br Conflict of interest br
Conflict of interest
CRediT authorship contribution statement Magdalena Olga Ciechanowska: Conceptualization, Data curation, Investigation, Methodology, Project administration, Writing - original draft. Magdalena Łapot: Formal analysis, Investigation, Methodology. Marek Kowalczyk: Writing - review & editing. Tadeusz Malewski: Methodology. Marek Brytan: Visualization. Bożena Antkowiak: Visualization. Franciszek Przekop: Investigation, Methodology.
Introduction In addition to the gonads, the Raltitrexed is one of the major organs that synthesizes estradiol (E2). For over 4 decades, a role of E2 in the regulation of neuronal function has been predicted. As early as 1971, Naftolin and colleagues reported that aromatase, the enzyme that converts androgens to E2, is present in the hypothalamus: Incubation of diencephalon obtained from male human fetuses with radiolabeled androstenedione yielded E2 and estrone (Naftolin et al., 1971). Subsequently, several pioneers in the field reported the presence of aromatase in the brain (Selmanoff et al., 1977; Steimer and Hutchison, 1980; Ellinwood et al., 1984; MacLusky et al., 1986; Roselli et al., 1987; Roselli et al., 2001) and have speculated about possible roles of neuroestrogens in brain functions as a neurotransmitter or neuromodulator (see Balthazart and Ball, 2006; Saldanha et al., 2011). This speculation is based on the facts that 1) E2 induces rapid changes in neuronal activity and behaviors (Yagi, 1973; Kelly et al., 1976; Hojo et al., 2008; Cross and Roselli, 1999; Cornil et al., 2005, Cornil et al., 2006; Kow and Pfaff, 2004; Remage-Healey et al., 2011), and 2) aromatase is present in axon terminals and the presynaptic boutons of the brain in various animals including monkeys and humans (Naftolin et al., 1996; Hojo et al., 2004; Peterson et al., 2005). In 2008, Remage-Healey et al. (2008) reported the most convincing evidence for neuroestradiol release in the songbird auditory cortex by direct in vivo measurements showing that local E2 concentration increased when the male bird is exposed to another male's songs. Ovarian E2 is indispensable for female reproductive functions. E2 is also known to facilitate learning/memory and protect from neuronal cell death throughout life (Morrison et al., 2006; Spencer et al., 2008; Brinton, 2009). Although a possible role of neuroestradiol in sex behavior, learning/memory, and neuroprotective function has been conceptually accepted, it has been completely ignored in reproductive neuroendocrinology. Perhaps, this is due to the well-established concept that reproductive cycles are regulated by the hypothalamo-pituitary-gonadal feedback circuit. However, while we were studying the rapid action of E2 on GnRH neurons, we almost accidentally found that neuroestradiol is significantly important for pulsatile release of GnRH and the preovulatory GnRH surge. In this review, I summarize a recent series of the findings in my laboratory supporting the concept that neuroestradiol participates in the control of GnRH secretion.
Rapid action of estradiol on GnRH neurons Using GnRH primary cultures derived from the monkey embryonic olfactory placode, we found that E2 induces rapid excitatory action on GnRH neurons. First, we observed that E2 at a 1 nM concentration stimulates firing activity of GnRH neurons within 60–120 s, lasting over 25 min (Abe and Terasawa, 2005). Second, exposure of GnRH neurons to E2 at 1 nM stimulates the frequency of intracellular calcium ([Ca2+]i) oscillations, the number of cells exhibiting [Ca2+]i oscillations, and the synchronization frequency of [Ca2+]i oscillations within 10 min (Abe et al., 2008; Noel et al., 2008). Third, exposure of GnRH neurons to E2 (1 nM) also stimulates GnRH release within 10 min (Noel et al., 2008). This rapid E2 action on GnRH neurons appears to be direct, as our primary cultures of GnRH neurons usually do not contain other types of neurons or glia, although numerous fibroblasts, epithelial cells, and unidentified non-neuronal cells are present (Terasawa et al., 1993; Richter et al., 2002). Together, we concluded that E2 induces a direct rapid excitatory action on primate GnRH neurons.