CoChat
Sign Up
Cited by 381Hypothalamic control of reproductive hormonesNeuropeptides and Animal PhysiologyRegulation of Appetite and Obesity

Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes

Open access
Rance, Naomi E., Dacks, Penny A., Mittelman-Smith, Melinda A., Romanovsky, Andrej A., Krajewski-Hall, Sally J.·2013·Frontiers in Neuroendocrinology
DOI 10.1016/j.yfrne.2013.07.003PMC PMC3833827
Open this paper in CoChat — free account

Abstract

Despite affecting millions of individuals, the etiology of hot flushes remains unknown. Here we review the physiology of hot flushes, CNS pathways regulating heat-dissipation effectors, and effects of estrogen on thermoregulation in animal models. Based on the marked changes in hypothalamic kisspeptin, neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes. In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R), the primary receptor for NKB. Furthermore, activation of NK3R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature. Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation. These data suggest that arcuate KNDy neurons relay estrogen signals to preoptic structures regulating heat-dissipation effectors, supporting the hypothesis that KNDy neurons participate in the generation of flushes.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that hypothalamic KNDy (kisspeptin/neurokinin B/dynorphin) neurons relay estrogen-withdrawal signals to preoptic thermoregulatory pathways and thereby contribute to hot flushes. Evidence from postmenopausal women and rat models links KNDy/NK3R signaling to LH pulses, cutaneous vasodilatation, and body temperature control.

Key findings

  • In postmenopausal women, infundibular (arcuate) neurons expressing estrogen receptor, kisspeptin, and NKB are hypertrophied, with increased NKB and kisspeptin gene expression; dynorphin neurons are enlarged but dynorphin mRNA-expressing neuron number is reduced. Ovariectomy induces and estrogen reverses these changes in monkeys.
  • Rat KNDy neurons project to preoptic thermoregulatory areas, including the median preoptic nucleus (MnPO), which expresses NK3R. Microinfusion of the NK3R agonist senktide (90 pmol) into the MnPO reduced body temperature by about 1.5 °C.
  • KNDy neuron ablation with NK3-SAP destroyed nearly all arcuate kisspeptin- and NKB-immunoreactive neurons and reduced arcuate dynorphin neurons by 76%. Ablated rats did not show the post-ovariectomy LH increase, had lower tail skin temperatures, better defended core temperature against heat, and did not respond to estrogen with reduced core temperature.
  • Ovariectomized rats without estrogen showed a thermoneutral zone shifted to lower ambient temperatures, with the skin vasodilatation threshold 4 °C lower than in estrogen-treated rats. Estrogen reduced dark-phase tail skin temperature by >3 °C, and a small core temperature rise preceded 65%–76% of hot flushes in women.

Methods

  • Narrative review and hypothesis paper synthesizing human postmortem hypothalamic studies, ovariectomy/estrogen-replacement studies in monkeys and rats, and the authors’ rat thermoregulation experiments.
  • Data include postmortem hypothalamic tissue from premenopausal and postmenopausal women; ovariectomized monkeys and rats with estrogen replacement; rat tail skin and core temperature recordings; Fos immunocytochemistry; anterograde tract-tracing; NK3R agonist microinfusion; and NK3-SAP ablation.
  • Main analysis is qualitative integration of anatomic, neuroendocrine, and thermoregulatory findings to support a KNDy-neuron mechanism for hot flushes.

Limitations

  • Stated: whether rats actually experience hot flushes after estrogen withdrawal is unknown; rats cannot report flush onset, so studies rely on objective measures such as tail skin temperature.
  • Stated: normal female rats show wide tail skin temperature fluctuations, and objective measures in women may reflect physiological events other than flushes; concordance between self-reported flushes and skin conductance can be limited.
  • Evident: the central hypothesis is largely indirect and not directly tested in humans; much of the causal evidence comes from rat models, and the review notes that roles for other KNDy peptides, substance P, or GnRH neurons remain to be explored.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.yfrne.2013.07.003

Cites

203 of 203 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 145 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Stereological analysis revealed no neuronal cell loss in the infundibular nucleus of postmenopausal women.

    “Stereological analysis revealed no neuronal cell loss in the infundibular nucleus of post-menopausal women (Abel and Rance, 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Abel and Rance, 2000

      Not checked in the free run.

  • Findingnone given

    In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R).

    “In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R), the primary receptor for NKB.”
    Quote in the paperNot a substantial claim
  • Findingnone given

    Activation of NK3R in the median preoptic nucleus reduces body temperature.

