P98 Extreme body growth and protein accretion under normal serum IGF-I concentrations in male but not in female mice – new models and new challenges for the somatomedin hypothesis

Parathyroid hormone (PTH) exerts both catabolic and anabolic actions on bone. Studies on the skeletal effects of PTH have seldom considered the effects of gender. Our study was designed to determine whether the response of mouse bone to PTH differed according to sex. As a first step, we analyzed gender differences with respect to bone mass and structural properties of 4 month old PTH treated (80 μg/kg per day for 2 weeks) male and female CD-1 mice. PTH significantly increased fat free weight/body weight, periosteal bone formation rate, mineral apposition rate, and endosteal single labeling surface, while significantly decreasing medullary area in male mice compared with vehicle treated controls, but induced no significant changes in female mice. We then analyzed the gender differences in bone marrow stromal cells (BMSC) isolated from 4 month old male and female CD-1 mice following treatment with PTH (80 μg/kg per day for 2 weeks). PTH significantly increased the osteogenic colony number and the alkaline phosphatase (ALP) activity (ALP/cell) by day 14 in cultures of BMSCs from male and female mice. PTH also increased the mRNA level of receptor activator of nuclear factor κB ligand in the bone tissue (marrow removed) of both females and males. However, PTH increased the mRNA levels of IGF-I and IGF-IR only in the bones of male mice. Our results indicate that on balance a 2-weeks course of PTH is anabolic on cortical bone in this mouse strain. These effects are more evident in the male mouse. These differences between male and female mice may reflect the greater response to PTH of IGF-I and IGF-IR gene expression in males enhancing the anabolic effect on cortical bone.

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The insulin-like growth factors and their binding proteins in a case of non-islet-cell tumour-associated hypoglycaemia

Journal of Endocrinology ◽

10.1677/joe.0.1310303 ◽

1991 ◽

Vol 131 (2) ◽

pp. 303-311 ◽

Cited By ~ 23

Author(s):

A. M. Cotterill ◽

J. M. P. Holly ◽

S. C. Davies ◽

V. J. Coulson ◽

P. A. Price ◽

...

Keyword(s):

Molecular Weight ◽

Islet Cell ◽

Plasma Insulin ◽

Binding Proteins ◽

Late Pregnancy ◽

Normal Serum ◽

Systemic Effects ◽

Igf Binding Proteins ◽

Igf I ◽

Igfbp 3

ABSTRACT Non-islet-cell tumours which induce hypoglycaemia are rare. Insulin-like growth factor-II (IGF-II) produced by some tumours is thought to be responsible for the hypoglycaemia and other systemic effects, despite normal or even low serum IGF-II levels. We studied a 44-year-old woman presenting with symptomatic hypoglycaemia associated with a large intraabdominal haemangiopericytoma. The serum IGF-II level was 455 μg/l when measured after acid-ethanol extraction (normal range (NR) 450–750 μg/l) and 1063 μg/l after acid chromatography (normal human serum pool 1068 μg/l). Levels of fasting plasma insulin, C-peptide, glucose and serum IGF-I levels were low before the operation (< 2 mU/l (NR <2-14), 0·23 nmol/l (NR 0-4-1-2), 3-1 mmol/l, (NR 3-7-5-9) and 002 U/ml respectively). After tumour removal, the symptoms resolved rapidly and the patient made a full recovery. Secretion of both insulin and growth hormone was suppressed before the operation in response to a 75 g glucose meal and to an infusion of 100 μg GH-releasing hormone (GHRH) respectively in comparison with studies after the operation. Serum IGF-II levels 6 weeks and 12 weeks after the operation fell to 385 μg/1 (777 μg/1; acid chromatography) and 280 μg/1 (647 μg/1; acid chromatography) and serum IGF-I levels increased to 0-35 U/ml and 0-26 U/ml. Serum before the operation and tumour extract contained chiefly a large molecular weight precursor IGF-II (molecular weight 15 000–20 000) which disappeared from the serum after the operation. The IGF-binding proteins (IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-4) were examined. The preoperation fasting serum IGFBP-1 level was lower than expected (31 μg/l (NR 20–70 μg/l)) and similar to levels at 6 weeks after the operation (33 μg/l). This was surprising given the differences in plasma insulin levels before and after the operation (< 2 mU/l versus 13 mU/l). Using Western ligand blotting techniques, serum IGFBP-3 levels were found to be low and IGFBP-2 appeared to be the dominant IGFBP before the operation. Serum IGFBP-3 levels after the operation fell further. This further decrease appeared, in part, to be due to the presence of a cation-dependent IGFBP-3-specific protease which has previously only been described in late pregnancy. We conclude that in this subject, despite normal serum IGF-II levels, the hypoglycaemia and systemic effects on insulin and GH secretion were due to increased bioavailability of a circulating tumour-produced precursor form of IGF-II. This increased bioavailability appears to be due to alterations in the circulating levels and perhaps affinities of the IGFBPs. Journal of Endocrinology (1991) 131, 303–311

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Coordinating the Distribution Chain: New Models for New Challenges

