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The testicular-hypothalamicpituitary 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 ϳ17 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 THE HYPOTHALAMUS, PITUITARY, AND TESTES produce endocrine hormones responsible for regulation of the prostate and other male sexual functions (12, 46). Exogenous endocrine active compounds can disrupt these processes. Some pesticides (e.g., vinclozolin and linuron) are known to have antiandrogenic activity (19,20). Toxic effects of antiandrogens in male rodents range from developmental effects such as reproductive malformations, retained nipples, and undescended testes to pubertal effects such as delayed puberty and reduced weights of prostate and other reproductive organs. In the pharmaceutical setting, therapeutic drugs such as finasteride, dutasteride, bicalutamide, and flutamide are used to treat benign prostatic hyperplasia and/or prostate cancer by inhibiting androgendependent growth processes.The mechanisms of action of antiandrogens are generally of two forms. The first is the androgen antagonist, which binds to the androgen receptor (AR) but does not stimulate DNA transcription, such as the pharmaceutical compounds flutamide and bicalutamide or the environmental compound vinclozolin. The second is the 5␣-reductase inhibitor, which blocks th...

This article is available online at http://www.jlr.org cludes the transfer of triglyceride (TG) from VLDL and LDL to HDL ( 1-3 ).The relationship between CETP and atherosclerosis/ coronary heart disease (CHD) is unclear, as is the importance of the net transfer of CE from HDL to apolipoprotein (apo)B-containing lipoproteins. CETP defi ciency and inhibition studies in animals and humans have produced confl icting results. Pharmacologic CETP inhibition has increased HDL cholesterol and reduced atherosclerosis in rabbit models ( 5 ). In humans, CETP defi ciency has been associated with both increased and decreased CHD risk ( 3, 5 ). The CETP inhibitors JTT-705 and torcetrapib have been shown to effectively reduce CETP activity in humans and raise HDL cholesterol, although the effect of this class of compounds on atherosclerosis and CHD risk is as yet unclear ( 6-8 ).Adding to this uncertainty is the termination of a Phase III torcetrapib study following an unexpected increase in deaths when dosed in combination with statin therapy versus statin therapy alone. "Off-target" activities of torcetrapib have been suggested as the reason for increased mortality and morbidity ( 9 ) and atherosclerotic plaque volume decreases were seen in the subset of patients having the greatest HDL changes ( 10 ). It is not yet known, however, if the increases in mortality and morbidity were caused entirely by the proposed mechanism or were in part due to changes in HDL subfractions or in functionality induced by CETP inhibition itself ( 11 ). Studies with other CETP inhibitors in development may shed light on whether this is a generalized phenomenon or specifi c to certain compounds, patient groups, or lipid phenotypes.The Cholesteryl ester transfer protein (CETP) plays a critical role in reverse cholesterol transport ( 1-3 ). CETP facilitates the net transfer of cholesterol ester (CE) from HDL to VLDL and LDL, which is followed by hepatic uptake of LDL via the LDL receptor ( 4 ). The CETP-mediated transfer of CE is part of a bidirectional exchange that also in-

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