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Am J Physiol Endocrinol Metab 281: E35-E53, 2001;
0193-1849/01 $5.00
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Vol. 281, Issue 1, E35-E53, July 2001

Mathematical model of FSH-induced cAMP production in ovarian follicles

F. Clément1, D. Monniaux2, J. Stark4, K. Hardy5, J. C. Thalabard3, S. Franks6, and D. Claude1

1 Institut National de Recherche en Informatique et Automatique, Unité de Recherche de Rocquencourt, Domaine de Voluceau, Rocquencourt, 78153 Le Chesnay Cedex; 2 Unité de Physiologie de la Reproduction et des Comportements, UMR 6073 Institut National de la Recherche Agronomique-Centre National de la Recherche Scientifique-Université F. Rabelais de Tours, 37380 Nouzilly; 3 Unité de Formation et de Recherche Necker, Biostatistiques-Informatique Médicale, Endocrinologie-Médecine de la Reproduction, Université Paris V, Groupe Hospitalier Necker-Enfants Malades, 75743 Paris, France; 4 Centre for Nonlinear Dynamics and its Applications, University College London, London WC1E 6BT; 5 Division of Pediatrics, Obstetrics and Gynecology, Department of Reproductive Science and Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London W12 0NN; and 6 Division of Pediatrics, Obstetrics and Gynecology, Department of Reproductive Science and Medicine, Imperial College of Science, Technology and Medicine, St. Mary's Hospital Medical School, London W2 1PG, United Kingdom

During the terminal part of their development, ovarian follicles become totally dependent on gonadotropin supply to pursue their growth and maturation. Both gonadotropins, follicle-stimulating hormone (FSH) and luteining hormone (LH), operate mainly through stimulatory G protein-coupled receptors, their signal being transduced by the activation of the enzyme adenylyl cyclase and the production of second-messenger cAMP. In this paper, we develop a mathematical model of the dynamics of the coupling between FSH receptor stimulation and cAMP synthesis. This model takes the form of a set of nonlinear, ordinary differential equations that describe the changes in the different states of FSH receptors (free, bound, phosphorylated, and internalized), coupling efficiency (activated adenylyl cyclase), and cAMP response. Classical analysis shows that, in the case of constant FSH signal input, the system converges to a unique, stable equilibrium state, whose properties are here investigated. The system also appears to be robust to nonconstant input. Particular attention is given to the influence of biologically relevant parameters on cAMP dynamics.

signal transduction; granulosa cells; follicle-stimulating hormone; cyclic adenosine monophosphate


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