Characterization of pituitary IGF-I receptors: modulation of prolactin and growth hormone

2002 ◽  
Vol 283 (2) ◽  
pp. R468-R476 ◽  
Author(s):  
Shira Fruchtman ◽  
Douglas C. McVey ◽  
Russell J. Borski
Keyword(s):  
Growth Hormone ◽  
Pituitary Gland ◽  
Morone Saxatilis ◽  
Pars Distalis ◽  
Gh Secretion ◽  
High Affinity ◽  
Igf I ◽  
Similar Affinity ◽  
Rostral Pars Distalis

There have been no studies in any vertebrate that have localized insulin-like growth factor (IGF)-I receptors in prolactin (PRL) cells or that have correlated pituitary binding to the potency of IGF-I in regulating both PRL and growth hormone (GH) secretion. We show that IGF-I binds with high affinity and specificity to the pituitary gland of hybrid striped bass ( Morone saxatilis × M. chrysops). IGF-I and IGF-II were equipotent in inhibiting saturable125I-IGF-I binding, whereas insulin was ineffective. IGF-I binds with similar affinity to the rostral pars distalis (>95% PRL cells) as the whole pituitary gland and immunohistochemistry colocalizes IGF-I receptors and PRL in this same region. Des(1–3)IGF-I, a truncated analog of IGF-I that binds with high affinity to IGF-I receptors but weakly to IGF-I binding proteins (IGFBPs), showed a similar inhibition of saturable125I-IGF-I binding, but it was more potent than IGF-I in stimulating PRL and inhibiting GH release. These results are the first to localize IGF-I receptors to PRL cells, correlate IGF-I binding to its efficacy in regulating GH and PRL secretion, as well as demonstrate that IGFBPs may play a significant role in modulating the disparate actions of IGF-I on PRL and GH secretion.

scholarly journals Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

2021 ◽  
pp. 1-24
Author(s):  
Jan M. Wit ◽  
Sjoerd D. Joustra ◽  
Monique Losekoot ◽  
Hermine A. van Duyvenvoorde ◽  
Christiaan de Bruin
Keyword(s):  
Growth Hormone ◽  
Differential Diagnosis ◽  
Growth Hormone Secretion ◽  
Normal Growth ◽  
Stimulation Test ◽  
Healthy Children ◽  
Genetic Causes ◽  
Gh Secretion ◽  
Igf I

The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak (“GH neurosecretory dysfunction,” GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of <i>GH1</i> or <i>GHSR</i>) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0–3.2 μg/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to <i>GH1</i> variants) but less on the role of <i>GHSR</i> variants. Several genetic causes of (partial) GHI are known (<i>GHR</i>, <i>STAT5B</i>, <i>STAT3</i>, <i>IGF1</i>, <i>IGFALS</i> defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes.

Effects of octreotide on insulin-like growth factor I and metabolic indices in growth hormone-treated growth hormone-deficient patients

1993 ◽  
Vol 129 (5) ◽  
pp. 399-408 ◽  
Author(s):  
Torben Laursen ◽  
Jens OL Jorgensen ◽  
Hans Ørskov ◽  
Jens Møller ◽  
Alan G Harris ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Animal Studies ◽  
Area Under The Curve ◽  
Insulin Like Growth Factor ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

