissues. LPL is negatively regulated by angiopoietin-like protein 4 (ANGPTL4) presumably by an FFA-dependent mechanism. Growth hormone (GH) suppresses LPL activity, but it is unknown whether this is mediated by FFA and ANGPTL4. Therefore, we investigated the concerted effect of GH on ANGPTL4 and LPL in the presence and absence of lipolysis in two in vivo studies in human subjects., Methods: In a randomized, placebo-controlled, cross-over study, nine obese men were examined after injection of 1) a GH bolus, and 2) a GH-receptor antagonist followed by four adipose tissue biopsies obtained over a 5-h period. In a second study, nine hypopituitary men were examined in a 2 × 2 factorial design including GH and acipimox (an anti-lipolytic agent), with biopsies from adipose tissue and skeletal muscle obtained during a basal period and a subsequent hyperinsulinemic-euglycemic clamp. The mRNA expression of ANGPTL4 and LPL as well as LPL activity were analyzed in the biopsies., Results: In both studies, GH increased serum FFA levels, upregulated ANGPTL4 mRNA expression and suppressed LPL activity. In study 2, acipimox completely suppressed FFA levels and antagonized the effects of GH on ANGPTL4 and LPL., Conclusions: These human in vivo studies demonstrate that GH upregulates ANGPTL4 mRNA and suppresses LPL activity via an FFA-dependent mechanism., Competing Interests: Declaration of competing interest JOLJ has received unrestricted research grants and lecture fees from Pfizer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Context: A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce GH secretion for the treatment of pituitary adenomas., Objective: To determine pharmacokinetics, safety, and tolerability and to monitor hormonal changes after single and multiple subcutaneous BIM23B065 administrations., Design: Randomized, double-blind, placebo-controlled, parallel-group design with five single and three 13-day multiple ascending-dose cohorts., Patients: A total of 63 healthy male white volunteers were enrolled (47 active, 16 placebo)., Main Outcome Measures: Pharmacokinetics, GH, prolactin (PRL), IGF-1, GH after GHRH administration, and general clinical safety criteria., Results: The maximum dosage of BIM23B065 administered in this study was 1.5 mg. BIM23B065 reduced the mean GH concentrations after 8 and 13 days of treatment. A decrease in GH release after GHRH administration indicated inhibition of the hypothalamic-pituitary-somatotropic axis. IGF-1 was not altered after single doses but showed a significant change from baseline after multiple dosing. PRL secretion was reduced in all subjects who were treated. Orthostatic hypotension and injection site reactions were commonly observed at high dosages. A 6-day uptitration period was included to successfully lower the cardiovascular effects in the multiple ascending dose part of the study., Conclusions: Proof of pharmacology of BIM23B065 was shown by a reduction in GH, IGF-1, and PRL concentrations in healthy male volunteers, supporting activity of the somatostatin analog and dopamine agonist moieties. The safety and tolerability of the higher dosing regions was limited mainly by orthostatic hypotension.

Aim: To investigate the added value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) sequences in predicting somatostatin analog (SSA) responses in patients with acromegaly., Material and Methods: This study included 55 active acromegaly patients with macroadenoma. Mean and maximum signal intensities were measured using region of interests in T2-weighted (T2W) and DCE-MRI sequences. Semi-quantitative values indicating relative signal intensity ratios and contrast-enhanced kinetics were obtained. Bivariate and multivariate analyses were used to determine whether the pathological granulation pattern of adenomas (dense versus others) was associated with patients' demographic variables and semi-quantitative MRI parameters., Results: Three parameters formed the logistic model, x2(3)=23.278, p < 0.0001: age (odds ratio [OR]=1.08), hypointensity of adenomas in T2W images (OR=15.45), and high maximum enhancement ratio in the second interval (ER2max) values (OR=2195.74). The overall accuracy of this model was 85.45% with an area under the curve of 0.880. Sensitivity, specificity, positive predictive, and negative predictive values of the model were 68.75%, 92.31%, 78.58%, and 87.8%, respectively., Conclusion: In patients with newly diagnosed acromegaly, the model created based on the relative T2W signal intensity, patient's age, and ER2 < submax parameter from DCE-MRI sequences might be used to more accurately predict SSA responses.

Curcumin is assumed to be a plant-derived therapeutic drug that triggers apoptotic cell death in vitro and in vivo by affecting different molecular targets such as NF-κB. Phase I/II trial of curcumin alone or with chemotherapeutic drugs has been accomplished in pancreatic, colon, prostate and breast cancer cases. Recently, autocrine growth hormone (GH) signaling-induced cell growth, metastasis and drug resistance have been demonstrated in breast cancer. In this study, our aim was to investigate the potential therapeutic effect of curcumin by evaluating the molecular machinery of curcumin-triggered apoptotic cell death via focusing on NF-κB signaling and polyamine (PA) metabolism in autocrine GH-expressing MCF-7, MDA-MB-453 and MDA-MB-231 breast cancer cells. For this purpose, a pcDNA3.1 (+) vector with a GH gene insert was transfected by a liposomal agent in all breast cancer cells and then selection was conducted in neomycin (G418) included media. Autocrine GH-induced curcumin resistance was overcome in a dose-dependent manner and curcumin inhibited cell proliferation, invasion-metastasis and phosphorylation of p65 (Ser536), and thereby partly prevented its DNA binding activity in breast cancer cells. Moreover, curcumin induced caspase-mediated apoptotic cell death by activating the PA catabolic enzyme expressions, which led to generation of toxic by-products such as H 2 O 2 in MCF-7, MDA-MB-453 and MDA-MB-231 GH+ breast cancer cells. In addition, transient silencing of SSAT prevented curcumin-induced cell viability loss and apoptotic cell death in each breast cancer cells. In conclusion, curcumin could overcome the GH-mediated resistant phenotype via modulating cell survival, death-related signaling routes and activating PA catabolic pathway.

Pegvisomant monotherapy is effective and safe in treatment of acromegaly. However, some clinicians combine pegvisomant with somatostatin analogues (SSA) or dopamine agonist (DA). In this analysis of ACROSTUDY, a long-term non-interventional study, the use of combination regimens was evaluated. Based on their baseline treatment, 2043 patients were retrospectively categorized as: long-acting SSA combined with pegvisomant, 'Combo SSA' 768 patients (38%); DA combined with pegvisomant, 'Combo DA' 123 (6%); pegvisomant monotherapy, 'Peg mono' 1128 (55%). Treatment patterns changed over the 10-year period, with recent patients more likely to receive any combination (20% in 2003 vs 54% in 2012). Combo SSA use varied widely among countries from 22% to 78%. Exposure periods of the three treatment modalities were defined from pegvisomant start until the last visit in ACROSTUDY; patients could switch treatment categories. At year 4, IGF-I was normal in 62% of Combo SSA, 63% of Combo DA and 65% of Peg mono groups. Pegvisomant was initiated as daily injections in 94% of patients in the Peg mono group, 66% of Combo SSA and 91% of Combo DA patients. During 6169 years of treatment exposure, 3424 adverse events (AEs) were reported in 946 (51%) patients, of which 617 (18%) were serious and 401 (12%) were considered treatment related. The reported incidence of serious AEs and treatment-related non-serious AEs were similar among the three treatment modalities. This analysis describes real-world clinical care and shows favorable efficacy and safety for Peg mono and combinations. Novel findings include an increased use of combination therapy over time and variability in treatment modalities between countries., (© 2018 The authors.)