Applied Optimization - Supply Chain Management: Models, Applications, and Research Directions ◽

10.1007/0-306-48172-3_9 ◽

2006 ◽

pp. 199-242

Author(s):

Anantaram Balakrishnan ◽

Joseph Geunes ◽

Michael S Pangburn

Keyword(s):

New Models ◽

Distribution Chain ◽

New Challenges

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Direct Postoperative and Follow-Up Results of Transsphenoidal Surgery in 19 Acromegalic Patients Pretreated with Octreotide Compared to Those in Untreated Matched Controls

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.10.6027 ◽

1999 ◽

Vol 84 (10) ◽

pp. 3551-3555 ◽

Cited By ~ 52

Author(s):

N. R. Biermasz ◽

H. van Dulken ◽

F. Roelfsema

Keyword(s):

Growth Factor ◽

Adjuvant Therapy ◽

Transsphenoidal Surgery ◽

Normal Serum ◽

Factor I ◽

Preoperative Serum ◽

Igf I ◽

Pretreated Patients ◽

Serum Gh

Abstract In this study 19 patients were preoperatively treated with octreotide for 1–17 months (mean, 5 months), with doses from 150–1500 μg daily, and those patients were matched to 19 untreated patients with comparable tumor classification and preoperative serum GH concentrations. Octreotide was started at 300 μg daily by sc injections or continuous sc infusion using a pump in increasing doses, depending on the responses of the serum GH and insulin-like growth factor I (IGF-I) concentrations. During pretreatment, seven patients achieved a serum GH concentration below 5 mU/L, whereas six patients normalized their serum IGF-I. Postoperatively, a serum GH concentration below 5 mU/L was achieved in 15 pretreated and 14 untreated patients, a normal serum IGF-I level (<2 sd) was achieved in 10 pretreated and 15 untreated patients, and normal serum GH suppression during GTT was reached in 12 treated and 14 control patients. No differences were found in complication rate or incidence of hypopituitarism caused by surgery. Adjuvant therapy was required in 7 treated and 5 untreated patients. At follow-up examination, 5.7 and 4 yr postoperatively, 10 pretreated and 12 control patients could be considered cured by surgery only, according to our criteria for remission (serum GH, <5 mU/L; normal GH suppression and normal serum IGF-Ι). In summary, we found no difference in direct postoperative and follow-up results of transsphenoidal surgery between pretreated patients and untreated patients. This finding is in discordance with other studies, which have claimed a beneficial effect of octreotide pretreatment.

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Developmental patterns of plasma insulin-like growth factor-I (IGF-I) and body growth in mice from lines divergently selected on the basis of plasma IGF-I

Journal of Endocrinology ◽

10.1677/joe.0.1240151 ◽

1990 ◽

Vol 124 (1) ◽

pp. 151-158 ◽

Cited By ~ 19

Author(s):

R. A. Siddiqui ◽

H. T. Blair ◽

S. N. McCutcheon ◽

D. D. S. Mackenzie ◽

P. D. Gluckman ◽

...

Keyword(s):

Body Composition ◽

Body Weight ◽

Growth Factor ◽

Plasma Concentrations ◽

Body Growth ◽

Insulin Like Growth Factor ◽

Developmental Patterns ◽

Factor I ◽

Igf I ◽

Growth Factor I

ABSTRACT A study was conducted to investigate developmental patterns of plasma concentrations of insulin-like growth factor-I (IGF-I), body growth and body composition in mice from lines selected for seven generations on the basis of low (L) or high (H) plasma IGF-I, and in a random-bred control (C) line. Litter size was standardized to eight individuals with equal sex ratios (as far as possible) within 48 h of birth. Pups were weaned at an average of 21 days and separated on the basis of sex. Blood samples were collected from one male and one female of each litter on days, 21, 42, 63 and 105 for analysis of plasma concentrations of IGF-I. The animals were then killed and analysed for water, fat and crude protein content. The plasma concentration of IGF-I was influenced by line (P<0·05) but not by sex. Significant (P< 0·001) differences in liveweight between mice from L and H lines were first evident at 21 days of age. From 28 until 105 days of age the H line was significantly (P< 0·001) heavier than both L and C lines, but differences between C and L lines were inconsistent and mostly non-significant. The growth velocity of the H line was significantly greater than that of C or L lines between 14 and 42 days of age, but differences in growth velocities of C compared with L lines were generally non-significant. Nose–anus length was significantly (P<0·01) affected by sex and line from 42 to 105 days of age, but anus–tail length was not affected by sex or line at any age. Effects of sex and line on empty (digesta-free) body weight and wet weights of carcass and skin plus viscera fractions followed a pattern similar to those of liveweights. The effects of sex and line on protein, water and fat content also paralleled their effects on body size. Differences between males and females, and between the lines, in amount of protein, water and fat could be entirely accounted for by the corresponding differences in body weight. It is concluded from these results that divergent selection on the basis of plasma IGF-I at 42 days of age resulted in lines of animals differing in plasma IGF-I from 21 days of age until maturity. These divergent concentrations of IGF-I are associated with differences between the lines in body growth, particularly during the period of accelerated growth at puberty, but not with changes in body composition. Journal of Endocrinology (1990) 124, 151–158