Animal studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent blood sampling during 38 h on two occasions. Regular GH therapy was discontinued 72 h prior to each study period. At the start of each study a subcutaneous (sc) injection of GH (3 IU/m2) was given (at 18.00 h). In a single-blinded crossover design, patients received a continuous sc infusion of either octerotide (200 μg/24 h) or placebo (saline). The pharmacokinetics of GH were similar on the two occasions. The area under the curve±sem of serum GH was 142.5±53.6 μg·l−1·h−1 (octreotide) and 144.8±41.8 μg·l−1·h−1 (placebo), (p=0.73); Cmax (μg/l) was 12.5±1.47 (octreotide) and 12.8±1.42 (placebo) (p=0.83), and Tmax (h) was 6.1±0.97 (octreotide) and 5.2±0.65 (placebo) (p=0.49). Growth hormone administration was associated with an increase in serum IGF-I (μg/l), which was identical during the two studies, from 85.3±19.4 to 174.25±30.3 for octreotide and from 97.0±26.4 to 158.8±28.2 for placebo. Mean IGF-I levels (μg/l) were 138.2±25.1 (octreotide) and 134.5±28.6 (placebo) (p=0.78). Similarly, the increase in IGF binding protein 3 (IGFBP-3) levels was identical. Mean IGFBP-3 levels (μg/l) were 2303±323 (octreotide) and 2200±361 (placebo) (p=0.25). Mean insulin levels were significantly lower during octreotide treatment (39.9±17.9 mU/l) than during placebo (59.7±17.8 mU/l) (p<0.05). Mean blood glucose levels were elevated significantly during octreotide infusion (5.98±0.23 mmol/l for octreotide and 5.07±0.16 mmol/l for placebo; p=0.001). Glucagon levels decreased non-significantly (p=0.07) and IGFBP-1 levels tended to increase during infusion of octreotide although not significantly (p=0.41). Levels of the lipid intermediates were identical on the two occasions. Alanine and lactate levels were significantly increased during octreotide infusion. Mean levels of blood alanine (μmol/l) were 470.8±24.2 (octreotide) and 360.1±17.8 (placebo) (p<0.02). Mean levels of blood lactate were 1038±81.0 (octreotide) and 894.4±73.8 (placebo) (p<0.04). We conclude that short-term continuous sc infusion of octreotide has no direct effect on the generation of IGF-I or the pharmacokinetics of exogenous GH in GH-deficient man.

Effect of actively immunizing sheep against growth hormone-releasing hormone or somatostatin on spontaneous pulsatile and neostigmine-induced growth hormone secretion

1995 ◽  
Vol 144 (1) ◽  
pp. 83-90 ◽  
Author(s):  
E Magnan ◽  
L Mazzocchi ◽  
M Cataldi ◽  
V Guillaume ◽  
A Dutour ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Weight ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Physiological Role ◽  
Gh Secretion ◽  
Igf I ◽  
Plasma Gh ◽  
Hypophysial Portal

Abstract The physiological role of endogenous circulating GHreleasing hormone (GHRH) and somatostatin (SRIH) on spontaneous pulsatile and neostigmine-induced secretion of GH was investigated in adult rams actively immunized against each neuropeptide. All animals developed antibodies at concentrations sufficient for immunoneutralization of GHRH and SRIH levels in hypophysial portal blood. In the anti GHRH group, plasma GH levels were very low; the amplitude of GH pulses was strikingly reduced, although their number was unchanged. No stimulation of GH release was observed after neostigmine administration. The reduction of GH secretion was associated with a decreased body weight and a significant reduction in plasma IGF-I concentration. In the antiSRIH group, no changes in basal and pulsatile GH secretion or the GH response to neostigmine were observed as compared to controls. Body weight was not significantly altered and plasma IGF-I levels were reduced in these animals. These results suggest that in sheep, circulating SRIH (in the systemic and hypophysial portal vasculature) does not play a significant role in pulsatile and neostigmine-induced secretion of GH. The mechanisms of its influence on body weight and production of IGF-I remain to be determined. Journal of Endocrinology (1995) 144, 83–90

scholarly journals Consensus Statement on the Standardization and Evaluation of Growth Hormone and Insulin-like Growth Factor Assays

2011 ◽  
Vol 57 (4) ◽  
pp. 555-559 ◽  
Author(s):  
David R Clemmons
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Normative Data ◽  
Consensus Statement ◽  
International Workshop ◽  
Research Society ◽  
Insulin Like Growth Factor ◽  
Gh Secretion ◽  
Assay Performance ◽  
Igf I

