Minireview: Kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion

Department of Obstetrics and Gynecology, University of Washington Seattle, Seattle, Washington, United States
Endocrinology (Impact Factor: 4.64). 04/2006; 147(3):1154-8. DOI: 10.1210/en.2005-1282
Source: PubMed

ABSTRACT The Kiss1 gene encodes a family of peptides called kisspeptins, which bind to the G protein-coupled receptor GPR54. Kisspeptin(s) and its receptor are expressed in the forebrain, and the discovery that mice and humans lacking a functional GPR54 fail to undergo puberty and exhibit hypogonadotropic hypogonadism implies that kisspeptin signaling plays an essential role in reproduction. Studies in several mammalian species have shown that kisspeptins stimulate the secretion of gonadotropins from the pituitary by stimulating the release of GnRH from the forebrain after the activation of GPR54, which is expressed by GnRH neurons. Kisspeptin is expressed abundantly in the arcuate nucleus (Arc) and the anteroventral periventricular nucleus (AVPV) of the forebrain. Both estradiol and testosterone regulate the expression of the Kiss1 gene in the Arc and AVPV; however, the response of the Kiss1 gene to these steroids is exactly opposite between these two nuclei. Estradiol and testosterone down-regulate Kiss1 mRNA in the Arc and up-regulate its expression in the AVPV. Thus, kisspeptin neurons in the Arc may participate in the negative feedback regulation of gonadotropin secretion, whereas kisspeptin neurons in the AVPV may contribute to generating the preovulatory gonadotropin surge in the female. Hypothalamic levels of Kiss1 and GPR54 mRNA increase dramatically at puberty, suggesting that kisspeptin signaling could mediate the neuroendocrine events that trigger the onset of puberty. Together, these observations demonstrate that kisspeptin-GPR54 signaling in the brain serves as an important conduit for controlling GnRH secretion in the developing and adult animal.

