scholarly journals Novel Relationships of Age, Visceral Adiposity, Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein Concentrations to Growth Hormone (GH) Releasing-Hormone and GH Releasing-Peptide Efficacies in Men during Experimental Hypogonadal Clamp

2009 ◽  
Vol 94 (6) ◽  
pp. 2137-2143 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Daniel M. Keenan ◽  
Joy N. Bailey ◽  
Adebordurin M. Adeniji ◽  
John M. Miles ◽  
...  
Keyword(s):  
Visceral Fat ◽  
Medical Center ◽  
Dominant Negative ◽  
Sex Steroid ◽  
Forward Selection ◽  
Gh Secretion ◽  
Igf I ◽  
Igf Binding ◽  
Abdominal Visceral Fat ◽  
Igf Binding Protein

Abstract Background: Sex steroids influence GH secretion in complex ways. Hypothesis: Analyses in a low sex-steroid milieu will help unveil the effects of age and other nonsteroidal regulators on GH secretion. Context: The study was conducted in a tertiary medical center. Subjects: The study group included 13 healthy young men and 12 healthy older men. Methods: We used GnRH agonist-induced down-regulation of testosterone and estradiol secretion, followed by consecutive infusion of l-arginine and GHRH or GHRP-2, to test secretagogue efficacies. Outcomes: We measured basal and pulsatile GH secretion. Results: During experimental testosterone/estradiol deprivation, older (57 ± 1.7 yr) men maintained: 1) 6.8-fold less pulsatile GH secretion (P < 0.001); and 2) 2-fold lower maximal GH responses to GHRH (P = 0.0065) and GHRP-2 (P = 0.022) than young (23 ± 1.1 yr old) individuals. Stepwise forward-selection regression analyses identified: 1) abdominal visceral fat as a dominant negative predictor of both GHRH (R2 = 0.49; P = 0.001) and GHRP-2 (R2 = 0.38; P = 0.005) efficacies; and 2) fasting IGF-I concentration as a major positive correlate of GHRH (R2 = 0.52; P < 0.001) and GHRP-2 (R2 = 0.31; P = 0.018) efficacies. Unstimulated pulsatile GH secretion was jointly correlated with IGF-I and IGFBP-3 (P = 0.039). Conclusion: Measures of body composition (abdominal visceral fat) and pulsatile GH action (IGF-I) explain up to one half of interindividual variability in the efficacies of GHRH and GHRP-2 in sex steroid-depleted men. Accordingly, normative ranges for maximal single peptide-stimulated GH secretion in short-term hypogonadal states should incorporate the influence of these determinants as well as age.

scholarly journals Determinants of GH-releasing hormone and GH-releasing peptide synergy in men

2009 ◽  
Vol 296 (5) ◽  
pp. E1085-E1092 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Cyril Y. Bowers
Keyword(s):  
Sex Steroids ◽  
Sex Steroid ◽  
Forward Selection ◽  
Releasing Hormone ◽  
Gh Secretion ◽  
Igf I ◽  
Igf Binding ◽  
Abdominal Visceral Fat ◽  
Igf Binding Protein ◽  
Igfbp 3

Age, sex steroids, and abdominal-visceral fat (AVF) jointly affect pulsatile growth hormone (GH) secretion. Pulsatile GH secretion in turn is controlled by GH-releasing hormone (GHRH), GH-releasing peptide (GHRP), and somatostatin. Marked stimulation of pulsatile GH secretion is achieved via GHRH-GHRP synergy. Nonetheless, how key modulators of GH secretion, such as age, sex steroids, and body mass index, modify GHRH-GHRP synergy is not known. The present strategy was to 1) infuse GHRH and GHRP-2 simultaneously to evoke synergy and 2) downregulate the gonadal axis with leuprolide and then restore placebo (Pl) or testosterone (T) to clamp the sex steroid milieu. Forty-seven men [18–74 yr of age, T = 7–1,950 ng/dl, estradiol (E2) = 5–79 pg/ml, insulin-like growth factor (IGF)-I = 115–817 μg/l, AVF = 11–349 cm2] were studied. GHRH-GHRP synergy correlated negatively with age and AVF (both P < 0.001) and positively with IGF-I ( P < 0.001) and IGF-binding protein (IGFBP)-3 ( P = 0.031). Unstimulated basal (nonpulsatile) GH secretion correlated positively with T ( P = 0.015) and E2 ( P = 0.004) concentrations. Fasting pulsatile GH secretion varied negatively with age ( P = 0.017) and positively with IGF-I ( P = 0.002) and IGFBP-3 ( P = 0.001). By stepwise forward-selection multivariate analyses, AVF, IGF-I, and IGFBP-3 together explained 60% of the variability in GHRH-GHRP synergy ( P < 0.001), E2 accounted for 17% of the variability in basal GH secretion ( P = 0.007), and IGF-I explained 20% of the variability in fasting pulsatile GH secretion ( P = 0.002). In conclusion, a paradigm examining GHRH-GHRP synergy under a sex steroid clamp reveals highly selective control of basal, pulsatile, and synergistic peptide-driven GH secretion by AVF, E2, and IGF-I in healthy men.

