Growth Hormone (GH)-Releasing Peptide Stimulation of GH Release from Human Somatotroph Adenoma Cells: Interaction with GH-Releasing Hormone, Thyrotropin- Releasing Hormone, and Octreotide.

The synthetic hexapeptide GH-releasing peptide (GHRP; His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) specifically stimulates GH secretion in humans in vivo and in animals in vitro and in vivo via a still unknown receptor and mechanism. To determine the effect of GHRP on human somatotroph cells in vitro, we stimulated cell cultures derived from 12 different human somatotroph adenomas with GHRP alone and in combination with GH-releasing hormone (GHRH), TRH, and the somatostatin analog octreotide. GH secretion of all 12 adenoma cultures could be stimulated with GHRP, whereas GHRH was active only in 6 adenoma cultures. In GHRH-responsive cell cultures, simultaneous application of GHRH and GHRP had an additive effect on GH secretion. TRH stimulated GH release in 4 of 7 adenoma cultures; in TRH-responsive cell cultures there was also an additive effect of GHRP and TRH on GH secretion. In 5 of 9 adenoma cultures investigated, octreotide inhibited basal GH secretion. In these cell cultures, GHRP-induced GH release was suppressed by octreotide. In 5 of 5 cases, the protein kinase-C inhibitor phloretin partly inhibited GHRP-stimulated GH release, but not basal GH secretion. In summary, GH secretion was stimulated by GHRP in all somatotroph adenomas investigated, indicating that its unknown receptor and signaling pathway are expressed more consistently in somatotroph adenoma cells than those for GHRH, TRH, and somatostatin. Our data give further evidence that GHRP-stimulated GH secretion is mediated by a receptor different from that for GHRH or TRH, respectively, and that protein kinase-C is involved in the signal transduction pathway. Because human somatotroph adenoma cell cultures respond differently to various neuropeptides (GHRH, TRH, somatostatin, and others), they provide a model for further investigation of the mechanism of action of GHRP-induced GH secretion

Obstructive Sleep Apnea Syndrome Is Less Frequent in Patients With Well-Controlled Acromegaly Treated With Somatostatin Analogues, Pegvisomant or in Combination

Background: Obstructive sleep apnea (OSA) often occurs in patients with active acromegaly and improves after treatment. Less is known about the development of OSA in patients after a longer period of control treated with somatostatin analogues (SSA) and pegvisomant. Methods: Seventy-nine patients (12 females, 17 males; age 49 +/- 14 years; body mass index 29.9 +/- 5.4 kg/m(2); IGF-1 184 +/- 73 mu g/L; disease duration 13 +/- 8 years (mean +/- standard deviation)) with wellcontrolled acromegaly treated with SSA (38%), pegvisomant (38%) or in combination (24%) who underwent ambulatory polygraphy were included in a prospective multicenter cross-sectional study. Results: Fourteen percent had OSA (range of apnea-hypopnea index (AHI) 5 -15). Patients with OSA (AHI >= 5 vs. < 5) had a longer disease duration (16 +/- 1 vs. 12 +/- 8 years; P = 0.01) and were older (61 +/- 9 vs. 47 +/- 13 years; P = 0.037). The AHI of all patients correlated with age (P = 0.01; r = 0.44). No differences were seen in terms of BMI and Epworth sleepiness scale score. Previous transsphenoidal surgery and radiation had no impact of the detection of OSA. The duration of well-controlled acromegaly was 7 +/- 3 years. Conclusion: OSA in patients with well-controlled acromegaly treated with SSA, pegvisomant or in combination is less frequent (14%) than previously described. Early treatment to reduce the active disease period should be aimed to prevent OSA

Retinoic acid stimulates meningioma cell adhesion to the extracellular matrix and inhibits invasion

Meningiomas are tumours derived from the arachnoid and pia mater. During embryogenesis, these membranes develop from the migrating craniofacial neural crest. We have previously demonstrated that meningiomas have characteristic features of embryonic meninges. Craniofacial neural crest derivatives are affected during normal development and migration by retinoic acid. We speculated, therefore, that meningioma cell migration and invasion would be affected in a similar way. In this study we investigated the mechanisms of invasion and migration in meningiomas and the effects of retinoic acid (RA). We found that low doses of RA inhibit in vitro invasion in meningioma cells, without affecting cell proliferation or viability. The matrix metalloproteinases MMP-2 (72 kDa gelatinase) and MMP-9 (92 kDa gelatinase), which play a key role in invasion in other tumours, are not affected by RA. RA inhibits cell migration on collagen I and fibronectin. A possible mechanism for these effects is provided by the fact that RA strongly stimulates adhesion of meningioma cells to extracellular matrix substrates. As in vitro invasion, migration and decreased adhesion to the extracellular matrix correlate with the clinical manifestation of tumour invasion, we conclude that RA induces a non-invasive phenotype in meningioma cells. © 1999 Cancer Research Campaig

