New Concepts of the Neuroendocrine Regulation of Gonadotropin Surges in Rats

Abstract

In species that ovulate spontaneously, two key events mediate the stimulation of preovulatory gonadotropin surges: 1) neurosecretion of a preovulatory LHRH surge and 2) an acute increase in responsiveness of the pituitary gland to the LHRH neurosecretory trigger. These processes, in turn, depend upon both the positive feedback actions of preovulatory estrogen secretions and specific neural signals for initiation of the surge. In female rats, the neural signals for the surge are principally derived from the 24-h neural clock, thereby limiting the timing of surges to the afternoon of proestrus. It remains unclear, however, how neural signals converge with endocrine signals (estrogen) in specific brain cells and how their cellular integration leads to appropriate secretion of gonadotropin surges. Previous work has suggested that estrogen may exert its facilitatory actions by opening a neural "gate," thereby allowing transmission of the daily neural signal to surge-initiating neuronal groups. How may estrogen act to render a neural pathway patent? A conventional view holds that steroid hormones can exert permissive effects on signaling efficacy by modulating neurotransmitter receptor expression, intracellular second messenger production, and protein kinase activity. However, recent evidence has suggested that estrogen may also have the capacity to permit cross-talk between neurotransmitter signaling pathways and parallel transcriptional regulatory pathways. The progesterone receptor is an estrogen-inducible transcription factor that has been shown to be transactivated--even in the absence of its cognate ligand--after stimulation of neurotransmitter receptors coupled to adenylate cyclase stimulation. Thus, the convergence of neural and endocrine signals for the stimulation of gonadotropin surges could occur at the level of the progesterone receptor: estrogen may stimulate expression of progesterone receptors, which in turn may be initially transactivated by synaptic signals. Activated progesterone receptors may thereafter regulate transcription of target genes that control transmitter synthesis and release in neural circuitries governing LHRH gene expression and/or pulsatile LHRH release. An analogous mechanism may operate in pituitary gonadotrophs, in which ligand-independent transactivation of progesterone receptors mediates integration of neurosecretory and estrogen positive feedback signals, leading to increased pituitary responsiveness to LHRH. It is proposed that the "seeding" of specific neuronal groups and pituitary gonadotrophs with progesterone receptors, and perhaps other inducible transcription factors, comprises an important basis of estrogen's permissive role in the stimulation of gonadotropin surges. The validity of this integrative model remains to be confirmed, as does its possible importance in generating gonadotropin surges in other species.

New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

“…Our findings extend this idea of genotropic-dependent LH surges to include a specific requirement for ERα-DNA binding, and therefore suggest that downstream genes involved in estrogen regulation of GnRH/LH surges likely contain EREs. The progesterone receptor (PR) gene is one downstream candidate known to be necessary for E 2 -induction of the LH surge (Chappell and Levine, 2000;Chappell et al, 1999;Levine, 1997), and is indeed regulated by estrogen through classical, ERE-dependent ERα signaling (Kraus et al, 1994). Accordingly, immunohistochemical analyses from our laboratory demonstrate that estrogen-induced PR expression is reduced in the anteroventral periventricular (AVPV) nucleus of the hypothalamus, a region critical for LH surges, in both ERα −/AA and ERα −/− females (our unpublished observations).…”

The regulation of neuroendocrine function: Timing is everything

“…In addition to direct connections to GnRH neurons, the SCN projects extensively to the anteroventral periventricular nucleus (AVPV), a brain region associated with the induction of the preovulatory LH surge (Le et al, 1997;Levine, 1997). The cells to which the SCN projects are estrogen-responsive (Watson et al, 1995), suggesting that the AVPV may be an important integration point for circadian and steroidal signals.…”

“…Positive feedback effects of estrogen serve a permissive role in initiating the LH surge upon the arrival of the signal from the circadian pacemaker (Barbacka-Surowiak et al, 2003;Levine, 1997); implants of an anti-estrogen into the POA block the LH surge (Petersen and Barraclough, 1989). This dependence on estrogen ensures the maturation of the follicle during the time of the surge, while the circadian dependence ensures that receptive behavior coincides with ovulation.…”

“…It remains unclear, however, how these two signals converge at the cellular level to allow integration at the appropriate time of day. One possibility is that estrogen alters neurochemical secretion by the SCN or the signaling efficacy of these chemicals via second messenger systems and kinases Levine, 1997). An alternative hypothesis is that estrogen stimulates ligand-independent progesterone receptor production, and the timed neuronal signal acts on progesterone receptors Levine, 1997;Levine et al, 2001).…”

“…One possibility is that estrogen alters neurochemical secretion by the SCN or the signaling efficacy of these chemicals via second messenger systems and kinases Levine, 1997). An alternative hypothesis is that estrogen stimulates ligand-independent progesterone receptor production, and the timed neuronal signal acts on progesterone receptors Levine, 1997;Levine et al, 2001). This scheme suggests that the effects of estrogen are integrated with the SCN signal at the level of progesterone receptors to ensure that the GnRH system is sensitive to the daily signal only during the preovulatory estrogen surge.…”