Abstract Growth hormone (GH) and insulin-like growth factor I (IGF-I) measurements are widely used in the diagnosis of disorders of GH secretion, evaluation of children with short stature from multiple causes, management of disorders that lead to nutritional insufficiency or catabolism, and monitoring both GH and IGF-I replacement therapy. Therefore, there is an ongoing need for accurate and precise measurements of these 2 peptide hormones. Representatives of the Growth Hormone Research Society, the IGF Society, and the IFCC convened an international workshop to review assay standardization, requirements for improving assay comparability, variables that affect assay interpretation, technical factors affecting assay performance, assay validation criteria, and the development and use of normative data. Special attention was given to preanalytical conditions, the use of international commutable reference standards, antibody specificity, matrix requirements, QC analysis, and interference by binding proteins. Recommendations for each of these variables were made for measurements of each peptide. Additionally, specific criteria for IGF-I were recommended for age ranges of normative data, consideration of Tanner staging, and consideration of the effect of body mass index. The consensus statement concludes that major improvements are necessary in the areas of assay performance and comparability. This group recommends that a commutable standard for each assay be implemented for worldwide use and that its recommendations be applied to accomplish the task of providing reliable and clinically useful results.

IGF-I does not affect the net increase in GH release in response to arginine

2002 ◽  
Vol 283 (4) ◽  
pp. E702-E710 ◽  
Author(s):  
Ralf Nass ◽  
Suzan S. Pezzoli ◽  
Ian M. Chapman ◽  
James Patrie ◽  
Raymond L. Hintz ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Young Adults ◽  
Growth Factor ◽  
Negative Feedback ◽  
Random Order ◽  
Feedback Effect ◽  
Insulin Like Growth Factor ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I

Arginine stimulates growth hormone (GH) secretion, possibly by inhibiting hypothalamic somatostatin (SS) release. Insulin-like growth factor I (IGF-I) inhibits GH secretion via effects at the pituitary and/or hypothalamus. We hypothesized that if the dominant action of IGF-I is to suppress GH release at the level of the pituitary, then the arginine-induced net increase in GH concentration would be unaffected by an IGF-I infusion. Eight healthy young adults (3 women, 5 men) were studied on day 2 of a 47-h fast for 12 h (35th-47th h) on four occasions. Saline (Sal) or 10 μg · kg−1 · h−1recombinant human IGF-I was infused intravenously for 5 h from 37 to 42 h of the 47-h fast. Arginine (Arg) (30 g iv) or Sal was infused over 30 min during the IGF-I or Sal infusion from 40 to 40.5 h of the fast. Subjects received the following combinations of treatments in random order: 1) Sal + Sal; 2) Sal + Arg; 3) IGF-I + Sal; 4) IGF-I + Arg. Peak GH concentration on the IGF-I + Arg day was ∼45% of that on the Sal + Arg day. The effect of arginine on net GH release was calculated as [(Sal + Arg) − (Sal + Sal)] − [(IGF-I + Arg) − (IGF-I + Sal)]. There was no significant effect of IGF-I on net arginine-induced GH release over control conditions. These findings suggest that the negative feedback effect of IGF-I on GH secretion is primarily mediated at the pituitary level and/or at the hypothalamus through a mechanism different from the stimulatory effect of arginine.

Expression, distribution, regulation and function of IGFs in the ovine fetal pituitary

1995 ◽  
Vol 14 (3) ◽  
pp. 323-336 ◽  
Author(s):  
F Lü ◽  
K Yang ◽  
V K M Han ◽  
J R G Challis
Keyword(s):  
Pituitary Gland ◽  
Endocrine Cells ◽  
Cell Types ◽  
Pars Intermedia ◽  
Pars Distalis ◽  
Paracrine Factors ◽  
Pomc Mrna ◽  
Pars Nervosa ◽  
Igf I ◽  
And Function

