Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors

Estrogen (E-2) stimulates GnRH surges by coupling a daily neural signal to neuronal circuitries governing GnRH release. We have hypothesized that E-2 promotes this coupling process by inducing expression of neuronal transcrip tion factors, which are subsequently activated by neurotransmitter-mediated mechanisms representing the daily neural signal. These experiments tested the specific hypothesis that the progesterone receptor (PR) functions in th is manner, viz. as an E-2-induced factor whose activation is necessary for the stimulation of GnRH surges. Two complimentary experiments were performe d to determine whether activation of hypothalamic PRs is obligatory for the stimulation of GnRH surges by E-2. In the first, the effects of a PR antag onist on GnRH and LH surges were assessed in ovariectomized (OVX), E-2-prim ed rats. Rats were OVX on diestrous day 2, treated with 30 mu g estradiol b enzoate or oil vehicle, sc, and then administered either oil vehicle or the type I antiprogestin, ZK98299 at 0900 h on proestrus. GnRH release rates a nd plasma LH levels were determined in each animal by microdialysis of medi an eminence and atrial blood sampling, respectively. Estrogen, but not oil vehicle, treatment evoked robust and contemporaneous GnRH and LH surges in animals that received no PR antagonist on proestrus. Additional treatment w ith ZK98299, however, completely blocked both GnRH and LH surges. In a seco nd experiment, specific involvement of anteroventral periventricular (AVPV) PRs in E-2-induced GnRH surges was assessed. Additional groups of OVX, E-2 -primed rats were fitted with intracerebroventricular cannulas, and PR anti sense oligonucleotides were infused into the third ventricle adjacent to th e AVPV to prevent expression of PR; in this periventricular region. Animals infused with PR antisense oligos did not exhibit any LH surges, whereas su rges were observed in saline-, missense-, and sense oligo-treated controls. Immunohistochemistry confirmed the effectiveness of PR antisense oligonucl eotides in blocking PR expression. These findings provide direct support fo r the hypothesis that activation of PRs, specifically those in hypothalamic regions including the AVPV, is an obligatory event in the stimulation of G nRH surges by E-2.