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  • Rapid action of E on GnRH neurons

    2022-05-18

    Rapid action of E2 on GnRH neurons has been known for some time. E2 hyperpolarizes guinea pig GnRH neurons, alters cAMP production in GT1-cells and stimulates or inhibits [Ca2+]i oscillations within 15 min (Lagrange et al., 1995; Navarro et al., 2003; Temple et al., 2004; Romanò et al., 2008). Importantly, all these studies including ours were conducted in in vitro systems, such as cultured GnRH neurons or sliced brains. Thus, the question arises as to whether “rapid E2 action” seen in in vitro studies also occurs in vivo? The negative and positive feedback effects of E2 on GnRH/LH release are well-established concepts. For example, systemic administration of E2 benzoate (EB) in OVX monkeys results in suppression of GnRH/LH release with a latency of ~2 h (Mizuno and Terasawa, 2005), whereas stimulatory action occurs with a latency of ~24 h (Yamaji et al., 1971; Karsch et al., 1973; Terasawa et al., 1982). However, there was so far no report showing that rapid action of E2 on GnRH release occurs with a latency shorter than 20 min in vivo in any mammalian species. Therefore, we examined the effects of a brief EB infusion into the median eminence of the serine protease on GnRH release using a microdialysis approach. In the monkey dense GnRH neuroterminals and some GnRH cell bodies are distributed in the median eminence (Goldsmith et al., 1993). Continuous infusion of EB stimulated, not suppressed, GnRH release in ovariectomized (OVX) monkeys in vivo within 10–20 min, similar to what had been seen in vitro (Fig. 1, Kenealy et al., 2013). Furthermore, a similar brief infusion of EB also stimulated kisspeptin release (see Kenealy et al., 2015). Kisspeptin neuroterminals and cell bodies are also seen in the median eminence (Ramaswamy et al., 2008). These findings led to another question: What is the underlying mechanism differentiating the E2 action resulting from the 2 modes of EB administration (systemic injection vs. local infusion to the median eminence)? There are at least 3 possible explanations. First, the difference may be due to the exposure period of the median eminence to E2. While the exposure period in the study of Kenealy et al. (2013) was 10–20 min, systemic EB injection would sustain elevated circulating levels for at least 18 h. Second, the difference may be due to the E2 concentration at the median eminence. While the EB exposure dose in the study by Kenealy et al. (2013) was 1 or 10 nM, in systemic injection we used 50 μg/kg and the local concentration produced in the median eminence is unknown. Third, the difference may be attributable to the site of action within the hypothalamus. The results from a subsequent study indicate that the exposure period does not account for the difference in the 2 modes of EB administration: EB infusion into the median eminence for a prolonged period (4 or 7 h) sustains elevated release of GnRH and kisspeptin over several hours (Fig. 2, Kenealy et al., 2015), similar to the release observed with a brief (10 or 20 min) infusion (Kenealy et al., 2013, Fig. 1). Likewise, the EB concentration at the median eminence does not likely differentiate the 2 modes of EB administration. Continuous or brief infusion of EB at doses ranging from 1 nM to 1 μM, which translates into one tenth of the concentration (0.1 to 100 nM) in the tissue at the median eminence due to the permeability of microdialysis membrane (Frost et al., 2008), stimulated release of GnRH and kisspeptin, whereas subcutaneous injection of EB at 50 μg/kg, which induces concentrations of 300 to 500 pg/ml or 1–1.5 nM in the circulation (Mizuno and Terasawa, 2005) suppressed both GnRH and kisspeptin release (Kenealy et al., 2015). In contrast, the site of EB exposure is critical for stimulating the release of GnRH and kisspeptin by EB. In the EB infusion experiment, the region exposed to EB is restricted within the median eminence, as the tips of microdialysis probes (determined by x-ray ventriculography) are all located within the median eminence (Kenealy et al., 2015), whereas systemically administered EB reaches a large portion of the brain as well as the pituitary gland, as shown by autoradiography (Pfaff et al., 1976). It is speculated that systemically administered EB binds to estrogen receptor alpha (ERα, ESR1) located in infundibular (arcuate) kisspeptin and neurokinin-B neurons (Rance, 2009) resulting in inhibitory action, whereas direct infusion of EB into the GnRH and kisspeptin neuroterminals induces rapid actions mediated through a membrane-initiated mechanism.