Somatostatin analogues in acromegaly and gastroenteropancreatic neuroendocrine tumours: past, present and future.

Acromegaly is a hormonal disorder that arises when the pituitary gland secretes excess growth hormone (GH), which in turn stimulates a concomitant increase in serum insulin-like growth factor 1 (IGF-1) levels. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) constitute a heterogeneous group of tumours that can secrete serotonin and a variety of peptide hormones that may cause characteristic symptoms known as carcinoid syndrome or other symptoms and hormonal hypersecretion syndromes depending on the tumour's site of origin. Current medical therapy for the treatment of acromegaly and GEP-NET involves the administration of somatostatin analogues that effectively suppress excess hormone secretion.

Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly.

Objective: The high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst2) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function.

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells.

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express insulin-like growth factor (IGF)-related factors [IGF1, IGF2; insulin receptor (IR)-A, IR-B; IGF-binding protein (IGFBP) 1-3] as well as somatostatin (SSTRs) and dopamine D2 receptors (D2Rs).

Objectives: To (1) compare mRNA expression of IGF-related factors in human pancreatic NET (panNET) cell lines with that in human GEP-NETs to evaluate the usefulness of these cells as a model for studying the IGF system in GEP-NETs, (2) determine whether panNET cells produce growth factors that activate IR-A, and (3) investigate whether somatostatin analogs (SSAs) and/or dopamine agonists (DAs) influence the production of these growth factors.

Methods: In panNET cells (BON-1 and QGP-1) and GEP-NETs, mRNA expression of IGF-related factors was measured by quantitative real-time PCR.

Cushing's syndrome: an update on current pharmacotherapy and future directions.

Introduction: Endogenous Cushing's syndrome (CS) is characterized by chronic overproduction of cortisol and is associated with increased mortality and morbidity. It can be caused by a pituitary adenoma, ectopic adrenocorticotropic hormone (ACTH) production or primary adrenal disease. Successful tumor-directed surgery is the keystone treatment.

Changes in circulating IGF1 receptor stimulating activity do not parallel changes in total IGF1 during GH treatment of GH-deficient adults.

Context: Previously we demonstrated that IGF1 receptor stimulating activity (IGF1RSA) offers advantages in diagnostic evaluation of adult GH deficiency (GHD). It is unknown whether IGF1RSA can be used to monitor GH therapy.

Objective: To investigate the value of circulating IGF1RSA for monitoring GH therapy.

Advances in the assessment of cortisol exposure and sensitivity.

Purpose Of Review: To review recent progress in the field of cortisol exposure and sensitivity, and its implications for research concerning obesity and related metabolic disturbances.

Recent Findings: In the past few years, scalp hair analysis had been successfully introduced as a marker for long-term cortisol exposure. With this relatively novel method, increased long-term cortisol levels have been linked to cardiovascular disease, metabolic syndrome, and stress-related measures.

Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors.

The mTOR pathway has recently been suggested as a new potential target for therapy in adrenocortical carcinomas (ACCs). The aim of the current study is to describe the expression of the mTOR pathway in normal adrenals (NAs) and pathological adrenals and to explore whether there are correlation between the expression of these proteins and the in vitro response to sirolimus. For this purpose, the MTOR, S6K1 (RPS6KB1), and 4EBP1 (EIF4EBP1) mRNA expression were evaluated in ten NAs, ten adrenal hyperplasias (AHs), 17 adrenocortical adenomas (ACAs), and 17 ACCs by qPCR, whereas total(t)/phospho(p)-MTOR, t/p-S6K, and t/p-4EBP1 protein expression were assessed in three NAs, three AHs, six ACAs, and 20 ACCs by immunohistochemistry.

Radiometrical, hormonal and biological correlates of skeletal growth in the female rat from birth to senescence.

Objective: We investigated the skeletal growth profile of female rats from birth to senescence (100weeks) on the basis of sequential radiometrical, hormonal and biochemical parameters.

