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A FEEDBACK MODEL FOR TESTICULAR-PITUITARY AXIS HORMONE KINETICS AND THEIR EFFECTS ON THE REGULATION OF THE PROSTATE IN ADULT MALE RATS
Barton, H A., L. K. Potter, AND M. G. Zager. A FEEDBACK MODEL FOR TESTICULAR-PITUITARY AXIS HORMONE KINETICS AND THEIR EFFECTS ON THE REGULATION OF THE PROSTATE IN ADULT MALE RATS. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
The testicular-hypothalamic-pituitary axis regulates male reproductive system functions. A model describing the kinetics and dynamics of testosterone (T), dihydrotestosterone (DHT) and luteinizing hormone (LH) was developed based on a model by Barton and Anderson (1997). The model describes the metabolism of T to DHT by 5 -reductase with feedback loops for the positive regulation of T synthesis by LH and negative regulation of LH by T and DHT, and simulates the maintenance of the adult prostate as a function of hormone concentrations. The regulatory processes involved in prostate maintenance include cell proliferation, apoptosis, fluid production and 5 -reductase activity, which is controlled by the occupancy of a single gene by the DHT-androgen receptor (AR) dimerized complex. The other processes are regulated by the occupancy of multiple genes, but each process is represented as a single DNA binding site in the model. The model simulates prostate dynamics for intact, castrated, T injected and T or DHT subcutaneously implanted rats. The activities of environmental antiandrogens, such as the fungicide vinclozolin and the therapeautic drug finasteride, are modeled as competitive ligands for the AR. After calibration, the model is able to simulate the castration-induced regression of the prostate with accuracy compared to experimental data, which show that the prostate regresses to approximately 17 percent of its intact weight at 14 days post-castration and 5 percent at 30 days post-castration. The model demonstrates accuracy compared to the data in predicting serum T and AR levels following castration. This model sets a basis for quantifying the kinetics and effects of exogenous endocrine active compounds on the prostate. Furthermore, it provides a framework to extend modeling efforts to the pubertal developmental period, including growth and changes in hormone synthesis and metabolism. (Funded by EPA/UNC Toxicology Research Program, Training Agreement CT827206. This abstract does not reflect EPA policy.)