Vol. 289, Issue 1, 371-377, April 1999

Down-Regulation Models and Modeling of Testosterone Production Induced by Recombinant Human Choriogonadotropin¹

Jean-Michel Gries, Alain Munafo, Herve C. Porchet and Davide Verotta

Department of Biopharmaceutical Sciences (J.-M.G., D.V.), School of Pharmacy, and Department of Epidemiology and Biostatistics (D.V.), University of California, San Francisco; Ares-Sevono (A.M.), Geneva, Switzerland; and Debio Pharm (H.C.P.), Lausanne, Switzerland

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.