Design: Weaning rats entered the study which was divided into two sections: a) sequential measurements of vertebral and tibial growths and bone mineral density (BMD), estimation of mineral content of the entire skeleton (BMC) and chemical analysis of vertebral Ca; and b) determination of basal and pulsatile growth hormone (rGH), insulin-like growth hormone (IGF-I), estradiol (E2), parathyroid hormone (PTH), osteocalcin (OC) and urinary d-pyridinoline (dp) throughout the experimental period.

Results: Vertebral and tibial growths ceased at week 25 whereas BMD and BMC as well as total vertebral Ca exhibited a peak bone mass at week 40.

Expert consensus document: A consensus on the medical treatment of acromegaly.

In March 2013, the Acromegaly Consensus Group met to revise and update guidelines for the medical treatment of acromegaly. The meeting comprised experts skilled in the medical management of acromegaly. The group considered treatment goals covering biochemical, clinical and tumour volume outcomes, and the place in guidelines of somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists, and alternative modalities for treatment including combination therapy and novel treatments.

β-Arrestin 1 and 2 and G protein-coupled receptor kinase 2 expression in pituitary adenomas: role in the regulation of response to somatostatin analogue treatment in patients with acromegaly.

Recent in vitro studies highlighted G protein-coupled receptor kinase (GRK)2 and β-arrestins as important players in driving somatostatin receptor (SSTR) desensitization and trafficking. Our aim was to characterize GRK2 and β-arrestins expression in different pituitary adenomas and to investigate their potential role in the response to somatostatin analog (SSA) treatment in GH-secreting adenomas (GHomas). We evaluated mRNA expression of multiple SSTRs, GRK2, β-arrestin 1, and β-arrestin 2 in 41 pituitary adenomas (31 GHomas, 6 nonfunctioning [NFPAs], and 4 prolactinomas [PRLomas]).

Glucocorticoid sensitivity in health and disease.

Glucocorticoids regulate many physiological processes and have an essential role in the systemic response to stress. For example, gene transcription is modulated by the glucocorticoid-glucocorticoid receptor complex via several mechanisms. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors.

Interferon-β is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane.

Adrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-β (IFN-β), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13 human ACCs, three adrenal hyperplasias, three adrenal adenomas, and in two ACC cell lines.

Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Graves' ophthalmopathy.

Context: There is a close association between levels of TSH binding inhibitory immunoglobulins (TBIIs) and Graves' ophthalmopathy (GO). In addition to the TSH receptor, the IGF-I receptor (IGF-IR) has been proposed to be a second autoantigen that plays a role in the pathogenesis of GO.

Objective: The aim was to study relationships between TBII and serum IGF-IR stimulating activity in relationship to age in patients with GO.

IGF-I bioactivity might reflect different aspects of quality of life than total IGF-I in GH-deficient patients during GH treatment.

Context: No relationship has been found between improvement in quality of life (QOL) and total IGF-I during GH therapy.

Aim: Our aim was to investigate the relationship between IGF-I bioactivity and QOL in GH-deficient (GHD) patients receiving GH for 12 months.

Methods: Of 106 GHD patients, 84 on GH treatment discontinued therapy 4 weeks before establishing baseline values and 22 were GH-naive.

Immunoreactivity score using an anti-sst2A receptor monoclonal antibody strongly predicts the biochemical response to adjuvant treatment with somatostatin analogs in acromegaly.

Context: Somatostatin receptor subtype 2 (sst2A) protein expression has been demonstrated to positively correlate with somatostatin analog treatment outcome in GH-secreting adenomas. Recently, a new rabbit monoclonal anti-sst2A antibody (clone UMB-1) has been validated as a reliable method to selectively detect sst2A protein levels in formalin-fixed tissues.

Objective: The aim of the study was to establish whether the evaluation of sst2A protein levels, assessed with a routine reproducible immunohistochemistry protocol using UMB-1 antibody, may predict the successful adjuvant therapy with somatostatin analogs in acromegalic patients.

