Continuous Human Metastin 45–54 Infusion Desensitizes G Protein-Coupled Receptor 54-Induced Gonadotropin-Releasing Hormone Release Monitored Indirectly in the Juvenile Male Rhesus Monkey (Macaca mulatta): A Finding with Therapeutic Implications

Seminara, Stephanie B.; DiPietro, Meloni J.; Ramaswamy, Suresh; Crowley, William F.; Plant, Tony M.

doi:10.1210/en.2005-1550

Cited by 205 publications

(179 citation statements)

References 31 publications

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“…Although counterintuitive, this effect may relate to possible antagonistic properties of the continuous kisspeptin infusion (which lasted for 20 h). Such treatment has been previously shown to desensitize Kiss1r-induced GNRH release (Seminara et al 2006) and reduced Kiss1r mRNA expression on GNRH neurons (Li et al 2012). Nevertheless, similar data (kisspeptin treatment stimulating NPY secretion) are also apparent using a cell line (Kim et al 2010).…”

Section: Pomc/cart Neuronssupporting

confidence: 52%

Kisspeptin and energy balance in reproduction

Bond¹,

Smith²

2014

Reproduction

102

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Kisspeptin is vital for the neuroendocrine regulation of GNRH secretion. Kisspeptin neurons are now recognized as a central pathway responsible for conveying key homeostatic information to GNRH neurons. This pathway is likely to mediate the well-established link between energy balance and reproductive function. Thus, in states of severely altered energy balance (either negative or positive), fertility is compromised, as is Kiss1 expression in the arcuate nucleus. A number of metabolic modulators have been proposed as regulators of kisspeptin neurons including leptin, ghrelin, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY). Whether these regulate kisspeptin neurons directly or indirectly will be discussed. Moreover, whether the stimulatory role of leptin on reproduction is mediated by kisspeptin directly will be questioned. Furthermore, in addition to being expressed in GNRH neurons, the kisspeptin receptor (Kiss1r) is also expressed in other areas of the brain, as well as in the periphery, suggesting alternative roles for kisspeptin signaling outside of reproduction. Interestingly, kisspeptin neurons are anatomically linked to, and can directly excite, anorexigenic POMC neurons and indirectly inhibit orexigenic NPY neurons. Thus, kisspeptin may have a direct role in regulating energy balance. Although data from Kiss1r knockout and WT mice found no differences in body weight, recent data indicate that kisspeptin may still play a role in food intake and glucose homeostasis. Thus, in addition to regulating reproduction, and mediating the effect of energy balance on reproductive function, kisspeptin signaling may also be a direct regulator of metabolism.

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Section: Pomc/cart Neuronssupporting

confidence: 52%

Kisspeptin and energy balance in reproduction

Bond¹,

Smith²

2014

Reproduction

102

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“…3). Metastin 45-54-induced desensitization, however, neither compromised the ability of the GnRH neuronal network to respond to stimulation with the glutamate agonist, NMDA, nor impaired the pituitary's ability to respond to physiologic stimulation with a bolus of synthetic GnRH (30). GPR54 was re-sensitized within 24 h following termination of the continuous metastin 45-54 infusion.…”

Section: Puberty and Its Neuroendocrine Determinantsmentioning

confidence: 94%

The role of KiSS-1 in the regulation of puberty in higher primates

Plant¹

2006

eur j endocrinol

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Puberty in higher primates is triggered by resurgence in the pulsatile secretion of hypothalamic GnRH after a hiatus in the robust release of this hypophysiotropic signal during childhood and juvenile development. Interestingly, the prepubertal decline in GnRH release is not associated with a marked reduction in the expression of either the gene that codes for GnRH (GnRH-1) or the decapeptide itself, and the network of GnRH neurons in the hypothalamus of the juvenile may by activated prematurely and with surprising ease by intermittent neurochemical stimulation with N-methyl-D-aspartate (NMDA), a glutamate receptor agonist. KiSS-1, a gene that encodes for kisspeptin-121, which is proteolytically cleaved to a 54 amino acid peptide, metastin, was initially studied in the context of tumor suppression. In 2003, however, inactivating mutations in the metastin receptor, GPR54, were reported to be associated with hypogonadotropic hypogonadism and absent puberty in man. Subsequent studies in the rhesus monkey have shown that GPR54 and KiSS-1 are expressed in the mediobasal hypothalamus (MBH), KiSS-1 expression in the MBH increases at the time of the pubertal resurgence in GnRH release and pulsatile, but not continuous, i.v. administration of metastin 45-54 in the juvenile male monkey elicits sustained GnRH release precociously. The significance of these findings in the context of the initiation of the onset of puberty is discussed.European Journal of Endocrinology 155 S11-S16

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“…However, this may be an issue of time and dose, as although tachyphylaxis has also been observed in long-term administration of KP-54 to women with hypothalamic amenorrhea 122 and in juvenile 168 and adult 169 monkeys, it was not observed in men receiving continuous infusion of KP-10 at near maximal LH stimulating levels over 22 hrs. 89 .…”

Section: Potential Therapeutic Applications Of Nkb Analoguesmentioning

confidence: 99%

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Millar

Newton

2013

Nat Rev Endocrinol

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Reproductive hormones impact on all stages of life from gamete production, fertilisation, fetal development and parturition, neonatal development and puberty through to adulthood and senescence.The reproductive hormone cascade has therefore been the target for the development of numerous drugs which modulate its activity at many levels. As the central regulator of the cascade, gonadotropinreleasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent deseases such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilisation (IVF) protocols. Recently-discovered neuroendocrine peptides, kisspeptin (KP) and neurokinin B (NKB), have also been identified as therapeutic targets and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade, GnRH, KP and NKB.

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Continuous Human Metastin 45–54 Infusion Desensitizes G Protein-Coupled Receptor 54-Induced Gonadotropin-Releasing Hormone Release Monitored Indirectly in the Juvenile Male Rhesus Monkey (Macaca mulatta): A Finding with Therapeutic Implications

Cited by 205 publications

References 31 publications

Kisspeptin and energy balance in reproduction

Kisspeptin and energy balance in reproduction

The role of KiSS-1 in the regulation of puberty in higher primates

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

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