Context: Growth hormone (GH) stimulates hepatic synthesis of very-low-density lipoproteins (VLDL), whereas hepatic steatosis develops as a result of GH deficiency. Steatosis is also a complication of tamoxifen treatment, the cause of which is not known. As tamoxifen inhibits the secretion and action of GH, we hypothesize that it induces steatosis by inhibiting hepatic VLDL export., Aim: To investigate whether tamoxifen reduces hepatic VLDL secretion., Design: Eight healthy, normolipidemic women (age: 64.4 ± 2.1 years) were studied in random sequence at baseline, after 2 weeks of tamoxifen (20 mg/day) and after 2 weeks of estradiol valerate (EV; 2 mg/day) treatments, separated by a 4-week washout period. The kinetics of apolipoprotein B (apoB), the structural protein of VLDL particles, were measured using a stable isotope 2H 3 -leucine turnover technique. VLDL-apoB fractional catabolic rate (FCR) was determined using a multicompartment model. VLDL-apoB secretion was estimated as the product of FCR and VLDL-apoB concentration. GH response to arginine stimulation, circulating levels of IGF-1, FFA, and TG, along with TG content in VLDL were measured., Results: Tamoxifen significantly ( P  < 0.05) reduced VLDL-apoB concentration and secretion by 27.3 ± 7.8% and 29.8 ± 10.2%, respectively. In contrast, EV did not significantly change VLDL-apoB concentration or secretion. Tamoxifen but not EV significantly reduced ( P  < 0.05) GH response to arginine stimulation. Both treatments significantly lowered ( P  < 0.05) circulating IGF-1., Conclusion: Inhibition of VLDL secretion may contribute to the development of fatty liver during tamoxifen therapy. As GH stimulates VLDL secretion, the development of steatosis may arise secondarily from GH insufficiency induced by tamoxifen., (© 2017 European Society of Endocrinology.)

Acromegaly is a chronic systemic disorder caused in the vast majority of cases by a GH-secreting pituitary adenoma and resulting in significant morbidity and mortality if left untreated. The treatment of choice is the trans-sphenoidal resection of the adenoma, and although 80% of patients with microadenomas or confined macroadenomas achieve biochemical remission, the surgical success rate for patients harboring tumors with extrasellar extension is below 50%. Thus, a considerable proportion of patients will require some form of adjuvant treatment. Acromegaly can be approached pharmacologically by inhibiting GH secretion by the tumor (somatostatin analogues, dopamine agonists) or by antagonizing GH actions at its target tissues (GH receptor antagonists). The primary pharmacological treatment of acromegaly is increasingly gaining acceptance by both physicians and patients. The decision to use primary pharmacological treatment has to take into account the clinical characteristics of the patient (presence of comorbidities that significantly increase the surgical risk) and the biological nature of the adenoma (tumor size and location), as well as other aspects such as the availability of a pituitary surgeon and the cost of medications. This review provides a critical summary and update of the pharmacological treatment of acromegaly focusing both, on well-established agents and strategies as well as on novel compounds that are currently being developed.

Objective: Patients with acromegaly can be treated with surgery, radiotherapy and/or medical treatment. In general, patients' beliefs about medication are associated with illness perceptions, a contributory factor of Quality of Life (QoL). At present, there are no quantitative studies on medication beliefs in patients with acromegaly. Here, we aimed to examine possible associations between medication beliefs, illness perceptions, and QoL. Furthermore we aimed to explore whether illness perceptions of patients with remission of acromegaly receiving medical treatment differ from patients without medical treatment., Design: Cross-sectional evaluation of 73 patients with remission of acromegaly (n = 28 patients with medication, n = 45 without medication). The Beliefs about Medicines Questionnaire (BMQ), Illness Perception Questionnaire-Revised (IPQ-R), EuroQoL-5D, and AcroQoL were used for the assessment., Results: Stronger beliefs about the necessity of medical treatment and stronger concerns about the adverse effects were associated with attributing more symptoms to acromegaly, perceiving more negative consequences, and having a stronger belief in a cyclical timeline (BMQ, all P < 0.05). Stronger beliefs about the necessity of medical treatment were associated with a worse disease-specific QoL (BMQ, P < 0.01). Patients with medical treatment perceived a more chronic timeline of their disease, compared to patients without medical treatment (IPQ-R, P = 0.002)., Conclusion: Negative medication beliefs were related to more negative illness perceptions and worse disease-specific QoL. Patients receiving medical treatment for acromegaly tend to perceive a more chronic timeline of their disease, compared to patients with remission without medical treatment. These psychological factors need to be taken into account when treating patients and developing a psychosocial education program aiming to improve QoL., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The purpose of this study was to evaluate the safety of the oral glucose tolerance test (OGTT) and its capacity to suppress growth hormone (GH) in diabetic patients without acromegaly. A total of 135 diabetic patients submitted to the OGTT for GH suppression were studied. The following selection criteria were applied: age between 20 and 70 years; body mass index≥18.5 and ≤27 kg/m2; absence of kidney, liver, or thyroid disease; no use of estrogens, androgens, corticosteroids, or levothyroxine. Adequate suppression of GH was defined as a nadir below the cut-off established for a sample of 200 normoglycemic subjects (<0.25 µg/L for men, <0.74 µg/L for premenopausal women, and <0.5 µg/L for postmenopausal women). Acromegaly was diagnosed in five patients. Among the 130 diabetic patients without known pituitary disease or a clinical suspicion of acromegaly, 95.5% of men, 94% of premenopausal women, and 96.6% of postmenopausal women presented adequate GH suppression (vs 97.5% of normoglycemic controls). In all patients without acromegaly, the lowest GH levels (nadir) were achieved after the administration of glucose and not during baseline measurement. None of the patients had acute complications [ketoacidosis, hyperosmolar state, and symptomatic marked hyperglycemia (>300 mg/dL)] on the day of the test and up to 3 days thereafter. We demonstrated the safety of the OGTT and its capacity to suppress GH in diabetic patients without acromegaly. In addition, we suggest the adoption of a protocol to prevent possible risks of the OGTT in patients with diabetes.

Context: The ghrelin receptor GHS-R1a is highly expressed in human somatotroph adenomas and exhibits unusually high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature., Objective: Using a GHS-R1a inverse agonist, modified substance P (MSP), we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as a putative therapeutic target., Design: The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (somatostatin receptor subtype 2 [sst2] agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied., Results: For all tumors, MSP inhibited GH secretion in a dose-dependent manner from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For five tumors, the effects of combined MSP plus octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs., Conclusions: The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist.

