Autoshortloop feedback regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by its metabolite, GnRH-(1–5)

Larco, Darwin O.; Williams, Melissa; Schmidt, Lauren; Sabel, Nick; Lange, Jason; Woller, Michael J.; Wu, Tao

doi:10.1007/s12020-014-0492-7

Cited by 11 publications

(8 citation statements)

References 31 publications

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“…GnRH is a hypothalamic neuronal secretory decapitate that plays an important regulatory role in the mammalian reproductive system. The present study supports the notion that GnRH-(1-5) is functionally capable of regulating the reproductive neuroendocrine system [38]. GnRH influences the reproductive processes mainly by regulating pituitary gonadotropin synthesis and release, which, in turn, modulate steroid genesis and gametogenesis [39,40].…”

Section: Introductionsupporting

confidence: 87%

Effects of Di-(2-ethylhexyl) Phthalate on the Hypothalamus–Uterus in Pubertal Female Rats

Liu

Jia

Zhou

et al. 2016

IJERPH

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Abstract:The pollution of endocrine disruptors and its impact on human reproductive system have attracted much attention. Di-(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, is widely used in food packages, containers, medical supplies and children's toys. It can cause diseases such as infertility, sexual precocity and uterine bleeding and thus arouse concerns from the society and scholars. The effect of DEHP on pubertal female reproductive system is still not well-studied. This study was to investigate the effects of DEHP on the hypothalamus-uterus in pubertal female rats, reveal the reproductive toxicity of DEHP on pubertal female rats and its mechanism, and provide scientific evidence for the evaluation of toxicity and toxic mechanism of DEHP on reproductive system. Forty-eight pubertal female rats were randomly divided into four groups and respectively administered via oral gavage 0, 250, 500, or 1000 mg/kg/d DEHP in 0.1 mL corn oil/20 g body weight for up to four weeks. Compared with control rats, the DEHP-treated rats showed: (1) higher gonadotropin-releasing hormone (GnRH) level in the hypothalamus; (2) higher protein levels of GnRH in the hypothalamus; and (3) higher mRNA and protein levels of GnRH receptor (GnRHR) in the uterus. Our data reveal that DEHP exposure may lead to a disruption in pubertal female rats and an imbalance of hypothalamus-uterus. Meanwhile, DEHP may, through the GnRH in the hypothalamus and its receptor on the uterus, lead to diseases of the uterus. DEHP may impose a negative influence on the development and functioning of the reproductive system in pubertal female rats.

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Section: Introductionsupporting

confidence: 87%

Effects of Di-(2-ethylhexyl) Phthalate on the Hypothalamus–Uterus in Pubertal Female Rats

Liu

Jia

Zhou

et al. 2016

IJERPH

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“…GnRH-(1–5), like its parent peptide, is involved in the regulation of the HPG axis. Both GnRH gene expression ( 4 ) and secretion ( 5 ) are stimulated by GnRH-(1–5). Additionally, the facilitation of lordosis by GnRH is mediated by its metabolism to GnRH-(1–5) ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Gonadotropin-Releasing Hormone-(1–5) Signaling Genes by Estradiol Is Age Dependent