scholarly journals Aromatase and 5α-Reductase Inhibition during an Exogenous Testosterone Clamp Unveils Selective Sex Steroid Modulation of Somatostatin and Growth Hormone Secretagogue Actions in Healthy Older Men

2009 ◽  
Vol 94 (3) ◽  
pp. 973-981 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Kristi L. Mielke ◽  
Mihaela Cosma ◽  
Cacia Soares-Welch ◽  
Remberto Paulo ◽  
...  
Keyword(s):  
Visceral Fat ◽  
Medical Center ◽  
Academic Medical Center ◽  
Older Men ◽  
Sex Steroid ◽  
Forward Selection ◽  
Growth Hormone Secretagogue ◽  
Gh Secretion ◽  
Academic Medical ◽  
Abdominal Visceral Fat

Abstract Background: How endogenous testosterone (Te), 5α-dihydrotestosterone (DHT), and estradiol (E2) regulate pulsatile GH secretion is not understood. Hypothesis: Conversion of Te to androgenic (Te→DHT) or estrogenic (Te→E2) products directs GH secretion. Subjects and Location: Healthy older men (N = 42, ages 50–79 yr) participated at an academic medical center. Methods: We inhibited 5α-reduction with dutasteride and aromatization with anastrozole during a pharmacological Te clamp and infused somatostatin (SS), GHRH, GH-releasing peptide-2 (GHRP-2), and l-arginine/GHRH/GHRP-2 (triple stimulus) to modulate GH secretion. Endpoints: Deconvolution-estimated basal and pulsatile GH secretion was assessed. Results: Administration of Te/placebo elevated Te by 2.8-fold, DHT by 2.6-fold, and E2 concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E2 by 89 and 86%, respectively. Stepwise forward-selection regression analysis revealed that 1) Te positively determines mean (P = 0.017) and peak (P &lt; 0.001) GH concentrations, basal GH secretion (P = 0.015), and pulsatile GH secretion stimulated by GHRP-2 (P &lt; 0.001); 2) Te and E2 jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E2, P = 0.031); and 3) DHT correlates positively with pulsatile GH secretion during SS infusion (P = 0.011). These effects persisted when abdominal visceral fat was included in the regression. Conclusion: The present outcomes suggest a tetrapartite model of GH regulation in men, in which systemic concentrations of Te, DHT, and E2 along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

The effects of insulin-like growth factor-I (IGF-I), IGF-II and des(1–3)IGF-I, a potent IGF analogue, on growth hormone and IGF-binding protein secretion from cultured rat anterior pituitary cells

1991 ◽  
Vol 130 (1) ◽  
pp. 93-99 ◽  
Author(s):  
J. M. Simes ◽  
J. C. Wallace ◽  
P. E. Walton
Keyword(s):  
Growth Factor ◽  
Anterior Pituitary ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Factor I ◽  
Anterior Pituitary Cells ◽  
Low Concentrations ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