Context: Targeted secretion inhibitors (TSIs), a new class of recombinant biotherapeutic proteins engineered from botulinum toxin, represent a novel approach for treating diseases with excess secretion. They inhibit hormone secretion from targeted cell types through cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor-activating protein receptor) proteins. qGHRH-LH(N)/D is a TSI targeting pituitary somatotroph through binding to the GHRH-receptor and cleavage of the vesicle-associated membrane protein (VAMP) family of SNARE proteins., Objective: Our objective was to study SNARE protein expression in pituitary adenomas and to inhibit GH secretion from somatotropinomas using qGHRH-LH(N)/D., Design: We analyzed human pituitary adenoma analysis for SNARE expression and response to qGHRH-LH(N)/D treatment., Setting: The study was conducted in University Hospitals., Patients: We used pituitary adenoma samples from 25 acromegaly and 47 nonfunctioning pituitary adenoma patients., Outcome: Vesicle-SNARE (VAMP1-3), target-SNARE (syntaxin1, SNAP-23, and SNAP-25), and GHRH-receptor detection with RT-qPCR, immunocytochemistry, and immunoblotting. Assessment of TSI catalytic activity on VAMPs and release of GH from adenoma cells., Results: SNARE proteins were variably expressed in pituitary samples. In vitro evidence using recombinant GFP-VAMP2&3 or pituitary adenoma lysates suggested sufficient catalytic activity of qGHRH-LH(N)/D to degrade VAMPs, but was unable to inhibit GH secretion in somatotropinoma cell cultures., Conclusions: SNARE proteins are present in human pituitary somatotroph adenomas that can be targeted by TSIs to inhibit GH secretion. qGHRH-LH(N)/D was unable to inhibit GH secretion from human somatotroph adenoma cells. Further studies are required to understand how the SNARE proteins drive GH secretion in human somatotrophs to allow the development of novel TSIs with a potential therapeutic benefit.

Acromegaly is predominantly caused by a pituitary adenoma, which secretes an excess of GH resulting in increased IGF1 levels. Most of the GH assays used currently measure only the levels of the 22 kDa form of GH. In theory, the diagnostic sensitivity may be lower compared with the previous assays, which have used polyclonal antibodies. Many GH-secreting adenomas are plurihormonal and may co-secrete prolactin, TSH and α-subunit. Hyperprolactinaemia is found in 30-40% of patients with acromegaly, and hyperprolactinaemia may occasionally be diagnosed before acromegaly is apparent. Although trans-sphenoidal surgery of a GH-secreting adenoma remains the first treatment at most centres, the role of somatostatin analogues, octreotide long-acting repeatable and lanreotide Autogel as primary therapy is still the subject of some debate. Although the normalisation of GH and IGF1 levels is the main objective in all patients with acromegaly, GH and IGF1 levels may be discordant, especially during somatostatin analogue therapy. This discordance usually takes the form of high GH levels and an IGF1 level towards the upper limit of the normal range. Pasireotide, a new somatostatin analogue, may be more efficacious in some patients, but the drug has not yet been registered for acromegaly. Papers published on pasireotide have reported an increased risk of diabetes mellitus due to a reduction in insulin levels. Pegvisomant, the GH receptor antagonist, is indicated - alone or in combination with a somatostatin analogue - in most patients who fail to enter remission on a somatostatin analogue. Dopamine-D2-agonists may be effective as monotherapy in a few patients, but it may prove necessary to apply combination therapy involving a somatostatin analogue and/or pegvisomant.

Background: Active acromegaly is associated with insulin resistance, but it is uncertain whether inflammation in adipose tissue is a contributing factor., Aim: To test if GH/IGF1 promotes inflammation in adipocytes, and if this is relevant for systemic insulin resistance in acromegaly. Furthermore, to investigate the effect of treatment modalities (transsphenoidal surgery (TS), somatostatin analogs (SAs), and pegvisomant (PGV)) on glucose metabolism and inflammatory biomarkers in acromegaly., Methods: The in vitro effects of GH/IGF1 on gene expression of adipokines in human adipocytes were investigated. Body composition, glucose metabolism, and circulating adipokines (adiponectin (AD), high-molecular weight AD (HMWAD), leptin, vascular endothelial growth factor-A (VEGF-A), monocyte chemotactic protein 1 (MCP1), and thioredoxin (TRX)) were measured in 37 patients with active acromegaly before and after treatment., Results: In vitro GH, but not IGF1, increased VEGF and MCP1 in human adipocytes. In all treatment groups, body fat increased and IGF1 decreased to the same extent. Fasting glucose decreased in the TS (P=0.016) and PGV (P=0.042) groups, but tended to increase in the SA group (P=0.078). Insulin and HOMA-IR decreased in both TS and SA groups, while the PGV group showed no changes. Serum VEGF and MCP1 decreased significantly in the TS group only (P=0.010, P=0.002), while HMWAD increased with PGV treatment only (P=0.018). A multivariate analysis model identified the changes in GH and VEGF as predictors of improvement in HOMA-IR after treatment (R²=0.39, P=0.002)., Conclusions: i) GH directly promotes inflammation of human adipocytes by increasing VEGF and MCP1 levels; ii) glucose metabolism and inflammation (VEGF and MCP1) improve to some extent after treatment, despite an increase in adipose tissue mass; and iii) the decrease in insulin resistance after therapy in acromegaly depends, to some extent, on treatment modalities.

Prolonged overproduction of growth hormone, like insulin-like growth factor-1 hypersecretion leads to acromegaly in adults. This is associated with several co-morbidities and increased mortality. Despite typical clinical features and modern diagnostic tools, it often takes years to diagnose from the onset of the disease. The aims of the treatment are to reduce or control tumour growth, inhibit growth hormone hypersecretion, normalize insulin-like growth factor-1 levels, treat co-morbidities and, therefore, reduce mortality. There are three approaches for therapy: surgery, medical management (dopamine agonists, somatostatin analogues and growth hormone receptor antagonist), and radiotherapy. Efficient therapy of the disease is based on the appropriate multidisciplinary team management. The review provides a summary of medical treatment for acromegaly.

Objective: GH secretion is regulated by an interplay between GH-releasing hormone (GHRH), somatostatin (SST), and other central and peripheral signals. Acylated ghrelin (AG) amplifies GH pulsatility acting, at least partially, independently from GHRH and SST. The GH response to GHRH is inhibited by recombinant human GH (rhGH), likely due to a SST-mediated negative GH auto-feedback. The effect of exogenous rhGH on the GH-releasing effect of AG has never been tested., Design and Methods: In six healthy volunteers, we studied the GH response to acute AG administration (1.0 μg/kg i.v.) during saline or rhGH infusion (4.0 μg/kg per h i.v.) or after 4-day rhGH (10.0 μg/kg s.c.) administration., Results: Compared with saline, rhGH infusion increased GH levels (P<0.01). During saline, acute i.v. AG induced a marked increase (P<0.01) in GH levels similar to those observed after AG administration during rhGH infusion. During s.c. rhGH, IGF1 levels rose from day 0 to day 5 (P<0.01). After 4-day s.c. rhGH, i.v. AG increased (P<0.01) GH levels, though significantly (P<0.05) less than on day 0., Conclusions: The marked somatotroph-releasing effect of AG is refractory to a direct GH auto-feedback whereas is markedly inhibited after 4-day rhGH administration, suggesting the possibility of a selective IGF1-mediated inhibitory feedback.