The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells

Rapamycin and its analogues have significant antiproliferative action against a variety of tumors. However, sensitivity to rapamycin is reduced by Akt activation that results from the ablative effects of rapamycin on a p70 S6K-induced negative feedback loop that blunts phosphoinositide 3-kinase (PI3K)-mediated support for Akt activity. Thus, sensitivity to rapamycin might be increased by imposing an upstream blockade to the PI3K/Akt pathway. Here, we investigated this model using the somatostatin analogue octreotide as a tool to decrease levels of activated Ser(473)-phosphorylated Akt (pAkt-Ser(473)) in pituitary tumor cells that express somatostatin receptors. Octreotide increased levels of phosphorylated insulin receptor substrate-1 that were suppressed by rapamycin, subsequently decreasing levels of pAkt-Ser(473) through effects on phosphotyrosine phosphatase SHP-1. Octreotide potentiated the antiproliferative effects of rapamycin in immortalized pituitary tumor cells or human nonfunctioning pituitary adenoma cells in primary cell culture, sensitizing tumor cells even to low rapamycin concentrations. Combined treatment of octreotide and rapamycin triggered G(1) cell cycle arrest, decreasing E2F transcriptional activity and cyclin E levels by increasing levels of p27/Kip1. These findings show that adjuvant treatment with a somatostatin analogue can sensitize pituitary tumor cells to the antiproliferative effects of rapamycin

Increased Prevalence of Anxiety-Associated Personality Traits in Patients with Cushing’s Disease: A Cross-Sectional Study

Background/Aims: Chronic hypercortisolism in Cushing’s disease (CD) hasbeen suggested to contribute to an altered personality profile in thesepatients. We aimed to test this hypothesis and attempted to determinethe effects of disease- and treatment-related factors that mightmoderate an altered personality in CD. Methods: We assessed 50 patientswith CD (74% biochemically controlled) and compared them to 60 patientswith non-functioning pituitary adenomas (NFPA) and 100 age-andgender-matched mentally healthy controls. Personality was measured bytwo standardized personality questionnaires, TPQ (Cloninger PersonalityQuestionnaire) and EPQ-RK (Eysenck Personality Questionnaire-RK).Results: Compared to mentally healthy controls, CD patients reportedsignificantly less novelty-seeking behaviour, including less exploratoryexcitability and less extravagance. On harm avoidant subscales, theypresented with more anticipatory worries and pessimism, higher fear ofuncertainty, shyness with strangers, fatigability and asthenia.Moreover, CD patients appeared to be less extraverted, more neurotic andsocially desirable. CD patients differed from NFPA patients in terms ofhigher neuroticism scores, and NFPA patients did not show alterednovelty-seeking behaviour or extraversion. In the subgroup analysis, CDpatients with persistent hypercortisolism displayed significantly higherfear of uncertainty, fatigability and asthenia, indicating high harmavoidance in total, than those in biochemical remission. Conclusion:Patients with CD showed a distinct pattern of personality traitsassociated with high anxiety in combination with traits of lowexternalizing behaviour. Such personality changes should be taken intoaccount in the diagnosis and treatment of CD patients, as they mightinterfere with the patient-physician communication and/or challenge thepatients’ social and psychological functioning

Metabolic and hormonal studies of Type 1 (insulin-dependent) diabetic patients after successful pancreas and kidney transplantation

