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Research ArticleArticle

Down-Regulation Models and Modeling of Testosterone Production Induced by Recombinant Human Choriogonadotropin

Jean-Michel Gries, Alain Munafo, Herve C. Porchet and Davide Verotta
Journal of Pharmacology and Experimental Therapeutics April 1999, 289 (1) 371-377;
Jean-Michel Gries
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Alain Munafo
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Herve C. Porchet
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Davide Verotta
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Abstract

Chorionic gonadotropin (CG) is a glycoprotein hormone, whose action is mediated by the luteinizing hormone/CG receptor. Testosterone concentrations from six pituitary-desensitized, healthy male volunteers were obtained after four different administrations of recombinant-human CG (rhCG). We present a modeling study to provide a possible explanation for the observations that increased exposure to rhCG induces higher and then lower testosterone concentrations and that marked rebound effects are observed at the end of repeated administration of rhCG. We used semimechanistic models (in which flexible functions represent unknown parts of the models) to identify the relationship of rhCG concentrations to the testosterone levels. Based on the results obtained with the semimechanistic models, different mechanistic down-regulation models were devised and tested. The final model uses a one-compartment model to describe the endogenous production rate of testosterone; rhCG affects the production rate with a mechanism consistent with a two-site binding site, with effect proportional to one-site bound concentration. The modeling results indicate that when rhCG concentration increases, the testosterone production rate increases to 45 times the baseline value. However, at an rhCG concentration of more than about 30 IU/liter, the production rate decreases. Simulations showed that both dose and dosing interval profoundly influence testosterone response to rhCG.

Footnotes

  • Send reprint requests to: D. Verotta, Ph.D., School of Pharmacy, Department of Biopharmaceutical Sciences, Box 0446, University of California, San Francisco, CA 94143-0446. E-mail:davide{at}ariel.ucsf.edu.

  • ↵1 This work was sponsored by a grant from Ares Services S.A. (a member of The Ares-Serono Group of companies) and in part by U.S. Department of Health and Human Services Grant GM51197.

  • Abbreviations:
    CG
    chorionic gonadotropin
    LH
    luteinizing hormone
    FSH
    follicle-stimulating hormone (follitropin)
    rhCG
    recombinant-human chorionic gonadotropin
    • Received July 23, 1998.
    • Accepted October 6, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 1
1 Apr 1999
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Research ArticleArticle

Down-Regulation Models and Modeling of Testosterone Production Induced by Recombinant Human Choriogonadotropin

Jean-Michel Gries, Alain Munafo, Herve C. Porchet and Davide Verotta
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 371-377;

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Research ArticleArticle

Down-Regulation Models and Modeling of Testosterone Production Induced by Recombinant Human Choriogonadotropin

Jean-Michel Gries, Alain Munafo, Herve C. Porchet and Davide Verotta
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 371-377;
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