Background: Large variability exists among different growth hormone (GH) assays owing to differences in calibration, antibody specificity, isoform recognition, and interference from GH binding protein (GHBP). The GH receptor antagonist Pegvisomant presents a new challenge because Pegvisomant interferes with many GH assays. A recent consensus conference established criteria for standardization and evaluation of GH assays. Following consensus recommendations, we developed a new GH assay on an automated analyzer (IDS-iSYS, Immunodiagnostic Systems)., Methods: A monoclonal antibody not cross-reacting with Pegvisomant was combined with a monoclonal antibody specific for 22-kD GH. Isoform specificity and interference from GHBP was tested and compared to that seen in 2 existing automated GH assays (Siemens Immulite, Diasorin Liaison). We also compared GH concentrations measured by the 3 assays for healthy volunteers and patients with acromegaly receiving different treatments. Using the iSYS assay, we also established nadir GH values during oral glucose load and analyzed changes in endogenous GH during Pegvisomant treatment., Results: Analytical and functional sensitivities were 0.01 μg/L and 0.04 μg/L, with a dynamic range from 0.04 to 100 μg/L. Intraassay CVs were 2%-4%, whereas interassay CVs were 5%-7% at GH concentrations between 1.7 and 27.5 μg/L. The assay was specific for 22-kD GH and not affected by GHBP. The presence of Pegvisomant, which leads to a negative bias on the Immulite and dramatic overestimation of GH on the Liaison, had no impact on the iSYS GH assay., Conclusions: The new assay fulfils recent consensus recommendations and presents a useful new tool for reliable measurement of GH., (© 2012 American Association for Clinical Chemistry)

Although recent advances in breast cancer treatment regimes have improved patient prognosis, resistance to breast cancer therapies, such as radiotherapy, is still a major clinical challenge. In the current study, we have investigated the role of autocrine human GH (hGH) in resistance to ionising radiation (IR)-based therapy. Cell viability and total cell number assays demonstrated that autocrine hGH promoted cell regrowth in the mammary carcinoma cell lines, MDA-MB-435S and T47D, and the endometrial carcinoma cell line, RL95-2, following treatment with IR. In addition, autocrine hGH enhanced MDA-MB-435S and T47D cell clonogenic survival following radiation exposure. The enhanced clonogenic survival afforded by autocrine hGH was mediated by JAK2 and Src kinases. Investigation into the DNA repair capacity demonstrated that autocrine hGH reduced IR-induced DNA damage in MDA-MB-435S and T47D cells. Functional antagonism of hGH increased RL95-2 sensitivity to IR in cell viability and total cell number assays, reduced clonogenic survival and enhanced the induction of DNA damage. Thus, autocrine hGH reduced sensitivity to treatment with IR in mammary and endometrial carcinoma cell lines in vitro, while functional antagonism of hGH sensitised endometrial carcinoma cells to IR. Functional antagonism of hGH, used in conjunction with radiotherapy, may therefore enhance treatment efficacy and improve the prognosis of patients with breast and endometrial cancer.

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.

Objective: Oestrogen antagonizes the action of growth hormone (GH). For women with combined GH and oestrogen deficiency, transdermal oestradiol is more favourable in this regard compared to oral oestradiol. Oral contraceptive pills containing ethinylestradiol (EE) are commonly used in young women with GHD and there is little information on the impact of this form of oestrogen., Design: A case note review of women with growth hormone deficiency (GHD) attending a tertiary endocrine clinic comparing the dose of GH and serum insulin-like growth factor 1 concentrations and the type of exogenous oestrogen., Methods: All women with GHD between the ages of 18 and 47 attending University College London Hospitals (UCLH) were included and grouped according to type of oestrogen replacement. Weight, GH dose and serum IGF-I concentrations were recorded at 121 visits in 88 women., Results: The daily dose of GH was significantly higher and the GH responsivity was significantly lower in the EE group compared to those taking no oestrogen and transdermal oestrogen. The additional cost of GH for women using EE compared to transdermal oestradiol was £6016 per patient per year. Effectiveness of GH improved in all women changing from EE to another form of oestrogen., Conclusion: Use of oral contraceptive pills containing EE should be avoided in women receiving treatment with GH. Alternative options include oral or transdermal hormone replacement therapy (HRT) preparations for those that require oestrogen replacement or a progesterone-based regimen for contraceptive purposes., (© 2012 Blackwell Publishing Ltd.)

Acromegaly remains a therapeutic challenge for the endocrinologist. Among the available therapeutic options, octreotide long-acting repeatable (Sandostatin(®) LAR(®), Novartis) plays a chief role, both as a primary therapy and as an adjuvant treatment after unsuccessful surgery. A plethora of papers and a meta-analysis have demonstrated its efficacy in: control of clinical picture; achievement of safe growth hormone and normal age-matched IGF-I levels (both factors associated with restoration of normal life expectancy) in 60-70% of patients; control of tumor volume (with real shrinkage in over half of cases); and halt or reversal of most acromegaly-associated comorbidities. Treatment is well tolerated in most patients and can be safely prolonged for many years if required.

Objective: GH secretion is impaired in lipodystrophic human immunodeficiency virus (HIV) patients and inversely related to lipodystrophy-related fat redistribution in men. Less is known about the underlying mechanisms involved in reduced GH secretion in HIV-infected women., Design: A case-control, cross-sectional study comparing GH/IGF1 status, body composition, and metabolic parameters in 92 nonobese women with HIV-related lipodystrophy and 63 healthy controls matched for age, ethnicity, sex, and body mass index (BMI)., Methods: GH, IGF1, IGF binding protein 3 (IGFBP3), GH after GHRH plus arginine (GHRH+Arg), several metabolic variables, and body composition were evaluated., Results: GH response to GHRH+Arg was lower in HIV-infected females than in controls. Using a cutoff of peak GH ≤ 7.5 μg/l, 20.6% of HIV-infected females demonstrated reduced peak GH response after GHRH+Arg. In contrast, none of the control subjects demonstrated a peak GH response ≤ 7.5 μg/l. Bone mineral density (BMD), quality of life, IGF1, and IGFBP3 were lowest in the HIV-infected females with a GH peak ≤ 7.5 μg/l. BMI was the main predictive factor of GH peak in stepwise multiregression analysis followed by age, with a less significant effect of visceral fat in the HIV-infected females., Conclusions: This study establishes that i) GH response to GHRH+Arg is lower in lipoatrophic HIV-infected women than in healthy matched controls, ii) BMI more than visceral adipose tissue or trunk fat influences GH peak in this population, and iii) HIV-infected women with a GH peak below or equal to 7.5 μg/l demonstrate reduced IGF1, IGFBP3, BMD, and quality of life.

