Progestin receptors: neuronal integrators of hormonal and environmental stimulation

Although it originally was believed that neuronal steroid hormone receptors require binding to cognate ligand for activation, more recent evidence suggests that the receptors can be activated indirectly by other compounds, such as neurotransmitters and growth factors, acting through their own membrane receptors and specific intracellular signaling pathways. For example, as is the case with facilitation of sexual behavior by progesterone, facilitation of sexual behavior by D(1)/D(5) dopamine receptor agonists is blocked by disruption of progestin receptors. Therefore, some dopamine agonists facilitate sexual behavior at least in part by a progestin receptor-dependent mechanism, as does progesterone. This "ligand-independent activation" of neuronal progestin receptors is not limited to dopamine agonists; a variety of other compounds, as well as mating stimulation, facilitate sexual receptivity by a progestin receptor-dependent process. Steroid hormone receptors also can be regulated by afferent input in another way. Various neurotransmitters upregulate or downregulate steroid hormone receptors in some neurons. This, in turn, presumably confers greater or decreased sensitivity to the particular factors that can activate the particular steroid receptor in those particular neurons. Therefore, steroid hormones are but one class of factors that can regulate and activate steroid hormone receptors. Some additional factors that activate steroid hormone receptors have been identified, as have some factors that can regulate concentrations of receptors. Relatively little is known at this time about the range of neurotransmitters, humoral factors, and intracellular signaling pathways that are involved.