Response to GH Treatment After Radiation Therapy Depends on Location of Irradiation

OBJECTIVES: Cancer survivors with GH deficiency (GHD) receive GH therapy (GHT) after 1+ year observation to ensure stable tumor status/resolution. HYPOTHESIS: Radiation therapy (RT) to brain, spine, or extremities alters growth response to GHT. AIM: Identify differences in growth response to GHT according to type/location of RT. METHODS: The Pfizer International Growth Database was searched for cancer survivors on GHT for ≥5 years. Patient data, grouped by tumor type, were analyzed for therapy (surgery, chemotherapy, RT of the focal central nervous system, cranial, craniospinal, or total body irradiation [TBI] as part of bone marrow transplantation), sex, peak stimulated GH, age at GHT start, and duration from RT to GHT start. Kruskal-Wallis test and quantile regression modeling were performed. RESULTS: Of 1149 GHD survivors on GHT for ≥5 years (male 733; median age 8.4 years; GH peak 2.8 ng/mL), 431 had craniopharyngioma (251, cranial RT), 224 medulloblastoma (craniospinal RT), 134 leukemia (72 TBI), and 360 other tumors. Median age differed by tumor group (P < 0.001). Five-year delta height SD score (SDS) (5-year ∆HtSDS; median [10th-90th percentile]) was greatest for craniopharyngioma, 1.6 (0.3-3.0); for medulloblastoma, 5-year ∆HtSDS 0.9 (0.0-1.9); for leukemia 5-year ∆HtSDS, after TBI (0.3, 0-0.7) versus without RT (0.5, 0-0.9), direct comparison P < 0.001. Adverse events included 40 treatment-related, but none unexpected. CONCLUSIONS: TBI for leukemia had significant impact on growth response to GHT. Medulloblastoma survivors had intermediate GHT response, whereas craniopharyngioma cranial RT did not alter GHT response. Both craniospinal and epiphyseal irradiation negatively affect growth response to GH therapy compared with only cranial RT or no RT

Diabetes in patients with acromegaly treated with pegvisomant: observations from acrostudy

Purpose: To explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study. Methods: Patients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4–5 yrs of PEGV treatment. Results: Among 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.0 ± 58.7 mg/dl at baseline, 116.4 ± 44.8 mg/dl at year 1 and 120.0 ± 44.3 mg/dl at yr 4. Mean HbA1c was 6.6 ± 1.2 % at yr 1 vs. 7.0 ± 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n = 109), mean blood glucose decreased by 20.2 mg/dl at yr 4, mean HbA1c was 7.0 ± 1.5% at baseline vs. 6.8 ± 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs. Conclusions: Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment

Spatial Proximity and Similarity of the Epigenetic State of Genome Domains

Recent studies demonstrate that the organization of the chromatin within the nuclear space might play a crucial role in the regulation of gene expression. The ongoing progress in determination of the 3D structure of the nuclear chromatin allows one to study correlations between spatial proximity of genome domains and their epigenetic state. We combined the data on three-dimensional architecture of the whole human genome with results of high-throughput studies of the chromatin functional state and observed that fragments of different chromosomes that are spatially close tend to have similar patterns of histone modifications, methylation state, DNAse sensitivity, expression level, and chromatin states in general. Moreover, clustering of genome regions by spatial proximity produced compact clusters characterized by the high level of histone modifications and DNAse sensitivity and low methylation level, and loose clusters with the opposite characteristics. We also associated the spatial proximity data with previously detected chimeric transcripts and the results of RNA-seq experiments and observed that the frequency of formation of chimeric transcripts from fragments of two different chromosomes is higher among spatially proximal genome domains. A fair fraction of these chimeric transcripts seems to arise post-transcriptionally via trans-splicing

A rapid method for analyzing serum pro-insulin-like growth factor-II in patients with non-islet cell tumor hypoglycemia.