Hydrophobic tag-assisted liquid-phase peptide synthesis technique and disulfide bond formation have been well-combined, leading to the efficient and practical preparation of a growth hormone-inhibiting peptide somatostatin. Intramolecular disulfide bond formation has successfully been carried out even under relatively high concentrations, enabling the effective peptide modifications in preparative scale., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Drug resistance is a major cause of chemotherapy failure in breast cancer patients with metastatic disease. We previously demonstrated that autocrine human growth hormone (hGH) plays a key role in oncogenic transformation and progression of mammary carcinoma. The present study investigated the role of autocrine hGH in the development of resistance to mitomycin C (MMC), an alkylating agent utilised in the treatment of advanced metastatic breast cancer. Stable forced expression of the hGH gene was established in the mammary carcinoma cell lines MDA-MB-231, MCF-7 and T47D. Autocrine hGH reduced the sensitivity of mammary carcinoma cells to MMC in cell viability assays and reduced MMC-induced apoptotic cell death when compared to a control cell line. In addition, autocrine hGH enhanced MDA-MB-231 clonogenic survival, anchorage independent cell growth, growth in 3D Matrigel and protected MDA-MB-231 cells from induction of DNA double-strand breaks following MMC treatment. Functional antagonism of hGH in the endometrial carcinoma cell line RL95-2, which endogenously expresses hGH, significantly increased the sensitivity of these cells to MMC-induced DNA damage and cell death. Thus, autocrine hGH promotes mammary and endometrial carcinoma cell resistance to MMC. These studies indicate a potential role for antagonism of autocrine hGH in chemoresistant breast cancer.

To establish whether somatostatin (SRIH) exerts its inhibitory effect on the nicotine-induced release of GH by interacting with an opioid pathway, normal volunteers were treated with naloxone during (2 no-filter) cigarettes smoking and with SRIH. Nicotine significantly increased serum GH levels about 3.5 fold. Naloxone alone did not change GH rise induced by cigarette smoking. The stimulatory effect of GH by nicotine was completely blocked by SRIH. In the presence of both SRIH and naloxone, GH levels rose 1.5 fold in response to nicotine. Since naloxone only partially reversed the inhibiting action of SRIH, only a partial involvement of opioid peptides in SRIH action might be supposed. Alternatively, SRIH and naloxone-sensitive opiates might produce this inhibiting effect on GH rise in response to cigarette smoking through independent pathways.

Acromegaly is a rare disease with typical clinical manifestations. Untreated acromegaly carries a 2-4-fold increase in mortality in long-term outcome. The goal of treatment is double, including biochemical control of the disease (normalization of serum IGF1 levels compared to age and gender matched controls, GH levels below 1 ng/ml after oral glucose load, or random GH below 2.5 ng/ml) and control of the tumor mass. The therapeutic modalities currently available for the treatment of acromegaly are: surgery, medical therapy, radiation therapy and their combinations. The cornerstones of medical therapy in acromegaly are the somatostatin receptor ligands due to their effectiveness in controlling GH excess in 60-70 % of patients and their beneficial effects on tumor volume. Somatostatin analogues have an established role as adjuvant therapy after non-curative surgery, and evidence suggests their use as primary treatment for selected patients. The long-term use of somatostatin receptor ligands is safe and they are well tolerated. Future medical therapy consists of pasireotide, a novel, universal somatostatin receptor agonist, and a new class of drugs named dopastatins. The latter so-called chimeric molecules have strong affinity for somatostatin receptors and dopamine-2 receptors, resulting in a more effective blocking of GH secretion, according to preliminary data. The authors of this paper review the current medical therapy of acromegaly, focusing on the role of somatostatin receptor ligands.

Context: Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial., Objective: To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA)., Design and Methods: Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (n=36) or SA (n=27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ))., Results: Total and bioactive IGF1 (μg/l) levels were similar (total: 185 ± 10 (SA) versus 171 ± 8 (surgery) (P=0.28); bioactive: 1.9 ± 0.2 vs 1.9 ± 0.1 (P=0.70)). Suppression of total and free GH (μg/l) during OGTT was blunted in the SA group (total GH(nadir): 0.59 ± 0.08 (SA) versus 0.34 ± 0.06 (surgery) (P=0.01); free GH(nadir): 0.43 ± 0.06 vs 0.19 ± 0.04 (P<0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (P=0.02). Disease-specific health status was better in patients after surgery (P=0.02)., Conclusions: i) Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

Growth hormone (GH)-secreting pituitary adenomas represent a common source of GH excess in patients with acromegaly. Whereas surgical extirpation of the culprit lesion is considered first-line treatment, as many as 19% of patients develop recurrent symptoms due to regrowth of previously resected adenomatous tissue or to continued growth of the surgically inaccessible tumor. Although medical therapies that suppress GH production can be effective in the management of primary and recurrent acromegaly, these therapies are not curative, and lifelong treatment is required for hormonal control. Stereotactic radiosurgery has emerged as an effective adjunctive treatment modality, and is an appealing alternative to conventional fractionated radiation therapy. The authors reviewed the growing body of literature concerning the role of radiosurgical procedures in the treatment armamentarium of acromegaly, and identified more than 1350 patients across 45 case series. In this review, the authors report that radiosurgery offers true hormonal normalization in 17% to 82% of patients and tumor growth control in 37% to 100% of cases across all series, while minimizing adverse complications. As a result, stereotactic radiosurgery represents a safe and effective treatment option in the multimodal management of primary or recurrent acromegaly secondary to GH-secreting pituitary adenomas.

Octreotide long-acting release (LAR) [Sandostatin LAR] is a somatostatin analogue with a well established clinical profile in patients with acromegaly. It binds to somatostatin receptor subtypes 2 and 5 with high potency to reduce the production and secretion of growth hormone (GH) and insulin-like growth factor (IGF)-I. Octreotide LAR is administered intramuscularly once every 28 days, in contrast to the subcutaneous formulation which requires administration two to three times daily. In several noncomparative trials, octreotide LAR was effective as primary therapy in normalizing GH and IGF-I levels and reducing tumour volume in patients with acromegaly. In addition, no significant difference was seen between octreotide LAR and surgery or lanreotide long-acting (LA) or lanreotide Autogel(R) (ATG) in small, randomized or observational, primary therapy trials. In another small, randomized trial, preoperative octreotide LAR followed by surgery was no more effective than surgery alone in terms of normalizing IGF-I levels, except in patients with macroadenoma. Octreotide LAR has also demonstrated good efficacy as postoperative adjuvant therapy, alone or in combination with pegvisomant, in randomized or noncomparative trials. In patients with different treatment histories (mixed populations), the efficacy of octreotide LAR appears to be generally similar to that of lanreotide ATG and greater than that of lanreotide LA, according to data from switching or crossover studies. Also in mixed populations, the efficacy of octreotide LAR was not significantly different to that of pegvisomant in terms of normalizing IGF-I levels in a randomized trial, and octreotide LAR demonstrated good efficacy in combination with cabergoline in a small, sequential-treatment trial. Octreotide LAR was generally well tolerated in clinical trials, with the most commonly occurring adverse events being gastrointestinal or hepatobiliary in nature. Thus, octreotide LAR continues to be a valuable option in the treatment of acromegaly.

