A MODEL FOR PHARMACOKINETICS AND PHYSIOLOGICAL FEEDBACK AMONG HORMONES OF THE TESTICULAR-PITUITARY AXIS IN ADULT MALE RATS - A FRAMEWORK FOR EVALUATING EFFECTS OF ENDOCRINE ACTIVE COMPOUNDS

The testicular-hypothalamic-pituitary axis controls reproductive funct ions in males. A description of the basic physiological interactions i n adult rats among testosterone, luteinizing hormone (LH), and follicl e stimulating hormone (FSH) was developed, permitting simulation of ho rmone levels in testes and blood. This model was used to simulate horm one levels in intact, castrate, ethane dimethanesulfonate-treated, and antiandrogen-treated rats. A large gradient of testosterone concentra tions from testicular interstitial fluid to low levels in peripheral b lood is created by the testicular blood flow. The dominant feedback lo op is positive regulation of testosterone synthesis by LH and negative feedback of testosterone on LH and FSH, The utility of the model for placing in vitro data in the context of in vivo physiology was illustr ated for the case of continued synthesis of testosterone by the isolat ed testes. In the absence of blood flow, very low residual testosteron e synthesis can substantially increase testosterone concentration in i solated testes. Effects of an exogenous endocrine active compound were illustrated by modeling altered LH and FSH regulation by testosterone in the presence of an antiandrogen acting as a competitive ligand for the androgen receptor. Increasing concentrations have no effect on st eady-state hormone levels until sufficient levels of antiandrogen are achieved to reduce negative feedback of testosterone on LH and FSH. In summary, a model has been developed that provides a basis for initiat ing evaluations of key issues of concern for the risk assessment of en docrine active compounds including in vitro to in vivo extrapolation a nd their dose-response behaviors. (C) 1998 Society of Toxicology.