Long-term normalization of glucose metabolism is necessary to prevent or ameliorate diabetic complications. Although pancreatic grafting is able to restore normal blood glucose and glycated haemoglobin, the degree of normalization of the deranged diabetic metabolism after pancreas transplantation is still questionable. Consequently glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide responses to oral glucose and i.v. arginine were measured in 36 Type 1 (insulin-dependent) diabetic recipients of pancreas and kidney allografts and compared to ten healthy control subjects. Despite normal HbA1 (7.2±0.2%; normal <8%) glucose disposal was normal only in 44% and impaired in 56% of the graft recipients. Normalization of glucose tolerance was achieved at the expense of hyperinsulinaemia in 52% of the subjects. C-peptide and glucagon were normal, while pancreatic polypeptide was significantly higher in the graft recipients. Intravenous glucose tolerance (n=21) was normal in 67% and borderline in 23%. Biphasic insulin release was seen in patients with normal glucose tolerance. Glucose tolerance did not deteriorate up to 7 years post-transplant. In addition, stress hormone release (cortisol, growth hormone, prolactin, glucagon, catecholamines) to insulin-induced hypoglycaemia was examined in 20 graft recipients and compared to eight healthy subjects. Reduced blood glucose decline indicates insulin resistance, but glucose recovery was normal, despite markedly reduced catecholamine and glucagon release. These data demonstrate the effectiveness of pancreatic grafting in normalizing glucose metabolism, although hyperinsulinaemia and deranged counterregulatory hormone response are observed frequently

Low Prevalence of Isolated Growth Hormone Deficiency in Patients After Brain Injury: Results From a Phase II Pilot Study

Growth hormone deficiency (GHD) results in an impaired health-related quality of life (HrQoL) and cognitive impairment in the attention and memory domain. GHD is assumed to be a frequent finding after brain injury due to traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (SAH) or ischemic stroke. Hence, we set out to investigate the effects of growth hormone (GH) replacement therapy in patients with isolated GHD after brain injury on HrQoL, cognition, and abdominal fat composition. In total, 1,408 patients with TBI, SAH or ischemic stroke were screened for inclusion. Of those, 54 patients (age 18-65 years) were eligible, and 51 could be tested for GHD with GHRH-L-arginine. In 6 patients (12%), GHD was detected. All patients with isolated GHD (n = 4 [8%], male, mean age +/- SD: 49.0 +/- 9.8 years) received GH replacement therapy for 6 months at a daily dose of 0.2-0.5 mg recombinant GH depending on age. Results were compared with an untreated control group of patients without hormonal insufficiencies after brain injury (n = 6, male, mean age +/- SD: 49.5 +/- 13.6 years). HrQoL as well as mood and sleep quality assessed by self-rating questionnaires (Beck Depression Index, Pittsburgh Sleep Quality Index) did not differ between baseline and 6 months within each group or between the two groups. Similarly, cognitive performance as assessed by standardized memory and attention tests did not show significant differences within or between groups. Body mass index was higher in the control vs. the GH replacement group at baseline (p = 0.038), yet not different at 6 months and within groups. Visceral-fat-by-total-fat-ratio measurements obtained from magnetic resonance imaging in 2 patients and 5 control subjects exhibited no consistent pattern. In conclusion, this single center study revealed a prevalence of GHD of about 12% (8% with isolated GHD) in brain injury patients which was lower compared with most of the previously reported cohorts. As a consequence, the sample size was insufficient to conclude on a benefit or no benefit of GH replacement in patients with isolated GHD after brain injury. A higher number of patients will be necessary to draw conclusions in future studies

Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population

GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 ± 5.9 vs. 27.3 ± 5.8 kg/m2; P = 0.020; waist circumference 100.9 ± 16.8 vs. 94.8 ± 15.5 cm; P = 0.031; hip circumference 110.7 ± 9.9 vs. 105.0 ± 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population

Macroscopic brain architecture changes and white matter pathology in acromegaly: a clinicoradiological study

Although long-term exposure of the brain to increased GH/IGF-1 likely influences cerebral functions, no in vivo studies have been directed towards changes of the brain structure in acromegaly. Here, we used high resolution magnetic resonance images to compare volumes of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) of forty-four patients with acromegaly to an age and gender matched, healthy control group (n = 44). In addition, white matter lesions (WMLs) were quantified and graded. Patients exhibited larger GM (+3.7% compared with controls, P = 0.018) and WM volumes (+5.1%, P = 0.035) at the expense of CSF. Differences of WML counts between patients and controls were subtle, however, showing more patients in the 21–40 lesions category (P = 0.044). In conclusion, this MRI study provides first evidence that acromegalic patients exhibit disturbances of the macroscopic brain tissue architecture. Furthermore, acromegalic patients may have an increased risk of neurovascular pathology, likely due to secondary metabolic and vascular comorbidities