Estradiol supplementation modulates growth hormone (GH) secretory-burst waveform and recombinant human insulin-like growth factor-I-enforced suppression of endogenously driven GH release in postmenopausal women.
The present study tests the mechanistic postulate that estrogen confers resistance to negative feedback by systemic IGF-I. To this end, eight postmenopausal women received a constant iv infusion of recombinant human (rh)IGF-I (10 micro g/kg.h x 6 h) and saline in randomized order on the 10th day of supplementation with oral estradiol (E(2)) and placebo (Pl). GH secretion was quantitated by 10-min blood sampling, immunochemiluminometry assay, and deconvolution analysis. Administration of E(2) compared with Pl followed by saline infusion: 1) stimulated pulsatile GH secretion ( micro g/liter.6 h), viz., 12 +/- 3.3 (Pl) and 18 +/- 4.6 (E(2)) (mean +/- SEM, paired comparison, P < 0.05); 2) halved the time latency (min) to achieve peak GH secretion after GHRH injection, 24 +/- 2.2 (Pl) and 12 +/- 2.1 (E(2)) (P < 0.01); and 3) did not alter the mass of GH secreted ( micro g/liter) in response to a maximally effective dose of GHRH, 30 +/- 7.2 (Pl) and 37 +/- 11 (E(2)). Exposure to E(2) compared with Pl followed by rhIGF-I infusion: 1) accelerated the rate of decline of GH concentrations by 3.3-fold, viz., absolute slope ( micro g/liter.1000 min), 3.8 (range, 2.5-5.0) (Pl) and 12 (range, 10-14) (E(2)) (P < 0.001); 2) augmented the algebraic decrement in GH concentrations ( micro g/liter) enforced by rhIGF-I infusion, 0.73 +/- 0.21 (Pl) and 1.6 +/- 0.25 (E(2)) (P < 0.01); 3) halved the time delay (min) to peak GHRH-induced GH secretion, 20 +/- 1.2 (Pl) vs. 10 +/- 1.3 (E(2)) min (P < 0.01). In contradistinction, E(2) did not alter: 1) the capability of rhIGF-I to suppress GHRH-stimulated GH secretory burst mass significantly, viz., by 50 +/- 8% (Pl) and 52 +/- 14% (E(2)) (P < 0.05 each vs. saline); 2) the hourly rate of rise of infused (total) IGF-I concentrations; and 3) total and ultrafiltratably free IGF-I concentrations ( micro g/liter) attained at the end of the two rhIGF-I infusions. In summary, compared with Pl, E(2) supplementation in postmenopausal women: 1) amplifies endogenously driven GH secretory-burst mass; 2) initiates rapid onset of GHRH-stimulated GH release; and 3) potentiates IGF-I-dependent suppression of unstimulated GH concentrations. Based upon companion modeling data, we postulate that E(2) facilitates the upstroke and IGF-I enforces the downstroke of high-amplitude GH secretory bursts in estrogen-replete individuals.
Division of Endocrinology and Metabolism,Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905, USA. veldhuis.johannes@mayo.edu
Johannes D
JD
Veldhuis
Stacey M
SM
Anderson
Petra
P
Kok
Ali
A
Iranmanesh
Jan
J
Frystyk
Hans
H
Ørskov
Daniel M
DM
Keenan
D004347:Drug Interactions; D004958:Estradiol / Q000008:administration & dosage*; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D019382:Human Growth Hormone / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D008875:Middle Aged; D008954:Models, Biological; D010758:Phosphorus / Q000097:blood; D017698:Postmenopause; D011188:Potassium / Q000097:blood; D011446:Prospective Studies; D011673:Pulsatile Flow; D011994:Recombinant Proteins / Q000008:administration & dosage
D011994:Recombinant Proteins; D019382:Human Growth Hormone; D010758:Phosphorus; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D011188:Potassium