CONTEXT: Non-islet cell tumor hypoglycemia (NICTH) results from the hypersecretion of pro-IGF-II by a large, usually mesenchymal tumor. Detection of pro-IGF-II in serum is a potential tumor marker in these patients. OBJECTIVE: The aim of this study was to validate a rapid and reliable method for determining serum pro-IGF-II. PATIENTS: Serum samples from 16 patients with NICTH were studied. MAIN OUTCOME MEASURE: The main outcome measure was serum concentration of pro-IGF-II determined by immunoblot analysis of pro-IGF-II and mature IGF-II after 16.5% tricine-SDS-PAGE, which was compared with pro-IGF-II measured by standard RIA after size-exclusion acid chromatography. RESULTS: The analyses of patients' sera by size-exclusion acid chromatography showed that 68 +/- 19% of IGF-II were present in the pro-IGF-II form, whereas only 18 +/- 4% corresponded to pro-IGF-II in controls. Scanning densitometry of immunoblots showed 67 +/- 16% in the bands corresponding to pro-IGF-II in patients' sera, compared with 27 +/- 9% in controls. The detection sensitivity of tricine-SDS-PAGE method was the same as for size-exclusion chromatography, but the tricine-SDS-PAGE method is quicker and requires smaller amounts of serum. CONCLUSION: Tricine-SDS-PAGE followed by IGF-II immunoblot analysis provides a rapid, reproducible, and sensitive method for the separation of serum pro-IGF-II from mature IGF-II and is a useful laboratory evaluation of patients with a clinical diagnosis of NICTH

Low circulating IGF-I levels in hyperthyroidism are associated with decreased GH response to GH-releasing hormone.

OBJECTIVE: Several abnormalities in the GH response to pharmacological stimuli have been described in hyperthyroidism. Both normal and high serum IGF-I levels have been reported, as well as a decrease in IGF-I bioactivity. We have evaluated the GH response to GH-releasing hormone (GHRH) in hyperthyroid patients and the effects of hyperthyroidism on serum IGF-I levels. The possible relations between nutritional status, thyroid hormones and IGF-I levels were also investigated. We also studied the influence of long-term beta-adrenoceptor blockade on the GH response to GHRH in these patients. DESIGN: In 18 hyperthyroid patients and in 12 control subjects, GHRH (100 micrograms) was administered as an i.v. bolus injection. Eight hyperthyroid patients and 8 control subjects received 50 micrograms GHRH i.v. Seven hyperthyroid patients were reevaluated after beta-adrenoceptor blockade. IGF-I and albumin levels were measured initially in all hyperthyroid patients and control subjects. Body composition was determined in 11 hyperthyroid patients and in a group of 33 matched normal controls. PATIENTS: Hyperthyroid patients were compared to control subjects. MEASUREMENTS: GH, TSH and free T4 were measured by immunofluorometric assay. IGF-I, total T3 and total T4 were measured by radioimmunoassay. Body composition was determined using a dual-energy X-ray absorptiometer. RESULTS: The GH response to 100 micrograms GHRH in hyperthyroid patients was blunted compared to control subjects. The mean peak GH levels and the area under the curve were significantly lower in hyperthyroid patients compared to control subjects (11 +/- 1 vs 27 +/- 5 micrograms/l and 820 +/- 113 vs 1879 +/- 355 micrograms/l 120 min, respectively; P &lt; 0.01). IGF-I levels were significantly reduced in hyperthyroid patients compared to controls (131 +/- 10 vs 201 +/- 16 micrograms/l, respectively; P &lt; 0.01). Ideal body weight, serum albumin levels and the lean body mass were also reduced in hyperthyroid patients. After beta-adrenoceptor blockade there were no changes in the blunted GH response to GHRH in hyperthyroid patients. CONCLUSION: Our data suggest that the blunted GH response to GHRH in hyperthyroidism is apparently not related to circulating IGF-I levels. It is possible that nutritional factors could play a role in the reduced circulating IGF-I levels found in these patients

Insulin-like growth factor-I and- II in combination inhibit the release of growth hormone-releasing hormone from the rat hypothalamus in vitro.

This study was designed to investigate the feedback loop between insulin-like growth factor-I (IGF-I) and IGF-II and the hypothalamic hormones growth hormone-releasing hormone (GHRH) and somatostatin (SS) using an in vitro rat hypothalamic model. IGF-I and, to lesser extent, IGF-II, both activate type 1 IGF receptors, while type 2 receptors are activated by IGF-II alone. IGF-I, IGF-II, their various specific analogues (Des[1-3]IGF-I, [Arg54/Arg55]IGF-II and [Leu27]IGF-II), insulin and the type 2 receptor antagonist beta-galactosidase were used on their own or in combination to study their effect on GHRH and SS release. Our results suggest that the simultaneous activation of type 1 and type 2 IGF receptors is needed for the negative feedback effect of IGFs on GHRH release in this in vitro system, in agreement with earlier findings in vivo. Somatostatin was not altered by any combination of peptides

Growth hormone replacement does not increase serum prostate-specific antigen in hypopituitary men over 50 years.

