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Mathematical model for the androgenic regulation of the prostate in intact and castrated adult male rats

¹Curriculum in Toxicology, University of North Carolina, Chapel Hill; ²National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, Office of Research and Development, United States Environmental Protection Agency; and ³National Center for Computational Toxicology, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina

Submitted 9 November 2005 ; accepted in final form 5 June 2006

The testicular-hypothalamic-pituitary axis regulates male reproductive system functions. Understanding these regulatory mechanisms is important for assessing the reproductive effects of environmental and pharmaceutical androgenic and antiandrogenic compounds. A mathematical model for the dynamics of androgenic synthesis, transport, metabolism, and regulation of the adult rodent ventral prostate was developed on the basis of a model by Barton and Anderson (1997). The model describes the systemic and local kinetics of testosterone (T), 5-dihydrotestosterone (DHT), and luteinizing hormone (LH), with metabolism of T to DHT by 5-reductase in liver and prostate. Also included are feedback loops for the positive regulation of T synthesis by LH and negative regulation of LH by T and DHT. The model simulates maintenance of the prostate as a function of hormone concentrations and androgen receptor (AR)-mediated signal transduction. The regulatory processes involved in prostate size and function include cell proliferation, apoptosis, fluid production, and 5-reductase activity. Each process is controlled through the occupancy of a representative gene by androgen-AR dimers. The model simulates prostate dynamics for intact, castrated, and intravenous T-injected rats. After calibration, the model accurately captures the castration-induced regression of the prostate compared with experimental data that show that the prostate regresses to 17 and 5% of its intact weight at 14 and 30 days postcastration, respectively. The model also accurately predicts serum T and AR levels following castration compared with data. This model provides a framework for quantifying the kinetics and effects of environmental and pharmaceutical endocrine active compounds on the prostate.

rodent ventral prostate; androgen receptor; testosterone; 5-dihydrotestosterone; testicular-hypothalamic-pituitary axis