Growth hormone is widely used clinically to promote growth and anabolism and for other purposes. Its actions are mediated via the growth hormone receptor, both directly by tyrosine kinase activation and indirectly by induction of insulin-like growth factor 1 (IGF-1). Insensitivity to growth hormone (Laron syndrome) can result from mutations in the growth hormone receptor and can be treated with IGF-1. This treatment is, however, not fully effective owing to the loss of the direct actions of growth hormone and altered availability of exogenous IGF-1. Excessive activation of the growth hormone receptor by circulating growth hormone results in gigantism and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of the receptor. Advances in understanding the mechanism of receptor activation have led to a model in which the growth hormone receptor exists as a constitutive dimer. Binding of the hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then phosphorylation of receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopoietin receptors.

The insulin-like growth factors (IGFs) acting via the type I IGF receptor (IGF-1R) regulate cancer cell proliferation, survival, metabolism and metastasis. Drugs targeting the IGF-1R are being tested in human clinical trials for cancer therapy and it seems likely that this class of drugs could be approved soon. Recent data suggests that insulin receptor, which is closely related to IGF-1R, should also be targeted to maximally inhibit the system. Furthermore, biomarkers that will identify patients whose tumors are driven by IGF-1R and biomarkers that allow monitoring or prediction of response are needed. This article reviews the different drugs against IGF-1R that are being tested in and how this receptor pathway can be optimally targeted for cancer therapy with an emphasis on breast cancer therapy.

To prolong the circulation half-life of human prolactin (hPRL), human GH (hGH), and their competitive antagonists, hPRL-G129R and hGH-G120R, we examined the effects of fusing a serum albumin-binding peptide (SA20) to their amino- or carboxyl-terminus. Fusion of the SA20 peptide to the amino-terminus of the ligands was less detrimental upon their ability to induce or inhibit signal transduction and cell proliferation in vitro than fusion to the carboxyl-terminus. Pharmacokinetic (PK) studies in mice revealed that the half-life of SA20-hPRL and SA20-hGH was prolonged and their clearance was reduced in comparison with hPRL and hGH. Pharmacodynamic (PD) studies in 8-week-old female mice revealed that lobuloalveolar development in mammary glands was greater in all three groups (daily, every 2 days, or every third day over a 12-day period) of mice treated with SA20-hPRL (4 mg/kg) compared with hPRL (3.59 mg/kg). Similarly, daily administration (i.p.) of SA20-hGH (8 mg/kg) or hGH (7.15 mg/kg) to 23-day-old female mice over a 40-day period revealed the superiority of SA20-hGH over hGH as measured by weight gain, body length, and lobuloalveolar development in the mammary glands. These findings indicate that SA20 modification of hPRL, hGH, and their respective antagonists improves their PK/PD properties.

Context: Stimulation of lipolysis, leading to increased blood concentrations of free fatty acids (FFAs), is a primary effect of GH and phosphorylation of intracellular signal transducer and activator of transcription (STAT)-5 is a primary mediator of the effects of GH., Objective: Based on preliminary results, we intended to test whether FFAs exert a negative feedback inhibition of STAT5 phosphorylation in skeletal muscle., Design and Participants: Eight healthy young men were investigated for 8 h on four occasions at four different FFA levels in a single blind, randomized manner. Acipimox was used to suppress FFA levels and Intralipid was infused to obtain appropriate FFA concentrations. Somatostatin was infused to control GH levels and GH, insulin, and glucagon were replaced. Muscle biopsies were taken after 8 h and compared with a fifth biopsy taken under normal basal conditions., Setting: The study was conducted at a university clinical research unit., Results: GH concentrations remained steady and comparable in all studies and FFA concentrations varied between 0.01 and 1.71 mmol/liter on the four occasions (P < 0.05). We observed a dose-dependent 40% decrease of STAT5 phosphorylation in skeletal muscle with increasing concentrations of FFAs., Conclusions: Our results strongly suggest the existence of a negative feedback loop, whereby effects of GH may be dampened by FFA inhibition of GH-dependent STAT5 phosphorylation. The mechanisms behind and biological consequences of this finding awaits additional studies.

Background: ACROSTUDY is an international noninterventional surveillance study open to all patients with acromegaly treated with the growth hormone antagonist pegvisomant. This web-based registry contains data reflecting actual clinical care of patients, and it is being used to monitor the long-term safety and efficacy of pegvisomant therapy for acromegaly. Since ACROSTUDY was launched in 2004, there has been an increase in cumulative patient recruitment from 116 patients in 2005 to over 500 by mid-2008. As of May 2008, over 300 centers in 10 countries have contributed data from 469 patients. At the time of inclusion, 84% of patients had already been treated with pegvisomant. Of the 469 patients, the majority had received somatostatin analogue treatment (63% had received octreotide and 34% had received lanreotide); 20% reported no prior medical treatment. Overall, 74% had prior transsphenoidal surgery, 3% had undergone craniotomy and 35% had received radiation therapy (including stereotactic radiosurgery). Interestingly, 67% were treated with pegvisomant alone at study start, 4% took pegvisomant with a dopamine agonist, 26% with a somatostatin analogue and 3% took pegvisomant with both types of analogues. The starting dose of pegvisomant was 10 mg/day for 65% of patients treated with subcutaneous daily injections, and the mean insulin-like growth factor I (IGF-I) concentration at baseline was 526 ng/ml. Annual assessments since study launch in 2004 found 62-78% of patients had normal IGF-I levels after 1-4 years of pegvisomant treatment at mean doses of 18.7-22 mg/day. Adverse events were reported for 13% of patients, including 6 serious adverse events considered possibly related to the drug. An increase in tumor size relative to the size at start of pegvisomant therapy was reported for 24 of the 469 patients (5.1%). Liver function test results more than twice the upper limit of normal were observed in 7.7%., Conclusions: Further analyses of the ACROSTUDY database will provide a better understanding of pegvisomant treatment in clinical practice., (Copyright 2009 S. Karger AG, Basel.)

Acromegaly is a rare disease usually caused by growth hormone (GH) hypersecretion, due to a pituitary adenoma; in very rare cases, acromegaly is due to ectopic secretion of GHRH, responsible for pituitary hyperplasia. Owing to its insidious onset, acromegaly is often diagnosed late (4 to > 10 years after onset), at an average age of about 40 years, in front of an acquired, slowly progressing disfigurement mainly involving the face and extremities. Acromegaly has also rheumatologic, cardiovascular, respiratory and metabolic consequences which determine its prognosis. The diagnosis is based on an increased serum GH concentration unsuppressed following an oral glucose load (oral glucose tolerance test -OGTT-) and an increased insulin-like growth factor-I (IGF-I); according to a 2000 Consensus statement, if the basal serum GH is above 0,4microg/L (1.2mIU/L) and/or if the IGF-I is elevated, an OGTT must be performed. If the lowest GH value (nadir) during OGTT remains above 1microg/L (3mIU/L), acromegaly is confirmed. With the generalized use of very sensitive assays nowadays, it has recently been considered that this cutoff should be decreased to 0,3microg/L (0.9mIU/L). Treatment is aimed at correcting (or preventing) tumor compression by excising the culprit lesion, and at reducing GH and IGF-I levels to normal values (or at least to a "safe" GH level of < 2microg/L or < 6mIU/L). A stepwise therapeutic strategy is used: transsphenoidal surgery is often the first-line treatment; when surgery fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogs and/or radiotherapy can be used, somatostatin analogs being generally preferred; the GH antagonist (pegvisomant) is used in patients that are resistant or intolerant to somatostatin analogs. Prognosis of acromegaly has improved in the recent years: adequate hormonal disease control is achieved in most cases, allowing life expectancy similar to that of the general population.