ABSTRACT The effects of insulin-like growth factor-I (IGF-I), IGF-II and des(1–3)IGF-I, a potent IGF-I analogue, on the secretion of GH and IGF-binding protein (IGFBP) from cultured rat anterior pituitary cells were measured. IGF-I and des(1–3)IGF-I stimulated GH secretion at low concentrations (maximally effective at 1 and 0·1 μg/l respectively) and inhibited GH secretion at higher concentrations. The half-maximal inhibitory concentrations (IC50) were approximately 20 μg/l and 1 μg/l for IGF-I and des(1–3)IGF-I respectively. Thus des(1–3)IGF-I was more potent than IGF-I in these effects on GH secretion. We postulate that the increased potency of des(1–3)IGF-I in affecting GH secretion is due to decreased binding of this peptide by pituitary IGFBP compared with IGF-I. In contrast with IGF-I and des(1–3)IGF-I, IGF-II did not stimulate GH secretion at low concentrations, but did inhibit GH secretion from pituitary cells with an IC50 of approximately 20 μg/l. Several IGFBPs ranging in molecular mass from 22 000 to 52 000 were detected in medium conditioned by cultured anterior pituitary cells. When measured by Western-ligand blotting and competitive ligand-binding techniques, these IGFBPs exhibited decreased binding of des(1–3)IGF-I compared with IGF-I and IGF-II. The production of IGFBP by anterior pituitary cells was stimulated by the addition of IGFs to the culture medium. Journal of Endocrinology (1991) 130, 93–99

scholarly journals Relative effects of estrogen, age, and visceral fat on pulsatile growth hormone secretion in healthy women

2009 ◽  
Vol 297 (2) ◽  
pp. E367-E374 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Susan B. Hudson ◽  
Dana Erickson ◽  
Joy N. Bailey ◽  
George Ann Reynolds ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Visceral Fat ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Analysis Of Covariance ◽  
Forward Selection ◽  
Gh Secretion ◽  
Abdominal Visceral Fat ◽  
Complex Regulation ◽  
Peptide Interaction

Growth hormone (GH) secretion is subject to complex regulation. How pre- and postmenopausal age (PRE, POST), estradiol (E2) availability, and abdominal visceral fat (AVF) jointly affect peptidyl-secretagogue drive of GH secretion is not known. To this end, healthy PRE ( n = 20) and POST ( n = 22) women underwent a low- vs. high-E2 clamp before receiving a continuous intravenous infusion of GH-releasing hormone (GHRH) or GH-releasing peptide (GHRP-2). According to analysis of covariance, PRE and POST women achieved age-independent hypo- and euestrogenemia under respective low- and high-E2 clamps. All four of age ( P < 0.001), E2 status ( P = 0.006), secretagogue type ( P < 0.001), and an age × peptide interaction ( P = 0.014) controlled pulsatile GH secretion. Independently of E2 status, POST women had lower GH responses to both GHRH ( P = 0.028) and GHRP-2 ( P < 0.001) than PRE women. Independently of age, GHRP-2 was more stimulatory than GHRH during low E2 ( P = 0.011) and high E2 ( P < 0.001). Stepwise forward-selection multivariate analysis revealed that computerized tomographic estimates of AVF explained 22% of the variability in GHRH action ( P = 0.002), whereas age and E2 together explained 60% of the variability in GHRP-2 drive ( P < 0.001). These data establish that age, estrogen status, and AVF are triple covariates of continuous peptide-secretagogue drive of pulsatile GH secretion in women. Each factor must be controlled for to allow valid comparisons of GH-axis activity.

scholarly journals The role of IGF binding protein-3 as a parameter of activity in acromegalic patients

1999 ◽  
pp. 145-148 ◽  
Author(s):  
I Halperin ◽  
R Casamitjana ◽  
L Flores ◽  
M Fernandez-Balsells ◽  
E Vilardell
Keyword(s):  
Binding Protein ◽  
Serum Levels ◽  
Glucose Load ◽  
Gh Secretion ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Normal Standard ◽  
Igfbp 3

