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

Abstract

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...

Effect of Daily Treatment with Thai Herb, Kaempferia parviflora, in Hershberger Assay Using Castrated Immature Rats

“…Testosterone has been shown to have an androgenic effect by increasing the accessory reproductive organ weights in studies using both castrated immature and adult male rats [5] and castrated adult male rats [6][7][8]. Testosterone propionate (TP) increases the reproductive organ weights, including those of the ventral prostate glands, seminal vesicles plus coagulation glands, glans penis, and bulbourethral glands, in F344, Sprague Dawley, and Wistar castrated immature rats [7,9].…”

Effect of Prolactin on the Population of Epithelial Cells From Ventral Prostate of Intact and Cyproterone Acetate‐Treated Peripubertal Rats: Stereological and Immunohistochemical Study

“…Although the rat prostate is an androgen-dependent organ, several studies indicate that it is androgen-sensitive, but does not require a chronic androgenic stimulus (Donjacour and Cunha, 1988). This androgen-dependence was demonstrated by the dramatic changes observed in rat prostate after surgical or pharmacological castration: androgenic deprivation causes regressive alterations due to the decrease of epithelial cells by apoptosis and to stromal reorganization (Potter et al, 2006;Augusto et al, 2008). In this sense, cyproterone acetate (CA), currently employed in antiandrogenic therapy for prostate cancer, is a potent and specific antagonist of steroid androgens in competition with dihydrotestosterone in the binding of androgen receptors (AR).…”

Establishment of a Novel Model for Studying the Effects of Extracts of Chinese Herb Medicine on Human Type II 5α-Reductase <i>in Vitro</i>

“…To screen inhibitors for hSRD5A2, several experimental systems have been adopted. For instance, in vitro enzymatic assay using prostate tissues of human or experimental animals is preferentially used, 13,14) as well as establishing a stable cell line expressing hSRD5A2 as an inhibitory screening model, 14) in which is contained SRD5A1, SRD5A2, or endogenous NADPH. 4,16,17) It is hard to obtain adequate amount of human specimens, and there is only 60％ homology between human and rodent SRD5A2, making it di‹cult for direct extrapolation, not separating hSRD5A2 from other interference factors.…”

“…After 4-week culture and screening, a large-scale volume of cell supernatant was obtained. 14) The cell supernatant was collected and puriˆed by centrifugation at 8000 rpm and 4°C for 10 min.…”