Low circulating IGF-I bioactivity is associated with human longevity: findings in centenarians' offspring.

Unlabelled: Centenarians' offspring represent a suitable model to study age-dependent variables (e.g. IGF-I) potentially involved in the modulation of the lifespan.

Circulating insulin-like growth factors may contribute substantially to insulin receptor isoform A and insulin receptor isoform B signalling.

Background: Only a fraction of circulating insulin-like activity is due to insulin itself. The aim of this study was to determine total serum insulin-like activity mediated via the insulin receptor isoform A (IR-A) and isoform B (IR-B) by using kinase receptor activation (KIRA) assays specific for the IR-A and IR-B.

Methods: The IR-A and IR-B KIRA assays use human embryonic kidney cells which have been transfected with the human IR-A or IR-B gene and quantify serum-mediated phosphorylation of the IR.

In vitro glucocorticoid sensitivity is associated with clinical glucocorticoid therapy outcome in rheumatoid arthritis.

Introduction: Genetic and disease-related factors give rise to a wide spectrum of glucocorticoid (GC) sensitivity in rheumatoid arthritis (RA). In clinical practice, GC treatment is not adapted to these differences in GC sensitivity. In vitro assessment of GC sensitivity before the start of therapy could allow more individualized GC therapy.

Glucocorticoid receptor gene polymorphisms and disease activity during pregnancy and the postpartum period in rheumatoid arthritis.

Introduction: The mechanism underlying the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and the subsequent postpartum flare is incompletely understood, and the disease course varies widely between pregnant RA patients. In pregnancy, total and free levels of cortisol increase gradually, followed by a postpartum decrease to prepregnancy values. The glucocorticoid receptor (GR) polymorphisms BclI and N363S are associated with relatively increased glucocorticoid (GC) sensitivity, whereas the 9β and ER22/23EK polymorphisms of the GR gene are associated with a relatively decreased GC sensitivity.

High IGFBP2 levels are not only associated with a better metabolic risk profile but also with increased mortality in elderly men.

Objective: Serum IGF-binding protein 2 (IGFBP2) concentrations are reduced in obese humans and increase after a prolonged period of fasting. We investigated the association between IGFBP2 levels and mortality together with other factors that are related to IGFBP2, including the metabolic syndrome and physical function.

Design: A prospective observational study at a clinical research center of 403 independently living elderly men (aged 73-94 years).

The role of mTOR inhibitors in the inhibition of growth and cortisol secretion in human adrenocortical carcinoma cells.

Patients with adrenocortical carcinoma (ACC) need new treatment options. The aim of this study was to evaluate the effects of the mTOR inhibitors sirolimus and temsirolimus on human ACC cell growth and cortisol production. In H295, HAC15, and SW13 cells, we have evaluated mTOR, IGF2, and IGF1 receptor expressions; the effects of sirolimus and temsirolimus on cell growth; and the effects of sirolimus on apoptosis, cell cycle, and cortisol production.

The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics.

Objective: The European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS).

Design And Methods: Baseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.

Estrogen receptor-alpha gene polymorphisms and body composition in children and adolescents.

Background/aims: Gender differences in body composition are largely explained by differences in sex hormones, such as estrogens. Associations between 2 polymorphisms in the estrogen receptor-α gene (ESR1) and body composition in children and adolescents were investigated.

Methods: Two comparable Dutch cohorts with a generational difference of about 20 years were investigated.

Prevalence and incidence of diabetes mellitus in adult patients on growth hormone replacement for growth hormone deficiency: a surveillance database analysis.

Context: GH replacement in adult GH-deficient patients may cause insulin resistance, raising concerns of potential increased risk of developing diabetes mellitus (DM).

Objective: Our objective was to assess DM prevalence and incidence in the international Hypopituitary Control and Complications Study (HypoCCS) surveillance database.

Design And Participants: GH-treated patients enrolled into HypoCCS (2922 U.