OBJECTIVE: The production of insulin-like growth factor binding protein-3 (IGFBP-3), the main IGF-I binding protein, is regulated by GH, and its serum levels are increased in acromegaly. We investigated its potential value as a parameter of acromegaly activity or remission in comparison with IGF-I, taking GH suppression below 2 microg/l after glucose load as the normal standard. METHODS: Data from 40 acromegalic patients (12 males and 28 females, aged 28 to 79 years) were obtained retrospectively from stored samples. From these, 145 pairs of IGF-I/IGFBP-3 values were collected; in 67 of them, simultaneous measurement of GH after glucose loading allowed their classification as active or inactive acromegaly. Relationships between IGF-I, IGFBP-3 and GH after glucose load were assessed, as well as differences between IGF-I and IGFBP-3 levels in active and inactive acromegaly. RESULTS: Significant positive correlation between IGF-I and IGFBP-3 in 145 samples was observed (r=0.49, P<0. 0001). As for the 67 samples in which activity or remission could be defined in terms of GH after glucose load, 50 were active and 17 inactive. Both IGF-I and IGFBP-3 significantly correlated with minimum GH (r=0.53, P<0.0001 and r=0.41, P<0.001 respectively). For both parameters, significant differences of means between active and inactive cases were observed (623+/-296 vs 300+/-108 ng/ml, P<0.0001 for IGF-I, and 4.1+/-1.3 vs 3.2+/-0.9 microg/ml, P<0.006 for IGFBP-3). Yet, when comparing in individual cases their classification as active or inactive with the finding of normal or increased IGF-I and IGFBP-3, among active cases 16% appeared as normal according to IGF-I, and 50% appeared as normal in terms of IGFBP-3. Among inactive cases, 23.5% appeared as active according to IGF-I, while 17.5% appeared as active in terms of IGFBP-3. CONCLUSION: Even though IGFBP-3 reflects GH secretion, it offers no advantage over IGF-I in the assessment of acromegaly, and it may underestimate disease activity in acromegalic patients.

scholarly journals Lack of Dietary Carbohydrates Induces Hepatic Growth Hormone (GH) Resistance in Rats

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 1948-1960 ◽  
Author(s):  
Maximilian Bielohuby ◽  
Mandy Sawitzky ◽  
Barbara J. M. Stoehr ◽  
Peggy Stock ◽  
Dominik Menhofer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Protein ◽  
Janus Kinase ◽  
Gh Secretion ◽  
Igf System ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
I Gene ◽  
Gh Resistance

GH is a well established regulator of growth, lipid, and glucose metabolism and therefore important for fuel utilization. However, little is known about the effects of macronutrients on the GH/IGF system. We used low-carbohydrate/high-fat diets (LC-HFD) as a model to study the impact of fat, protein, and carbohydrates on the GH/IGF-axis; 12-wk-old Wistar rats were fed either regular chow, a moderate, protein-matched LC-HFD, or a ketogenic LC-HFD (percentage of fat/protein/carbohydrates: chow, 16.7/19/64.3; LC-HF-1, 78.7/19.1/2.2; LC-HF-2, 92.8/5.5/1.7). After 4 wk, body and tibia length, lean body mass, and fat pad weights were measured. Furthermore, we investigated the effects of LC-HFD on 1) secretion of GH and GH-dependent factors, 2) expression and signaling of components of the GH/IGF system in liver and muscle, and 3) hypothalamic and pituitary regulation of GH release. Serum concentrations of IGF-I, IGF binding protein-1, and IGF binding protein-3 were lower with LC-HF-1 and LC-HF-2 (P &lt; 0.01). Both LC-HFD-reduced hepatic GH receptor mRNA and protein expression, decreased basal levels of total and phosphorylated Janus kinase/signal transducers and activators of transcription signaling proteins and reduced hepatic IGF-I gene expression. Hypothalamic somatostatin expression was reduced only with LC-HF-1, leading to increased pituitary GH secretion, higher IGF-I gene expression, and activation of IGF-dependent signaling pathways in skeletal muscle. In contrast, despite severely reduced IGF-I concentrations, GH secretion did not increase with LC-HF-2 diet. In conclusion, lack of carbohydrates in LC-HFD induces hepatic GH resistance. Furthermore, central feedback mechanisms of the GH/IGF system are impaired with extreme, ketogenic LC-HFD.

scholarly journals Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women

2004 ◽  
pp. 161-171 ◽  
Author(s):  
A Lukanova ◽  
E Lundin ◽  
A Zeleniuch-Jacquotte ◽  
P Muti ◽  
A Mure ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Steroid Hormones ◽  
Sex Steroids ◽  
Sex Steroid ◽  
Cross Sectional ◽  
Igf I ◽  
Igf Binding ◽  
Post Menopausal ◽  
Igf Binding Protein ◽  
Igfbp 3

OBJECTIVE: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. CONCLUSIONS: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

Reduced free IGF-I and increased IGFBP-3 proteolysis in Turner syndrome: modulation by female sex steroids

