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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3414-3420
Copyright © 1997 by The Endocrine Society


From the Clinical Research Centers

Estrogen and Testosterone, But Not a Nonaromatizable Androgen, Direct Network Integration of the Hypothalamo-Somatotrope (Growth Hormone)-Insulin-Like Growth Factor I Axis in the Human: Evidence from Pubertal Pathophysiology and Sex-Steroid Hormone Replacement1

Johannes D. Veldhuis, Daniel L. Metzger, Paul M. Martha, Jr., Nelly Mauras, James R. Kerrigan, Bruce Keenan, Alan D. Rogol and Steve M. Pincus

Division of Endocrinology (J.D.V.), Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; Pediatric Endocrinology (D.L.M.), University of British Columbia, Vancouver, BC V6H 3V4, Canada; Genentech, Inc. (P.M.M.), South San Francisco, California 94080; Nemours Children’s Clinic (N.M.), Jacksonville, Florida 32207-8426; Department of Pediatrics (J.R.K.), East Tennessee State University, Johnson City, Tennessee 37614-0578; Department of Pediatrics (B.K.), University of Texas Medical Branch, Galveston, Texas 77555-0363; Department of Pediatrics (A.D.R.), University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; and (S.M.P.) Guilford, Connecticut 06437

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology, Department of Internal Medicine and National Science foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville 22908. E-mail: JDV{at}Virginia.Edu

Activation of the gonadotropic and somatotropic axes in puberty is marked by striking amplification of pulsatile neurohormone secretion. In addition, each axis, as a whole, constitutes a regulated network whose feedback relationships are likely to manifest important changes at the time of puberty. Here, we use the regularity statistic, approximate entropy (ApEn), to assess feedback activity within the somatotropic (hypothalamo-pituitary/GH-insulin-like growth factor I) axis indirectly. To this end, we studied pubertal boys and prepubertal girls or boys with sex-steroid hormone deficiency treated short-term with estrogen, testosterone, or a nonaromatizable androgen in a total of 3 paradigms. First, our cross-sectional analysis of 53 boys at various stages of puberty or young adulthood revealed that mean ApEn, taken as a measure of feedback complexity, of 24-h serum GH concentration profiles is maximal in pre- and mid-late puberty, followed by a significant decline in postpubertal adolescence and young adulthood (P = 0.0008 by ANOVA). This indicates that marked disorderliness of the GH release process occurs in mid-late puberty at or near the time of peak growth velocity, with a return to maximal orderliness thereafter at reproductive maturity. Second, oral administration of ethinyl estradiol for 5 weeks to 7 prepubertal girls with Turner’s syndrome also augmented ApEn significantly (P = 0.018), thus showing that estrogen per se can induce greater irregularity of GH secretion. Third, in 5 boys with constitutionally delayed puberty, im testosterone administration also significantly increased ApEn of 24-h GH time series (P = 0.0045). In counterpoint, 5 {alpha}-dihydrotestosterone, a nonaromatizable androgen, failed to produce a significant ApEn increase (P > 0.43). We conclude from these three distinct experimental contexts that aromatization of testosterone to estrogen in boys, or estrogen itself in girls, is likely the proximate sex-steroid stimulus amplifying secretory activity of the GH axis in puberty. In addition, based on inferences derived from mathematical models that mechanistically link increased disorderliness (higher ApEn) to network changes, we suggest that sex-steroid hormones in normal puberty modulate feedback within, and hence network function of, the hypothalamo-pituitary/GH-insulin-like growth factor I axis.




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J. Clin. Endocrinol. Metab.Home page
G. Van den Berghe, R. C. Baxter, F. Weekers, P. Wouters, C. Y. Bowers, and J. D. Veldhuis
A Paradoxical Gender Dissociation within the Growth Hormone/Insulin-Like Growth Factor I Axis during Protracted Critical Illness
J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 183 - 192.
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J. Clin. Endocrinol. Metab.Home page
J. Van Wyk
Insulin-Like Growth Factors and Skeletal Growth: Possibilities for Therapeutic Interventions
J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4349 - 4354.
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J. Clin. Endocrinol. Metab.Home page
P. C. Hindmarsh, E. Dennison, S. M. Pincus, C. Cooper, C. H. D. Fall, D. R. Matthews, P. J. Pringle, and C. G. D. Brook
A Sexually Dimorphic Pattern of Growth Hormone Secretion in the Elderly
J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2679 - 2685.
[Abstract] [Full Text]


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J. Clin. Endocrinol. Metab.Home page
R. K. Støving, J. D. Veldhuis, A. Flyvbjerg, J. Vinten, J. Hangaard, O. G. Koldkjær, J. Kristiansen, and C. Hagen
Jointly Amplified Basal and Pulsatile Growth Hormone (GH) Secretion and Increased Process Irregularity in Women with Anorexia Nervosa: Indirect Evidence for Disruption of Feedback Regulation within the GH-Insulin-Like Growth Factor I Axis
J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2056 - 2063.
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J. Clin. Endocrinol. Metab.Home page
N. Shah, W. S. Evans, C. Y. Bowers, and J. D. Veldhuis
Tripartite Neuroendocrine Activation of the Human Growth Hormone (GH) Axis in Women by Continuous 24-Hour GH-Releasing Peptide Infusion: Pulsatile, Entropic