ABSTRACT Activation of the fetal pituitary-adrenal axis is crucial for fetal organ maturation and the onset of parturition in sheep. Many factors including corticotrophin-releasing hormone (CRH) and arginine vasopressin secreted from the hypothalamus, and growth factors produced within the pituitary may be involved in the regulation of maturation of the fetal pituitary gland. IGFs have mitogenic and differentiation-promoting capacities in a variety of organs and are synthesized as paracrine factors within developing tissues. However, there is little information concerning the synthesis, distribution, regulation and function of IGFs in the fetal pituitary gland at different times during pregnancy. Therefore, we have localized IGF-I and IGF-II mRNAs and peptides, and determined the effect of cortisol on the level of IGF-II mRNAs in the pituitary glands of developing sheep fetuses. We examined the possible effects of IGFs on corticotroph function in cultures of adenohypophysial cells from term fetuses. Seven species of IGF-II transcripts of 1·2–6·0 kb were identified by Northern blot analysis in the pituitary gland of fetuses between day 60 of gestation and term (day 145). The levels of IGF-II mRNAs did not change significantly during pregnancy, although there was a trend for the presence of higher levels of IGF-II mRNAs at day 60 of gestation. IGF-I mRNA was not detectable. By in situ hybridization, IGF-II mRNA was localized to non-endocrine cells and to cells lining the blood vessels of the pars distalis, to some presumed endocrine cells in the pars distalis and pars intermedia, and to clusters of cells in the pars nervosa. In contrast, IGF-I and IGF-II peptides were detected in the presumed endocrine cells in the pars distalis and pars intermedia but not in the pars nervosa. Incubation of adenohypophysial cells from term fetuses with IGF-I, but not IGF-II, for 48 h increased specific 125I-Tyr-ovine CRH binding. However, neither IGF-I nor IGF-II had any significant effects on the basal or CRH-stimulated immunoreactive (ir)-ACTH output, the level of POMC mRNA or the number of ir-ACTH positive cells. Infusion of cortisol to fetuses starting at day 96 of gestation for 100 h or at days 120–125 of gestation for 84 h did not affect the level of IGF-II mRNAs in the pars distalis but decreased the levels of POMC mRNA. These results are consistent with IGFs having the potential to influence fetal pituitary function, although probably on cell types other than the corticotrophs. The likely sources of IGFs may be predominantly local (IGF-II) or from extrapituitary sources (IGF-I).

Negative feedback of insulin-like growth factor-I on growth hormone secretion by porcine pituitary cells

1995 ◽  
Vol 75 (1) ◽  
pp. 57-61 ◽  
Author(s):  
C. Farmer ◽  
H. Lapierre
Keyword(s):  
Growth Hormone ◽  
Negative Feedback ◽  
Culture Media ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Age Related ◽  
Igf I

Pituitaries from female Yorkshire pig fetuses (90 d, n = 26; 110 d, n = 17) and 6-mo-old pigs (n = 5) were enzymatically dispersed, plated, and cultured for 47 h. The cells were then rinsed and incubated for 22 h with testing media containing 0, 50, 100, 200, 300 or 400 ng mL−1 of IGF-I. Half of the wells from each concentration of IGF-I were then incubated for an additional 3 h with concentrations of IGF-I similar to those in the previous incubation, while the other half also had GRF added to the testing media to reach a final concentration of 10−8 M. Culture media were then collected from all the wells, were frozen, and later assayed for GH. Irrespective of whether GRF was present, IGF-I decreased pituitary secretion of GH (P < 0.001). A significant negative response to IGF-I was already present at the dose of 50 ng mL−1 (P < 0.0001). However, the extent of the GH response to IGF-I seen in pigs of various ages differed depending on whether GRF was present. The present results therefore establish that IGF-I does exert a negative feedback on pituitary GH secretion in swine and that the age-related changes in this feedback are dependent on the presence of GRF. In swine, it appears that high circulating concentrations of GH in late-gestation fetuses are not a result of a lesser sensitivity of the somatotroph to the inhibitory actions of IGF-I. Key words: Pig, cell culture, pituitary, IGF-I, growth hormone, age

scholarly journals Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation

2011 ◽  
Vol 301 (4) ◽  
pp. R1143-R1152 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Cyril Y. Bowers
Keyword(s):  
Body Mass Index ◽  
Growth Hormone ◽  
Body Mass ◽  
Negative Feedback ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Gh Secretion ◽  
Model Free ◽  
Preclinical Investigation ◽  
Igf I