Background: Pulsatile GH secretion declines in older men. The causal mechanisms are unknown. Candidates include deficient feedforward (stimulation) by endogenous secretagogues and excessive feedback (inhibition) by GH or IGF-I due to age and/or relative hypoandrogenemia., Hypothesis: Testosterone (T) supplementation in healthy older men will restrain negative feedback by systemic concentrations of IGF-I., Subjects: Twenty-four healthy men (ages, 50 to 75 yr; body mass index, 24 to 30 kg/m(2)) participated in the study., Methods: We performed a prospectively randomized, double-blind, placebo-controlled assessment of the impact of pharmacological T supplementation on GH responses to randomly ordered separate-day injections of recombinant human IGF-I doses of 0, 1.0, 1.5, and 2.0 mg/m(2)., Analysis: Deconvolution and approximate entropy analyses of pulsatile, basal, and entropic (pattern-sensitive) modes of GH secretion were conducted., Results: Recombinant human IGF-I injections 1) elevated mean and peak serum IGF-I concentrations dose-dependently (both P < 0.001); 2) suppressed pulsatile GH secretion (P = 0.003), burst mass (P = 0.025), burst number (P = 0.005), interpulse variability (P = 0.032), and basal GH secretion (P = 0.009); and 3) increased secretory pattern regularity (P = 0.020). T administration did not alter experimentally controlled IGF-I concentrations, but it elevated mean GH concentrations (P = 0.015) and stimulated pulsatile GH secretion (frequency P = 0.037, mass per burst P = 0.038). Compared with placebo, T attenuated exogenous IGF-I's inhibition of GH secretory-burst mass (P < 0.038) without restoring pulse number, basal secretion, or pattern regularity., Conclusion: The capability of systemic T to mute IGF-I feedback on pulsatile GH secretion suggests a novel mechanism for augmenting GH production.

The efficacy and safety of the long-acting repeatable formulation of octreotide (OCT-LAR) treatment in patients suffering from acromegaly was investigated retrospectively in Shizuoka prefecture, Japan. Thirty patients (11 male, 19 female; average age, 48.9 years old), 29 of whom had undergone transsphenoidal surgery previously, were treated with OCT-LAR. OCT-LAR was injected i.m. every 4 weeks with an intended protocol of 20 mg over 24 months, however, 46.7% of patients required the dose of OCT-LAR to be increased. The final average dose of OCT-LAR was 25.0 +/- 6.8 mg. Administering OCT-LAR significantly decreased serum GH and insulin-like growth factor 1 (IGF-1) levels (from 13.7 +/- 11.9 to 5.8 +/- 7.3 microg/L and from 585 +/- 263 to 339 +/- 193.7 microg/L after 3 months, respectively). Among patients treated with OCT-LAR, 56.7% expressed

In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH-GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor-GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH-IGF-I axis.

Recent published data have demonstrated elevated levels of human GH (hGH) in endometriosis and endometrial adenocarcinoma. Herein, we demonstrate that autocrine production of hGH can enhance the in vitro and in vivo oncogenic potential of endometrial carcinoma cells. Forced expression of hGH in endometrial carcinoma cell lines RL95-2 and AN3 resulted in an increased total cell number through enhanced cell cycle progression and decreased apoptotic cell death. In addition, autocrine hGH expression in endometrial carcinoma cells promoted anchorage-independent growth and increased cell migration/invasion in vitro. In a xenograft model of human endometrial carcinoma, autocrine hGH enhanced tumor size and progression. Changes in endometrial carcinoma cell gene expression stimulated by autocrine hGH was consistent with the altered in vitro and in vivo behavior. Functional antagonism of hGH in wild-type RL95-2 cells significantly reduced cell proliferation, cell survival, and anchorage-independent cell growth. These studies demonstrate a functional role for autocrine hGH in the development and progression of endometrial carcinoma and indicate potential therapeutic relevance of hGH antagonism in the treatment of endometrial carcinoma.

Background: Somatostatin analogs previously considered as adjuvant therapy in acromegaly are increasingly used as a first-line therapy in selected cases., Objective: To review the octreotide LAR pharmacological and clinical data, and discuss the impact of this agent on current treatment regimens., Methods: We reviewed PubMed publications since the first use of octreotide LAR in acromegaly, and historical articles related to the discovery and development of this molecule. We chose, for efficacy and safety data, reviews, clinical and randomized controlled trials that included >or=10 patients., Results/conclusion: Octreotide LAR controls acromegaly in approximately 50-60% of patients by inhibiting GH and IGF-I secretion, and by reducing tumor size. This drug is well tolerated in most patients.

Aim: Free fatty acids (FFAs) are important fuels and have vital protein-sparing effects, particularly during conditions of metabolic stress and fasting. However, it is uncertain whether these beneficial effects are evident throughout the physiological range or only occur at very high FFA concentrations. It is also unclear whether secondary alterations in hormone levels and ketogenesis play a role. We therefore aimed at describing dose-response relationships between amino acid metabolism and circulating FFA concentrations at clamped hormone levels., Methods: Eight healthy men were studied on four occasions (6 h basal, 2 h glucose clamp). Endogenous lipolysis was blocked with acipimox and Intralipid was infused at varying rates (0, 3, 6 or 12 microL kg(-1) min(-1)) to obtain four different levels of circulating FFAs. Endogenous growth hormone, insulin and glucagon secretion was blocked by somatostatin (300 microg h(-1)) and replaced exogenously. 15N-phenylalanine, 2H4-tyrosine and 13C-urea were infused continuously to assess protein turnover and ureagenesis., Results: We obtained four distinct levels of FFA concentrations ranging from 0.03 to 2.1 mmol L(-1) and 3-hydroxybutyrate concentrations from 10 to 360 micromol L(-1). Whole-body phenylalanine turnover and phenylalanine-to-tyrosine degradation decreased with increasing FFA levels as did insulin-stimulated forearm fluxes of phenylalanine. Phenylalanine, tyrosine and urea concentrations also decreased progressively, whereas urea turnover was unperturbed., Conclusion: Circulating FFAs decrease amino acid concentrations and inhibit whole-body phenylalanine fluxes and phenylalanine-to-tyrosine conversion. Our data cover FFA concentrations from 0 to 2 mmol L(-1) and indicate that FFAs exert their protein conserving effects in the upper physiological range (>1.5 mmol L(-1)).