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Abnormalities of hypothalamic-pituitary-adrenal and hypothalamic-somatotrophic axes in Fawn-Hooded rats

Acta Endocrinologica ◽

10.1530/eje.0.1410290 ◽

1999 ◽

pp. 290-296 ◽

Cited By ~ 7

Author(s):

F Gomez ◽

P Grauges ◽

A Lopez-Calderon ◽

A Armario

Keyword(s):

Hippocampal Formation ◽

Binding Capacity ◽

Normal Serum ◽

Central Nucleus ◽

Sprague Dawley ◽

Hypothalamic Pituitary Adrenal ◽

Corticotrophin Releasing Factor ◽

Sd Rats ◽

Normal Expression ◽

Igf I

Fawn-Hooded (FH) rats show central and peripheral abnormalities in serotoninergic functions and have attracted attention as an animal model of some pathologies, including depression and hypertension. In addition, these rats show a reduced growth rate. As the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in both depression and hypertension, and the hypothalamic-somatotrophic (HSM) axis has a major role in growth, these two endocrine axes were characterised in FH rats as compared with outbred Sprague-Dawley (SD) rats in basal conditions. FH rats showed normal serum ACTH and corticosterone concentrations, but reduced serum corticosterone binding capacity. At a central level, normal expression of mRNA for glucocorticoid type II receptors in the hippocampal formation and mRNA for corticotrophin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus were observed in FH rats, whereas expression of mRNA for CRF in the central nucleus of the amygdala was enhanced compared with the expression in SD rats. Serum GH concentrations were normal in FH rats, IGF-I tended to be lower, and mRNA for somatostatin (SRIF) in the periventricular nucleus of the hypothalamus was significantly lower in FH rats than in SD rats. The reduced SRIF gene expression in rats with normal or slightly reduced GH and IGF-I, respectively, might be secondary to a defective central and peripheral response to IGF-I, compatible with the reduced growth of FH rats. The present results suggest that FH rats have abnormalities in both HPA and HSM axes that might be related to some of their physiopathological characteristics.

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ESE audit on management of Adult Growth Hormone Deficiency in clinical practice

Acta Endocrinologica ◽

10.1530/eje-20-1180 ◽

2020 ◽

Author(s):

Luciana Maria Martel-Duguech ◽

Jens Otto L. Jorgensen ◽

Marta Korbonits ◽

Gudmundur Johannsson ◽

Susan M Webb ◽

...

Keyword(s):

Clinical Practice ◽

Educational Status ◽

Normal Serum ◽

European Countries ◽

Hormone Deficiency ◽

Dose Titration ◽

Childhood Onset ◽

Adult Growth ◽

Igf I ◽

Healthcare Administrators

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform. Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD. Design: On-line survey in endocrine centres throughout Europe. Patients and Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018. Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved. Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

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A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly

Acta Endocrinologica ◽

10.1530/eje-08-0267 ◽

2008 ◽

Vol 159 (2) ◽

pp. 89-95 ◽

Cited By ~ 283

Author(s):

I M Holdaway ◽

M J Bolland ◽

G D Gamble

Keyword(s):

Meta Analysis ◽

Serum Levels ◽

Somatostatin Analogues ◽

Normal Serum ◽

Mortality Data ◽

Standardized Mortality Ratio ◽

Endocrine Society ◽

Igf I ◽

Serum Gh

ObjectiveFormal studies of acromegaly have found increased mortality associated with the disorder, although reduction of serum levels of GH and IGF-I by treatment appears to improve survival. A meta-analysis of mortality studies in acromegaly has thus been performed to assess the effect of lowering serum GH and IGF-I on survival.Design and methodsMedline was searched for studies under ‘acromegaly’, ‘mortality’ and ‘cause of death’ (1965–2008), and abstracts of recent meetings of the US Endocrine Society were hand searched. Studies were restricted to those presenting mortality data according to serum GH and IGF-I at last follow-up, and with mortality expressed as a standardized mortality ratio (SMR).ResultsPatients with random serum GH <2.5 μg/l following treatment, mostly measured by standard RIA, had mortality close to expected levels (SMR 1.1, 95% confidence interval (CI) 0.9–1.4) compared with an SMR of 1.9 (95% CI 1.5–2.4) for those with final GH >2.5 μg/l. Similarly, a normal serum IGF-I for age and sex at last follow-up after treatment was associated with an SMR of 1.1 (95% CI 0.9–1.4) compared with an SMR of 2.5 (95% CI 1.6–4.0) for those with continued IGF-I elevation. There was a significant trend for reduced mortality in series reporting frequent use of somatostatin analogues and in studies reporting high (>70%) rates of biochemical remission after treatment.ConclusionsClinicians treating acromegalic patients should aim for random serum GH <2.5 μg/l measured by RIA (probably <1 μg/l measured by modern sensitive immunoassay) and normal serum IGF-I values, to restore the elevated mortality of the condition to normal levels.

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