OBJECTIVE: Epidemiological studies have shown an increased risk for prostate carcinoma in men with serum IGF-I in the upper part of the age-related reference range. Recombinant human GH (rhGH) is widely used in patients with GH deficiency, usually raising the serum IGF-I levels into the normal range: safety surveillance is therefore mandatory, with particular regard to neoplasia. The aim was to examine whether rhGH replacement in hypopituitary adults is associated with changes in serum prostate-specific antigen (PSA) as a surrogate marker of changes in prostatic growth. DESIGN AND METHODS: A prospective longitudinal study was used with a median follow-up of 22 (range 2.5-32) months, in which 41 men aged over 50 years with adult onset hypopituitarism and GH deficiency during rhGH replacement were examined. Serum PSA and IGF-I were measured at baseline and at latest follow-up. RESULTS: Mean serum PSA remained unchanged during rhGH replacement, with a median follow-up of 2 years. No correlation was found between the individual changes in serum IGF-I and changes in serum PSA. CONCLUSIONS: These data are reassuring thus far regarding the safety of GH replacement in relation to the prostate in this patient group

Acromegaly or chronic renal failure: a diagnostic dilemma.

Uraemic patients may have markedly elevated serum GH concentrations yet, for hitherto unknown reasons, they do not develop acromegaly. We discuss the diagnostic dilemma presented by a 33-year-old Caucasian male with chronic renal failure (creatinine clearance 10 ml/min) secondary to polycystic kidney disease, elevated GH concentrations (fasting concentration of 22.6 rising to 77.9 mU/l 30 minutes after a 75-g oral glucose load) as well as acromegalic features. Review of the patient's relatives and the findings of a normal serum IGF-I concentration and a normal pituitary fossa on magnetic resonance imaging, suggest that the patient's acromegalic appearance is a familial trait and his abnormal GH dynamics a result of his renal failure rather than acromegaly. The patient's normal GH bioactivity and reduced GH binding protein concentration supports the current belief that chronic renal failure leads to an increase in peripheral tissue resistance to GH due to decreased GH receptor numbers. These changes, together with reduced IGF-I bioactivity, may explain why patients with chronic renal failure do not develop acromegaly in the presence of abnormally elevated levels of GH

IGF-I levels rise and GH responses to GHRH decrease during long-term prednisone treatment in man.

Glucocorticoid excess is associated with a blunted GH response to GHRH. IGF-I levels in hypercortisolism are controversial and have been reported as low, normal or high. The aim of this study was to evaluate longitudinally time-dependent changes in the GH response to GHRH, IGF-I, IGFBP-3 and albumin values in patients during corticotherapy. Six patients received GHRH before and after one week and one month of prednisone administration (20-60 mg/d, orally). IGF-I, IGFBP-3 and albumin were determined in each test, at time 0. Ten normal controls were also evaluated in one occasion. There were no differences in basal GH values, GH response to GHRH, IGF-I and IGFBP-3 levels between controls and patients before starting corticotherapy. Albumin (g/l; mean+/-SE) values were lower in patients before treatment (31+/-4) than in controls (43+/-1). After one week of prednisone administration there was a significant decrease in peak GH (microg/l) levels (before: 18.8+/-7.4; 1 week: 5.0+/-1.3), which was maintained after one month (8.1+/-3.5). IGF-I (microg/l) levels increased significantly, from 145+/-23 to 205+/-52 after one week of therapy, reaching levels of 262+/-32 after one month. IGFBP-3 (mg/l) values did not increase significantly (before: 2.1+/-0.2; 1 week: 2.5+/-0.3; 1 month: 2.8+/-0.2). Albumin levels showed a significant rise both after one week (36+/-4) and one month (42+/-3) of corticotherapy. In summary, we observed a marked decrease in the GH response to GHRH after one week and one month of prednisone administration associated with an increase in circulating IGF-I and albumin values. The physiological implications of these findings are still uncertain. It is possible that glucocorticoids increase hepatic IGF-I and albumin synthesis, although other mechanisms may have a role