Although stimulatory (feedforward) and inhibitory (feedback) dynamics jointly control neurohormone secretion, the factors that supervise feedback restraint are poorly understood. To parse the regulation of growth hormone (GH) escape from negative feedback, 25 healthy men and women were studied eight times each during an experimental GH feedback clamp. The clamp comprised combined bolus infusion of GH or saline and continuous stimulation by saline GH-releasing hormone (GHRH), GHRP-2, or both peptides after randomly ordered supplementation with placebo (both sexes) vs. E2 (estrogen; women) and T (testosterone; men). Endpoints were GH pulsatility and entropy (a model-free measure of feedback quenching). Gender determined recovery of pulsatile GH secretion from negative feedback in all four secretagog regimens (0.003 ≤ P ≤ 0.017 for women>men). Peptidyl secretagog controlled the mass, number, and duration of feedback-inhibited GH secretory bursts (each, P < 0.001). E2/T administration potentiated both pulsatile ( P = 0.006) and entropic ( P < 0.001) modes of GH recovery. IGF-I positively predicted the escape of GH secretory burst number and mode ( P = 0.022), whereas body mass index negatively forecast GH secretory burst number and mass ( P = 0.005). The composite of gender, body mass index, E2, IGF-I, and peptidyl secretagog strongly regulates the escape of pulsatile and entropic GH secretion from autonegative feedback. The ensemble factors identified in this preclinical investigation enlarge the dynamic model of GH control in humans.

Serum Ghrelin Concentrations are Increased in Children With Growth Hormone Insensitivity and Decrease During Long-Term Insulinlike Growth Factor-I Treatment

2008 ◽  
Vol 56 (1) ◽  
pp. 26-31 ◽  
Author(s):  
Aysin Uckun-Kitapci ◽  
Andrea M. Haqq ◽  
Jonathan Q. Purnell ◽  
Kenneth Newcomb ◽  
Hakan Gulkesen ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Normal Control ◽  
Blood Draw ◽  
Gh Secretion ◽  
Factor I ◽  
Insulinlike Growth Factor ◽  
Igf I ◽  
Growth Factor I ◽  
Insulinlike Growth Factor I

BackgroundGhrelin increases food intake, body weight, and growth hormone (GH) secretion. Serum concentrations of ghrelin are low in obese hyperinsulinemic persons, are reduced by infusion of insulin into normal-weight subjects, and are increased in underweight hypoinsulinemic patients with anorexia nervosa. Laron syndrome is an autosomal recessive disorder of GH insensitivity that results in decreased insulinlike growth factor-I (IGF-I) synthesis and growth failure. These patients have elevated GH levels, excess adipose tissue, and are insulin resistant. Because IGF-I has insulinlike actions and patients with GH insensitivity syndrome (GHIS) exhibit excess adiposity, we sought to determine whether ghrelin levels were elevated in these patients and potentially regulated by IGF-I replacement.MethodsThirteen children with GHIS and 20 normal control children matched for age, sex, and body mass index underwent complete physical examination and a fasting blood draw at baseline. The GHIS subjects then underwent follow-up fasting blood draws during therapy with human recombinant IGF-I (80-120 μg/kg, given subcutaneously twice daily). Fasting glucose, insulin, and IGF-I concentrations were measured at the time of collection. Fasting total ghrelin levels were measured on stored serum samples.ResultsThe GHIS subjects had 2-fold higher fasting ghrelin levels (2926 ± 1869 pg/mL) compared with the normal control children (1492 ± 493 pg/mL; P = 0.009), and mean ghrelin values were reduced 56% during 6.4 ± 0.2 years of IGF-I replacement (P < 0.05).ConclusionsGrowth hormone resistance and low IGF-I levels are associated with elevated ghrelin levels, which may potentiate GH secretion and adiposity in these children. Suppression of ghrelin during IGF-I treatment suggests a novel mechanism potentially regulating ghrelin levels.

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