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    • "Kisspeptin-ir neurons in the ARC are targets of estrogen negative feedback, are involved in GnRH/LH pulse generation , and provide tonic and direct stimulatory drive to GnRH neurons (Adachi et al., 2007; Dungan et al., 2006; Kinoshita et al., 2005; Smith, 2008). In agreement, our data show that for C and PF females, when circulating levels of sex steroids declined (OVX), the number of kisspeptin neurons in the ARC increased over Sham levels, and conversely, when circulating levels of E 2 increased (OVX + E 2 H), numbers kisspeptin-ir neurons in the ARC decreased back to Sham levels, reflecting the role of E 2 in negative feedback in the ARC. "
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    ABSTRACT: Background Prenatal alcohol exposure (PAE) has adverse effects on reproductive function and hypothalamic–pituitary–gonadal (HPG) activity. Kisspeptin neurons play a role in mediating feedback effects of estradiol (E2) and progesterone (P4) on the HPG axis. We hypothesized that PAE will have long-term effects on the response of kisspeptin neurons to E2 and P4.Methods Adult female rats (53 to 58 days) from prenatal ad libitum-fed control (C), pair-fed (PF), and alcohol-exposed (PAE) groups were subjected to Sham ovariectomy (OVX) or OVX without or with replacement with low or high physiological levels of E2 and P4, and terminated under basal conditions. E2 and P4 levels, and the response of kisspeptin-ir neurons in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei to these hormones, were measured. As the E2 signal is conveyed to kisspeptin neurons via estrogen receptor-α (ER-α), we investigated PAE effects on the number of kisspeptin-ir/ER-α-ir neurons. To determine whether PAE alters interactions between kisspeptin and gonadotropin-releasing hormone (GnRH) neurons, close contacts between kisspeptin-ir fibers and GnRH-ir cell bodies were examined.ResultsOur data present the novel finding that kisspeptin-ir neurons in the ARC of PAE females show differential responses to E2 and to the combined treatment with E2 and P4 compared with controls: (i) OVX increased the number of kisspeptin-ir neurons in C and PF, but not PAE females compared with their Sham counterparts; (ii) E2 replacement restored kisspeptin-ir cell numbers to Sham levels in C and PF females but caused a robust down-regulation of kisspeptin-ir neurons below Sham levels in PAE females; (iii) OVX and replacement with high physiological concentrations of E2 resulted in fewer kisspeptin-ir cells in PAE than C females; (iv) OVX and replacement with high levels of both E2 and P4 markedly decreased the number of kisspeptin-ir neurons, below levels observed following E2 alone, in PF and C females, but had no significant effect in PAE females.Conclusions These data suggest that a possible mechanism underlying adverse effects of PAE on HPG function involves actions of alcohol on the kisspeptin system.
    Alcoholism Clinical and Experimental Research 11/2014; 38(11). DOI:10.1111/acer.12561 · 3.31 Impact Factor
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    • "Pulses of steroid hormones are conserved temporal signals that control developmental transitions and sexual maturation in animals (Dungan et al., 2006; Rewitz et al., 2013; Tennessen and Thummel, 2011; Yamanaka et al., 2013). In insects, pulses of the steroid hormone ecdysone coordinate the developmental transition from the juvenile larval stage to a reproductively mature adult, a process called metamorphosis (Rewitz and O'Connor, 2011; Yamanaka et al., 2013). "
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    ABSTRACT: Steroid hormones trigger the onset of sexual maturation in animals by initiating genetic response programs that are determined by steroid pulse frequency, amplitude and duration. Although steroid pulses coordinate growth and timing of maturation during development, the mechanisms generating these pulses are not known. Here we show that the ecdysone steroid pulse that drives the juvenile-adult transition in Drosophila is determined by feedback circuits in the prothoracic gland (PG), the major steroid-producing tissue of insect larvae. These circuits coordinate the activation and repression of hormone synthesis, the two key parameters determining pulse shape (amplitude and duration). We show that ecdysone has a positive-feedback effect on the PG, rapidly amplifying its own synthesis to trigger pupariation as the onset of maturation. During the prepupal stage, a negative-feedback signal ensures the decline in ecdysone levels required to produce a temporal steroid pulse that drives developmental progression to adulthood. The feedback circuits rely on a developmental switch in the expression of Broad isoforms that transcriptionally activate or silence components in the ecdysone biosynthetic pathway. Remarkably, our study shows that the same well-defined genetic program that stimulates a systemic downstream response to ecdysone is also utilized upstream to set the duration and amplitude of the ecdysone pulse. Activation of this switch-like mechanism ensures a rapid, self-limiting PG response that functions in producing steroid oscillations that can guide the decision to terminate growth and promote maturation.
    Development 10/2013; 140(23). DOI:10.1242/dev.099739 · 6.27 Impact Factor
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    • "Control of the onset of puberty has been the goal of ongoing investigation. The discovery of kisspeptin as a hypothalamic trigger of gonadotropin secretion allowed for increased understanding of the developmental physiology [42] "
    Chapter: Gymnastics
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    ABSTRACT: The childhood athlete represents a dynamic endocrine system that changes as growth and pubertal maturation proceed. The endocrine systems act to maintain homeostasis while also regulating energy metabolism, and the elite athlete encounters unique stressors to both systems. Of particular relevance are the endocrine axes regulating growth hormone (GH) and insulin-like growth factor-1 (IGF-1) production, the adrenal glands, and the reproductive system. The adrenal axis is critical for the management of stress, including that associated with strenuous physical training. GH and IGF-1 secretions undergo dramatic increases in association with pubertal maturation. All of these systems are closely tied to energy metabolism. Regulation of energy intake relative to expenditure is controlled by a complex system of chemical and behavioral factors. Many of these chemical factors, particularly leptin and ghrelin, are also intimately tied to regulation of pubertal maturation, thus mediating a relationship between net energy availability and growth and development.
    Gymnastics, 08/2013: pages 28-39; , ISBN: 9781118357583
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