et al. 2017

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Gonadotropin-releasing hormone (GnRH) is a key regulatory molecule of the hypothalamus–pituitary (PIT)–gonadal (HPG) axis that ultimately leads to the downstream release of estradiol (E2) and progesterone (P). These gonadal steroids feed back to the hypothalamus and PIT to regulate reproductive function and behavior. While GnRH is thought to be the master regulator of reproduction, its metabolic product GnRH-(1–5) is also biologically active. Thimet oligopeptidase 1 (also known as EP24.15) cleaves GnRH to form GnRH-(1–5). GnRH-(1–5) is involved in regulation of the HPG axis, exerting its actions through a pair of orphan G protein-coupled receptors, GPR101 and GPR173. The physiological importance of GnRH-(1–5) signaling has been studied in several contexts, but its potential role during reproductive senescence is poorly understood. We used an ovariectomized (OVX) rat model of reproductive senescence to assess whether and how GnRH-(1–5) signaling genes in hypothalamic subnuclei change in response to aging and/or different estradiol replacement regimens designed to model clinical hormone replacement in women. We found that Gpr101 and Gpr173 mRNA expression was increased with age in the arcuate nucleus, while expression of Gpr173 and EP24.15 increased with age in the medial preoptic area. Treatment with E2 in younger OVX animals increased expression of Gpr101, Gpr173, and EP24.15. However, older animals treated with E2 showed decreased expression of these GnRH-(1–5) signaling genes, displaying an age-related decline in responsiveness to E2. To our knowledge, this is the first study to systematically assess the effects of age and different clinically relevant regimens of E2 replacement on GnRH-(1–5) signaling genes.

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“…EP24.15 immunoreactivity is sensitive to hormonal fluctuations: increasing on pro‐oestrous day of the rat oestrous cycle within the median eminence, with a peak expression coinciding with the LH surge . Unlike GnRH, GnRH‐(1‐5) robustly stimulates GnRH gene expression and stimulates GnRH secretion . Moreover, the GnRH facilitation of lordosis behaviour is actually mediated by its metabolism to GnRH‐(1‐5) .…”

Section: Control Of the Lh Surgementioning

confidence: 99%

Peripheral and Central Mechanisms Involved in the Hormonal Control of Male and Female Reproduction

Rudolph

Bentley

Calandra

et al. 2016

J Neuroendocrinology

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Reproduction involves the integration of hormonal signals acting across multiple systems to generate a synchronised physiological output. A critical component of reproduction is the luteinising hormone (LH) surge, which is mediated by oestradiol (E2) and neuroprogesterone interacting to stimulate kisspeptin release in the rostral periventricular nucleus of the third ventricle in rats. Recent evidence indicates the involvement of both classical and membrane E2 and progesterone signalling in this pathway. A metabolite of gonadotrophin-releasing hormone (GnRH), GnRH-(1-5), has been shown to stimulate GnRH expression and secretion, and has a role in the regulation of lordosis. Additionally, gonadotrophin release-inhibitory hormone (GnIH) projects to and influences the activity of GnRH neurones in birds. Stress-induced changes in GnIH have been shown to alter breeding behaviour in birds, demonstrating another mechanism for the molecular control of reproduction. Peripherally, paracrine and autocrine actions within the gonad have been suggested as therapeutic targets for infertility in both males and females. Dysfunction of testicular prostaglandin synthesis is a possible cause of idiopathic male infertility. Indeed, local production of melatonin and corticotrophin-releasing hormone could influence spermatogenesis via immune pathways in the gonad. In females, vascular endothelial growth factor A has been implicated in an angiogenic process that mediates development of the corpus luteum and thus fertility via the Notch signalling pathway. Age-induced decreases in fertility involve ovarian kisspeptin and its regulation of ovarian sympathetic innervation. Finally, morphological changes in the arcuate nucleus of the hypothalamus influence female sexual receptivity in rats. The processes mediating these morphological changes have been shown to involve the rapid effects of E2 controlling synaptogenesis in this hypothalamic nucleus. In summary, this review highlights new research in these areas, focusing on recent findings concerning the molecular mechanisms involved in the central and peripheral hormonal control of reproduction.

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Autoshortloop feedback regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by its metabolite, GnRH-(1–5)

Cited by 11 publications

References 31 publications

Effects of Di-(2-ethylhexyl) Phthalate on the Hypothalamus–Uterus in Pubertal Female Rats

Effects of Di-(2-ethylhexyl) Phthalate on the Hypothalamus–Uterus in Pubertal Female Rats

Regulation of Gonadotropin-Releasing Hormone-(1–5) Signaling Genes by Estradiol Is Age Dependent

Peripheral and Central Mechanisms Involved in the Hormonal Control of Male and Female Reproduction

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