Mathematical model for the androgenic regulation of the prostate in intact and castrated adult male rats.
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), 5alpha-dihydrotestosterone (DHT), and luteinizing hormone (LH), with metabolism of T to DHT by 5alpha-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 5alpha-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 approximately 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.
Potter
Laura K
LK
Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC, USA.
Zager
Michael G
MG
Barton
Hugh A
HA
D000728:Androgens / Q000097:blood* / Q000494:pharmacology; D000818:Animals; D013196:Dihydrotestosterone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007275:Injections, Intravenous; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009919:Orchiectomy; D009929:Organ Size; D010902:Pituitary Gland / Q000502:physiology; D011467:Prostate / Q000033:anatomy & histology / Q000502:physiology*; D051381:Rats; D015203:Reproducibility of Results; D013739:Testosterone / Q000097:blood* / Q000494:pharmacology
D000728:Androgens; D013196:Dihydrotestosterone; D013739:Testosterone; D007986:Luteinizing Hormone