NEW CONCEPTS OF THE NEUROENDOCRINE REGULATION OF GONADOTROPIN SURGES IN RATS

In species that ovulate spontaneously, two key events mediate the stim ulation of preovulatory gonadotropin surges: 1) neurosecretion of a pr eovulatory LHRH surge and 2) an acute increase in responsiveness of th e pituitary gland to the LHRH neurosecretory trigger. These processes, in turn, depend upon both the positive feedback actions of preovulato ry estrogen secretions and specific neural signals for initiation of t he surge. In female rats, the neural signals for the surge are princip ally derived from the 24-h neural clock, thereby limiting the timing o f surges to the afternoon of proestrus. It remains unclear, however, h ow neural signals converge with endocrine signals (estrogen) in specif ic brain cells and how their cellular integration leads to appropriate secretion of gonadotropin surges. previous work has suggested that es trogen may exert its facilitatory actions by opening a neural ''gate,' ' thereby allowing transmission of the daily neural signal to surge-in itiating neuronal groups. How may estrogen act to render a neural path way patent? A conventional view holds that steroid hormones can exert permissive effects on signaling efficacy by modulating neurotransmitte r receptor expression, intracellular second messenger production, and protein kinase activity. However, recent evidence has suggested that e strogen may also have the capacity to permit cross-talk between neurot ransmitter signaling pathways and parallel transcriptional regulatory pathways. The progesterone receptor is an estrogen-inducible transcrip tion factor that has been shown to be transactivated-even in the absen ce of its cognate ligand-after stimulation of neurotransmitter recepto rs coupled to adenylate cyclase stimulation. Thus, the convergence of neural and endocrine signals for the stimulation of gonadotropin surge s could occur at the level of the progesterone receptor: estrogen may stimulate expression of progesterone receptors, which in turn may be i nitially transactivated by synaptic signals. Activated progesterone re ceptors may thereafter regulate transcription of target genes that con trol transmitter synthesis and release in neural circuitries governing LHRH gene expression and/or pulsatile LHRH release. An analogous mech anism may operate in pituitary gonadotrophs, in which ligand-independe nt transactivation of progesterone receptors mediates integration of n eurosecretory and estrogen positive feedback signals, leading to incre ased pituitary responsiveness to LHRH. It is proposed that the ''seedi ng'' of specific neuronal groups and pituitary gonadotrophs with proge sterone receptors, and perhaps other inducible transcription factors, comprises an important basis of estrogen's permissive role in the stim ulation of gonadotropin surges. The validity of this integrative model remains to be confirmed, as does its possible importance in generatin g gonadotropin surges in other species.