2001 ◽  
Vol 280 (2) ◽  
pp. E308-E314 ◽  
Author(s):  
Claus Højbjerg Gravholt ◽  
Jan Frystyk ◽  
Allan Flyvbjerg ◽  
Hans Ørskov ◽  
Jens Sandahl Christiansen
Keyword(s):  
Turner Syndrome ◽  
Final Height ◽  
Steroid Treatment ◽  
Sex Steroid ◽  
Female Sex ◽  
Igf I ◽  
Igf Binding ◽  
17Β Estradiol ◽  
Igf Binding Protein ◽  
Igfbp 3

The bioactivity of the growth hormone-insulin-like growth factor (IGF) system is reduced in Turner syndrome and may explain the reduction seen in final height. We compared levels of free and total IGF-I, immunoreactive and Western ligand blot IGF-binding protein (IGFBP)-3, and IGFBP-3 proteolysis in women with Turner syndrome ( n = 23) before (TB) and during 6 mo treatment with 17β-estradiol and norethisterone. An age-matched group of controls ( n = 24) was included. Total IGF-I and immunoreactive levels of IGFBP-3 were comparable in TB and controls, whereas free IGF-I ( P = 0.02) in TB was less than in controls. Western ligand blotting (WLB)-IGFBP-3 was significantly lower in TB than in controls ( P = 0.0005). Accordingly, IGFBP-3 proteolysis was greater in Turner syndrome ( P = 0.001). Female sex steroid treatment increased WLB-IGFBP-3 ( P = 0.0005), whereas immunoreactive IGFBP-3 and IGFBP-3 proteolysis were normalized ( P = 0.004). Free IGF-I remained unchanged ( P = 0.8), with a tendency toward a decrease in total IGF-I ( P = 0.1). In conclusion, despite normal total IGF-I and immunoreactive IGFBP-3, free serum IGF-I is less and IGFBP-3 proteolysis is greater in Turner syndrome than in controls. During sex steroid treatment, IGFBP-3 proteolysis normalized, without any change in free IGF-I.

scholarly journals Preservation of GHRH and GH-releasing peptide-2 efficacy in young men with experimentally induced hypogonadism

2009 ◽  
Vol 161 (2) ◽  
pp. 293-300 ◽  
Author(s):  
Johannes D Veldhuis ◽  
Daniel M Keenan ◽  
Joy N Bailey ◽  
John M Miles ◽  
Cyril Y Bowers
Keyword(s):  
Young Men ◽  
Short Term ◽  
Double Blind ◽  
Gh Secretion ◽  
The Face ◽  
Igf Binding ◽  
Abdominal Visceral Fat ◽  
Low Testosterone ◽  
Igf Binding Protein ◽  
Igfbp 3

BackgroundSomatostatin (SS), GHRH, GH-releasing peptide (GHRP), and the sex-steroid milieu regulate GH secretion.ObjectiveTo test whether GHRH and GHRP remain effective secretagogs in the face of short-term hypogonadism.DesignProspective, randomized double-blind.MethodsHealthy young men (n=24) received a GnRH agonist twice 3 weeks apart followed by placebo (n=13, Pl) or testosterone (n=11, testosterone) addback. Subjects were then given consecutive i.v. infusions of l-arginine (to restrain SS outflow) and a maximally effective dose of GHRH or GHRP-2 (to test corresponding secretagog pathways).ResultsGH secretion stimulated by l-arginine/GHRH and by l-arginine/GHRP-2 was unaffected by combined testosterone/estradiol (E2) depletion. The low testosterone/E2 milieu decreased basal (nonpulsatile) GH secretion (P=0.038), without altering fasting pulsatile GH secretion or IGF1 or IGF-binding protein (IGFBP)-3 concentrations. IGFBP-1 (P<0.0001) and abdominal visceral fat (AVF, P=0.017) correlated negatively with fasting basal GH secretion. By contrast, IGF1 (P=0.0012) and IGFBP-3 (P=0.015) correlated positively with fasting pulsatile GH secretion. AVF (P=0.0024) was a negative determinant, and IGF1 a positive determinant (P=0.018), of GHRH-driven GH pulses. Responses to GHRP-2 were unrelated to any of these factors.Conclusionl-arginine/GHRP-2 appears to be an especially robust stimulus of GH secretion, since efficacy is unmodified by profound short-term hypogonadism, a range of AVF estimates, and a spectrum of IGF1, IGFBP-1, and IGFBP-3 concentrations. Whether robustness also applies to chronic hypogonadism is not known.

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