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  • br Regulation of gonadotropins by GnRH GnRH

    2021-10-09


    Regulation of gonadotropins by GnRH GnRH is released from the hypothalamus, and its release pattern is known to be pulsatile. That is, the pulse frequency and amplitude of GnRH release vary physiologically during reproductive cycles in females, and differentially stimulate the production and release of LH and FSH (Crowley et al., 1985). Previous experiments clearly demonstrated that pulsatile, but not continuous, release of GnRH was necessary to maintain secretion of LH and FSH from the anterior pituitary (Knobil, 1980). Moreover, changes in GnRH pulse frequency differentially regulate gonadotropins. Administration of a high frequency of GnRH pulses was shown to increase the secretion of LH, whereas lower frequencies of GnRH pulses resulted in decreases in LH secretion, but increases in FSH (Wildt et al., 1981). Thus, changes in the pulse frequency of GnRH release determine the predominant output of pituitary gonadotropins; the so-called ‘GnRH pulse generator’ is the main regulator of the secretory mode of pituitary gonadotropins. Several central and peripheral factors are involved in the neuronal activity of GnRH neurons. Neurotransmitters such as epinephrine and norepinephrine augment GnRH secretion, whereas dopamine and serotonin inhibit it. The ovarian sex steroids estradiol (E2) and progesterone have regulatory effects on GnRH secretion and its pulsatility. E2 has both stimulatory and inhibitory effects, depending on the stage of the menstrual cycle, while progesterone exerts an inhibitory action on GnRH neuronal activity. In the menstrual cycle during the follicular phase, the preovulatory GnRH surge is initiated by secretion of E2 and low progesterone concentrations (Evans et al., 1997). In contrast, increases in E2 and progesterone concentrations do not stimulate GnRH release during the luteal phase. Thus, these sex hormones modulate the activity of GnRH neurons; however, the expression of estrogen receptor α (ERα) and the progesterone receptor has not been fully clarified in GnRH neurons (Hu et al., 2008, Spratt and Herbison, 2001).
    GnRH-producing cell model, GT1-7 The hypothalamus is the control center for many physiological processes, yet has been difficult to study in detail because of the inherent heterogeneity of this CORM-3 synthesis region. The population of GnRH neurons is small and only about 800 cells are distributed in a dispersed pattern in the forebrain; thus, in vivo investigation of GnRH neurons is technically challenging. Immortalized clonal cell lines represent an unlimited, homogeneous population of neurons that can be manipulated using molecular techniques. GT1-7 cells have proven to be a valuable GnRH-expressing cell model for studying GnRH neurons (Liposits et al., 1991, Mellon et al., 1990). GT1-7 cells were created from a transgenic mouse utilizing 5′ flanking DNA of the rat GnRH gene to target expression of SV40 T-antigen in GnRH neurons (Mellon et al., 1990) and have a number of characteristics common to normal GnRH neurons. In addition, GT1-7 cells express a number of genes that are relevant to energy homeostasis, reproduction, and circadian rhythms. The characteristics of hypothalamic cell lines including GT1-7 cells were well documented in a previous review article (Mayer et al., 2009). The expression of ERα in GnRH neurons is still controversial, but there is a growing body of evidence demonstrating the expression of functional ERs in GnRH neurons (Hrabovszky et al., 2007, Hrabovszky et al., 2001). Both ERα and ERβ have been detected in GT1-7 cells (Navarro et al., 2003, Roy et al., 1999).
    Identification of kisspeptin as a regulator of GnRH After the discovery of pathological mutations in the gene encoding the kisspeptin receptor in patients with idiopathic hypogonadotropic hypogonadism in 2003, a new concept related to the regulation of the HPG axis was established, and detailed mechanisms of this area are still under investigation (de Roux et al., 2003, Seminara et al., 2003). Kisspeptin, which is encoded by the KISS1 gene, was first identified as a metastatic inhibiting factor in melanoma cells (Lee et al., 1996), and was subsequently found to bind to orphan G protein-coupled receptor 54 (GPR54) (Ohtaki et al., 2001), which is now named the kisspeptin receptor (Kiss1R). Thus far, it is generally agreed that kisspeptin neurons within the hypothalamus contact GnRH neurons and stimulate the release of GnRH by kisspeptin binding the Kiss1R within GnRH neurons (Clarke et al., 2015, Maggi et al., 2015). GnRH released from GnRH neurons subsequently reaches the pituitary gland via portal circulation and stimulates the release of pituitary gonadotropins. GT1-7 cells were demonstrated to maintain episodic neurosecretion of GnRH (Krsmanovic et al., 1999), and it has been reported that E2 alters pulsatile GnRH secretion through ERs (Hu et al., 2008). GnRH is also involved in its own secretion through GnRH receptors in GT1-7 cells (Larco et al., 2015). Novaira et al., 2009, Novaira et al., 2012 reported a functional role for the kisspeptin/GPR54 system in GT1-7 cells and revealed that kisspeptin stimulated GnRH secretion and gene expression in these cells. Similarly, Terasaka et al. (2013) demonstrated the stimulatory effect of kisspeptin on GnRH synthesis and showed the inhibitory effect of bone morphogenetic proteins on kisspeptin’s effects. E2 exerts inhibitory effects on GnRH secretion and gene expression in GT1-7 cells, but negative regulation of GnRH by E2 is antagonized by kisspeptin stimulation (Novaira et al., 2009). We also examined the effect of kisspeptin on GnRH mRNA expression. Although GT1-7 cells express Kiss1Rs, they did not transcribe GnRH mRNA in response to kisspeptin (Sukhbaatar et al., 2013). It is possible that Kiss1R function was lost in these cells or diminished by changes in cell characteristics due to immortalization or multiple passages. Indeed, when GT1-7 cells were transfected with Kiss1R expression vectors and an increase in Kiss1R was confirmed, these cells clearly responded to kisspeptin, and intracellular signaling such as extracellular signal-regulated kinase (ERK) activation and the cAMP pathway were certainly activated in Kiss1R-overexpressing GT1-7 cells, but GnRH expression was not increased (Sukhbaatar et al., 2013). A GnRH-neuron-containing cell population from fetal rat brain responded to exogenous kisspeptin and showed increased GnRH gene expression (Sukhbaatar et al., 2016). Interestingly, GT1-7 cells, although classically known for their GnRH-secreting characteristic, also basally produce and secrete kisspeptin (Quaynor et al., 2007).