Estrogenic Regulation of the GnRH Neuron

Abstract

Reproductive function is regulated by the secretion of luteinizing hormone (LH) and follicle-stimulating hormone from the pituitary and the steroid hormones from the gonads. The dynamic changes in the levels of the reproductive hormones regulate secondary sex characteristics, gametogenesis, cellular function, and behavior. Hypothalamic GnRH neurons, with cell bodies located in the basal hypothalamus, represent the final common pathway for neuronally derived signals to the pituitary. As such, they serve as integrators of a dizzying array of signals including sensory inputs mediating information about circadian, seasonal, behavioral, pheromonal, and emotional cues. Additionally, information about peripheral physiological function may also be included in the integrative signal to the GnRH neuron. These signals may communicate information about metabolic status, disease, or infection. Gonadal steroid hormones arguably exert the most important effects on GnRH neuronal function. In both males and females, the gonadal steroid hormones exert negative feedback regulation on axis activity at both the level of the pituitary and the hypothalamus. These negative feedback loops regulate homeostasis of steroid hormone levels. In females, a cyclic reversal of estrogen feedback produces a positive feedback loop at both the hypothalamic and pituitary levels. Central positive feedback results in a dramatic increase in GnRH secretion (Moenter et al., 1992; Xia et al., 1992; Clarke, 1993; Sisk et al., 2001). This is coupled with an increase in pituitary sensitivity to GnRH (Savoy-Moore et al., 1980; Turzillo et al., 1995), which produces the massive surge in secretion of LH that triggers ovulation. While feedback regulation of the axis in males is in part mediated by estrogen receptors (ER), there is not a clear consensus as to the relative role of ER versus AR signaling in males (Lindzey et al., 1998; Wersinger et al., 1999). Therefore, this review will focus on estrogenic signaling in the female.

Expanding the role of tachykinins in the neuroendocrine control of reproduction

“…Furthermore, GnRH neurons lack the ability to sense most factors that influence reproductive function, such as endogenous signals (e.g. sex steroid hormones (Radovick et al 2012, Hrabovszky & Liposits 2013, Roa 2013) as well as environmental cues (e.g. stressors (Dobson et al 2003)).…”

Actions of sex steroids on kisspeptin expression and other reproduction-related genes in the brain of the teleost fish european sea bass

“…Thus further studies will be needed to determine if these effects are directly mediated in kisspeptin neurons, or if other steroid-sensitive neurons are involved or certain chemical transmitters interact with hypothalamic neuropeptides, such as kisspeptins. In this context, an increasing body of evidence supports the idea that GnRH neurons in mammals are regulated by distinct neuronal networks and interactions via specific cell-cell signalling molecules, which may be affected by the modulatory influence of gonadal steroids (Bellefontaine et al, 2011;Prevot, 2002;Radovick et al, 2012). In mice, nitric oxide (NO) is probably involved in mediating the estrogenic positive feedback of Kiss1 onto GnRH neurons (Hanchate et al, 2012).…”

“…However, studies in mammals have also documented the close anatomical relationships between the Kiss1 and Gnrh-1 neurons, leading to the notion that Kiss1 neurons mediate the feedback signal from the gonad to GnRH (Bellefontaine et al, 2011;Oakley et al, 2009;Prevot, 2002;Radovick et al, 2012). However, in teleost fish, with the exception of one cichlid fish (Parhar et al, 2004), data from zebrafish (Servili et al, 2011), medaka (Kanda et al, 2012) and sea bass (Escobar et al, 2013b) all failed to confirm the presence of kiss receptors in gnrh neurons.…”

Hypothalamic gonadotropin-releasing hormone (GnRH) receptor neurons fire in synchrony with the female reproductive cycle

“…Cetrorelix also significantly inhibited the activity in GnRHR neurons during metestrus and diestrus but could not cause the complete shift to tonic firing, possibly because of the involvement of other hormones or synaptic input from adjacent neurons. Hypothalamic GnRH is released in pulses that increase in frequency and intensity during late proestrus (Radovick et al 2012;Sisk et al 2001). Estradiol levels rise during the estrous cycle, peaking during proestrus (Butcher et al 1974), and differentially affecting GnRH-secreting neurons (Abe and Terasawa 2005;Chu et al 2009).…”