Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E-2)-treated, progesterone receptorknockout (PRKO) mice

It is well known that estrogen (E-2) stimulates expression of progesterone receptors (PRs), thereby inducing responsiveness of several tissues to the actions of progesterone (P). Recent studies have also suggested, however, t hat biological actions previously ascribed to E-2 alone may also be mediate d by activation of E-2-induced PRs, even independently of signal changes in P concentrations. In the present experiments, the progesterone receptor kn ockout (PRKO) mice were used to assess the role of PR activation in the pos itive feedback actions of E-2 on gonadotropin release. Ovariectomized (OVX) PRKO mice were tested for their capacity to mount primary gonadotropin sur ges in response to exogenous E-2, and to exhibit a GnRH self-priming effect in response to sequential injections of the decapeptide. Wild-type (WT) an d PRKO mice were OVX, treated with both 17 beta-estradiol and estradiol ben zoate (EB), and then killed at 1900 h on day 7 postOVX. Plasma LH RIA revea led that WT mice exhibited surges in response to the E-2 treatment; the PRK O mice, however, showed no elevation in plasma LH above untreated controls. Instead, plasma LH levels in E-2-treated, OVX PRKO mice decreased signific antly in comparison to untreated OVX PRKO mice, suggesting that E-2 can exe rt a negative feedback influence on LH release in PRKO mice, despite the ab sence of positive feedback effects. A slight but significant rise in plasma FSH was observed in E-2-treated OVX WT mice in comparison to untreated con trols: an effect not seen in E-2-treated OVX PRKO mice, reinforcing the obs ervation that estrogen's positive feedback effects are compromised in PRKO mice. In a second experiment, E-2-treated OVX WT and PRKO mice were given e ither one or two pulses of GnRH 60 min apart, and killed 10 min later. The WT mice were found to exhibit a robust GnRH self-priming effect, as WT mice receiving two GnRH pulses displayed LH responses approximately 2-fold grea ter than those receiving only one pulse. By contrast, PRKO mice receiving t wo GnRH pulses exhibited no additional increase in plasma LH levels. We con clude that PR activation is obligatory for expression of the GnRH self-prim ing effect as well as for generation of E-2-induced LH and FSH surges. The extent to which failure of LH surge secretion in PRKO mice is due to the ab sence of GnRH self-priming, lack of hypothalamic GnRH surges, and/or defect s in other processes remains to be determined. These observations clearly d emonstrate, however, that the presence of PR is an absolute requirement for the transmission of E-2-induced signals leading to gonadotropin surges.