In the vast majority of cases, basal serum GH and IGF-1 levels are markedly increased in patients with obvious clinical signs and symptoms of acromegaly. The oral glucose tolerance test (OGTT) is useful for diagnosis in the minority of patients who have weak GH hypersecretion. The cutoff for a "normal" GH nadir in the OGTT remains to be agreed. The type of GH assay, its sensitivity, the type of standard used by the manufacturer, the patient's age and especially gender, must all be taken into account. Recent studies using new highly sensitive assays suggest an upper normal GH nadir of 0.71 microg/l for female healthy patients, but no "universal" cut-off has yet been defined for healthy males (from 0.057 to 0.25 microg/l). The 1 microg/l cutoff proposed for the diagnosis of acromegaly in a 2000 consensus should be abandoned in favor of a 0.30 microg/l cutoff. Clinicians should know which assay is used, together with its sensitivity and the standard, before making therapeutic decisions. A more pragmatic view should probably be adopted when assessing the treatment response. Indeed, if "cure" is defined not with the <1 microg/l GH nadir but on the basis of healthy control values, many patients will not be considered controlled. However, the clinical relevance of such goal (e.g. achieving GH nadir <0.4 microg/l rather than <1 microg/l) in terms of prognosis and prediction of outcome on long term is not firmly established. Thus, from a pragmatic point of view, achieving a normal age-adjusted IGF-1 level and a GH nadir below 1 microg/l during OGTT will probably remain relevant for defining remission and good disease control in terms of morbidity and mortality in acromegaly.

Background: GH nonsuppression after oral glucose is diagnostic for GH excess, but normative data are lacking in children. Adult data cannot be extrapolated to children given the pubertal increase in GH concentration. In addition, because GH levels are higher in pubertal girls than boys, nadir GH may differ across gender., Objective: Our objective was to determine whether nadir GH during an oral glucose tolerance test (OGTT) is gender and pubertal stage specific. We hypothesized that nadir GH would be higher in girls, and at the pubertal stage known to correspond with peak height velocity (Tanner 2-3 in girls and Tanner 3-4 in boys) and maximal GH concentrations. SUBJECTS/ METHODS: A 2-h OGTT using 2.35 g/kg oral glucose (maximum 100 g) was performed in 64 girls and 43 boys, 9-17 yr (10th-90th percentiles for body mass index). Girls were grouped as group 1 (Tanner 1), group 2 (Tanner 2-3), and group 3 (Tanner 4-5), and boys as group 1 (Tanner 1-2), group 2 (Tanner 3-4), and group 3 (Tanner 5)., Results: Nadir GH was higher in girls than boys, and in group 2 girls and boys than the other two groups. The upper limit for nadir GH was highest in group 2 girls (1.57 ng/ml), and lower for the other two groups of girls (0.64 ng/ml), and for boys (0.50 ng/ml). All but one girl, and all boys suppressed to less than 1.0 ng/ml. There were 16 girls and five boys who had a nadir GH of more than 0.3 ng/ml., Conclusion: GH suppression after oral glucose is gender and pubertal stage specific.

To determine whether blockade of the exercise-induced increase in growth hormone (GH) secretion may affect the regional lipolytic rate in the post-exercise recovery period, the aim of the present experiments was to study the effect of infusion of the somatostatin analogue octreotide on the s.c., abdominal adipose tissue metabolism, before, during and after exercise in healthy, fasting, young male subjects. The adipose tissue net releases of fatty acids and glycerol were measured by arterio-venous catheterizations and simultaneous measurements of adipose tissue blood flow with the local Xe-clearance method. Nine subjects were studied during 1-h basal rest, and then during continuous octreotide infusion during 1-h rest, 1-h exercise at 50% of maximal oxygen consumption and 4-h post-exercise rest. A control study on seven subjects was performed under similar conditions but without octreotide infusion. The results show that octreotide infusion during rest increased lipolysis and fatty acid release from the abdominal, s.c. adipose tissue. The exercise-induced increase in lipolysis and fatty acid release does not seem to be affected by octreotide when compared with the control study without octreotide infusion while the post-exercise increase in lipolysis is inhibited by octreotide, suggesting that the exercise-induced increase in GH secretion plays a role for the post-exercise lipolysis in s.c., abdominal adipose tissue.

Context and Objective: A single missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C) yields a mutant GH-R77C peptide, which was described as natural GH antagonist., Design, Setting, and Patients: Heterozygosity for GH-R77C/wt-GH was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SD score) and partial GH insensitivity was diagnosed. His mother and grandfather were also carrying the same mutation and showed partial GH insensitivity with modest short stature., Interventions and Results: Functional characterization of the GH-R77C was performed through studies of GH receptor binding and activation of Janus kinase 2/Stat5 pathway. No differences in the binding affinity and bioactivity between wt-GH and GH-R77C were found. Similarly, cell viability and proliferation after expression of both GH peptides in AtT-20 cells were identical. Quantitative confocal microscopy analysis revealed no significant difference in the extent of subcellular colocalization between wt-GH and GH-R77C with endoplasmic reticulum, Golgi, or secretory vesicles. Furthermore studies demonstrated a reduced capability of GH-R77C to induce GHR/GHBP gene transcription rate when compared with wt-GH., Conclusion: Reduced GH receptor/GH-binding protein expression might be a possible cause for the partial GH insensitivity with delay in growth and pubertal development found in our patients. In addition, this group of patients deserves further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity.

Context: GH and other stress hormones stimulate lipolysis, which may result in free fatty acid (FFA)-mediated insulin resistance. However, there are also indications that FFAs in the very low physiological range have the same effect., Objective: The objective of the study was to address systematically the dose-response relations between FFAs and insulin sensitivity., Design: We therefore examined eight healthy men for 8 h (6 h basal and 2 h glucose clamp) on four occasions., Intervention: Intralipid was infused at varying rates (0, 3, 6, 12 microl.kg(-1).min(-1)); lipolysis was blocked by acipimox; and endogenous GH, insulin, and glucagon secretion was blocked by somatostatin and subsequently replaced at fixed rates., Results: This resulted in four different FFA levels between 50 and 2000 micromol/liter, with comparable levels of insulin and counterregulatory hormones. Both in the basal state and during insulin stimulation, we saw progressively decreased glucose disposal, nonoxidative glucose disposal, and forearm muscle glucose uptake at FFA levels above 500 micromol/liter. Apart from forearm glucose uptake, the very same parameters were decreased at low FFA levels (approximately 50 micromol/liter). FFA rate of disposal was linearly related to the level of FFAs, whereas lipid oxidation reached a maximum at FFA levels approximately 1000 micromol/liter., Conclusion: In the presence of comparable levels of all major metabolic hormones, insulin sensitivity peaks at physiological levels of FFAs with a gradual decrease at elevated as well as suppressed FFA concentrations. These data constitute comprehensive dose-response curves for FFAs in the full physiological range from close to zero to above 2000 micromol/liter.