The Role of Kisspeptin and RFamide‐Related Peptide‐3 Neurones in the Circadian‐Timed Preovulatory Luteinising Hormone Surge

Khan, A. R.; Kauffman, A. S.

doi:10.1111/j.1365-2826.2011.02162.x

Cited by 99Hypothalamic control of reproductive hormonesNeuropeptides and Animal PhysiologyNeuroendocrine regulation and behavior

The Role of Kisspeptin and RFamide‐Related Peptide‐3 Neurones in the Circadian‐Timed Preovulatory Luteinising Hormone Surge

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Khan, A. R., Kauffman, A. S.·2012·Journal of Neuroendocrinology

DOI 10.1111/j.1365-2826.2011.02162.xPMC PMC3384704

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Abstract

Many aspects of female reproduction often require intricate timing, ranging from the temporal regulation of reproductive hormone secretion to the precise timing of sexual behaviour. In particular, in rodents and other species, ovulation is triggered by a surge in pituitary luteinising hormone (LH) secretion that is governed by a complex interaction between circadian signals arising in the hypothalamus and ovarian‐derived oestradiol signals acting on multiple brain circuitries. These circadian and hormonal pathways converge to stimulate a precisely‐timed surge in gonadotropin‐releasing hormone (GnRH) release (i.e. positive‐feedback), thereby triggering the preovulatory LH surge. Reflecting its control by afferent circadian signals, the preovulatory LH surge occurs at a specific time of day, typically late afternoon in nocturnal rodents. Although the specific mechanisms mediating the hormonal and circadian regulation of GnRH/LH release have remained poorly understood, recent findings now suggest that oestradiol and circadian signals govern specific reproductive neuropeptide circuits in the hypothalamus, including the newly‐identified kisspeptin and RFamide‐related peptide (RFRP)‐3 neuronal populations. Neurones producing kisspeptin, the protein product of the Kiss1 gene, and RFRP‐3 have been shown to provide excitatory and inhibitory input to GnRH neurones, respectively, and are also influenced by sex steroid and circadian signals. In the present review, we integrate classic and recent findings to form a new working model for the neuroendocrine regulation of the circadian‐timed preovulatory LH surge in rodents. This model proposes kisspeptin and RFRP‐3 neuronal populations as key nodal points for integrating and transducing circadian and hormonal signals to the reproductive axis, thereby governing the precisely‐timed LH surge.

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Evidence supports the AVPV/PeN kisspeptin role in the LH surge: Kiss1 expression is higher in females, these neurons have ERα and activate during the surge, and Kiss1 or Kiss1R knockout mice lack the surge even with E2.
“Supporting this hypothesis, AVPV/PeN Kiss1 gene expression is greater in females than males (males do not show an LH surge), Kiss1 neurons in the AVPV/PeN express ERα and show increased neuronal activation exclusively during the LH surge, and Kiss1 knockout (KO) mice and Kiss1R KO mice do not exhibit an LH surge even with exogenous E2 treatment3,5.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [5]
In “The kisspeptin system: function and neuroanatomy” (page unavailable), the paper reports higher AVPV/PeN Kiss1 expression in females, ERα expression and surge-time activation in these neurons, and absent LH surges in Kiss1- and Kiss1R-null mice after E2 treatment. But it also reports a conflicting study in which E2-treated Kiss1R-null mice displayed small LH surges, so the categorical knockout claim omits an important qualification. (LLM, conf=0.90)
Experimental — accuracy not yet measured
E2-induced AVPV/PeN kisspeptin expression accompanies increased neuronal activation and peptide release onto GnRH neurons to drive the preovulatory GnRH/LH surge.
“This E2-induced expression of AVPV/PeN kisspeptin occurs with an increase in kisspeptin neuronal activation and peptide release onto GnRH neurons to drive the pre-ovulatory surge of GnRH and LH3,5.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [5]
In “The kisspeptin system: function and neuroanatomy” (page unavailable), the review reports that E2 increases AVPV/PeN Kiss1 expression in female rodents and that these neurons show c-Fos activation at the LH surge. Its “Current Model” section describes stimulatory input from these neurons to GnRH neurons, but the cited passages do not establish increased kisspeptin peptide release onto GnRH neurons; they also frame the neurons’ role in driving the surge as a model rather than a demonstrated causal sequence. (LLM, conf=0.85)
Experimental — accuracy not yet measured
AVPV/PeN kisspeptin neurons are thought to mediate E2 positive feedback that triggers the female preovulatory LH surge.
“In contrast, kisspeptin neurons in the AVPV/PeN are thought to be involved in mediating E2-positive feedback which triggers the preovulatory LH surge in females5.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [5]

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Authors: Khan, A. R., & Kauffman, A. S.
Affiliations: University of California San Diego (US)
Corresponding author: Kauffman, A. S.
ORCID: Kauffman, A. S.
Venue: Journal of Neuroendocrinology
Publisher: Wiley
Published: 2011-12-20
Volume: 24
Issue: 1
Pages: 131-143
ISSN: 0953-8194 (ISSN-L)
1365-2826
DOI: 10.1111/j.1365-2826.2011.02162.x
PMC: PMC3384704
OpenAlex: W1484971035
Cited by: 99
References: 172
Citations by year: 2026: 1 · 2025: 3 · 2023: 3 · 2022: 8 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 2 · 2015: 11 · 2014: 12 · 2013: 15 · 2012: 11
FWCI: 1.98
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Neuroendocrinology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065856, P50HD012303, U54HD012303, R00HD056157)
Topics: Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Keywords: kisspeptin, luteinizing hormone surge, circadian timing, hypothalamic neuropeptides, estradiol, neuroendocrine regulation of reproduction, KISS1
MeSH terms: Animals, Circadian Rhythm, Female, Hypothalamus, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Neurons, Neuropeptides, Pituitary Gland, Kisspeptins

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The Role of Kisspeptin and RFamide‐Related Peptide‐3 Neurones in the Circadian‐Timed Preovulatory Luteinising Hormone Surge

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