    “Furthermore, activation of NK3R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Senktide markedly increased the number of Fos-ir nuclei in the MnPO, with minimal effects on adjacent nuclei.

    “In addition, senktide markedly increased the number of Fos-ir nuclei in the MnPO, with minimal effects on adjacent nuclei (Dacks et al., 2011a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dacks et al., 2011a

      Not checked in the free run.

  • Findingcitation

    The ambient temperature threshold for skin vasodilatation is 4 °C lower in ovariectomized rats compared to ovariectomized rats receiving estrogen.

    “Remarkably, the ambient temperature threshold for skin vasodilatation was 4 °C lower in ovariectomized rats, compared to ovariectomized rats receiving estrogen (Dacks and Rance, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dacks and Rance, 2010

      Not checked in the free run.

  • May combine two claims. 30
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Findingreasoning

    Ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation.

    “Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    On proestrous night, average tail skin temperature is significantly decreased with decreased variability.

    “Interestingly, on proestrous night (when endogenous estrogen levels are high), the average tail skin temperature was significantly decreased, with decreased variability (Fig. 7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the neutral ambient temperature of 29.0 °C, vasoconstriction occurred in vehicle-infused animals, but not in rats in which senktide was microinfused in the MnPO.

    “In our study, however, at the neutral ambient temperature of 29.0 °C, vasoconstriction occurred in vehicle-infused animals, but not in rats in which senktide was microinfused in the MnPO.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The dark phase reduction in tail skin temperature by estrogen is large (>3 °C) and consistent.

    “In contrast, the dark phase reduction in tail skin temperature by estrogen is large (>3 °C) and consistent (Fig. 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LH did not significantly increase after ovariectomy in KNDy ablated rats, and their serum LH was lower regardless of estrogen replacement.

    “In contrast, LH did not significantly increase after ovariectomy in KNDy ablated rats, and their serum LH was lower regardless of estrogen replacement.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    KNDy-ablated rats were able to better defend their core temperatures against heat than control rats, and unlike controls, did not respond to estrogen treatment with a reduction in core temperature.

    “Moreover, KNDy-ablated rats were able to better defend their core temperatures against heat than control rats, and unlike controls, did not respond to estrogen treatment with a reduction in core temperature.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    KNDy neuron ablation consistently reduced tail skin temperatures, indicating that KNDy neurons facilitate cutaneous vasodilatation.

    “Remarkably, KNDy neuron ablation consistently reduced tail skin temperatures, indicating that KNDy neurons facilitate cutaneous vasodilatation (Fig. 12) (Mittelman-Smith et al., 2012a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mittelman-Smith et al., 2012a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dynorphin neurons are enlarged in the infundibular nucleus of postmenopausal women, but the number of dynorphin mRNA-expressing neurons is reduced.

    “Dynorphin neurons are also enlarged in the infundibular nucleus of postmenopausal women, but the number of dynorphin mRNA-expressing neurons is reduced (Rometo and Rance, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rometo and Rance, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The hypertrophied neurons in the postmenopausal infundibular nucleus express estrogen receptor, kisspeptin and neurokinin B.

    “These neurons express estrogen receptor, kisspeptin and neurokinin B (NKB) and the cellular hypertrophy is accompanied by increased neurokinin B and kisspeptin gene expression (Fig. 1) (Rance et al., 1990; Rance and Young, 1991; Rometo et al., 2007).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Rance et al., 1990 source

      Not checked in the free run.

    • cites Rance and Young, 1991

      Not checked in the free run.

    • cites Rometo et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Women's Health Initiative Study raised questions about the long-term safety of estrogen replacement therapy.

    “The most effective treatment of hot flushes is estrogen replacement therapy, but the Women’s Health Initiative Study raised questions about the long-term safety of this treatment (Rossouw et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rossouw et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ovariectomy induces neuronal hypertrophy and increased NKB and kisspeptin gene expression in young cynomolgus monkeys, and estrogen replacement reverses these changes.

    “The hypertrophy and increased kisspeptin and NKB gene expression in postmenopausal women are secondary to estrogen withdrawal, because these changes are induced by ovariectomy (Fig. 2) and reversed by estrogen replacement of young cynomolgus monkeys (Abel et al., 1999; Rometo et al., 2007; Sandoval-Guzmán et al., 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Abel et al., 1999

      Not checked in the free run.

    • cites Rometo et al., 2007 source

      Not checked in the free run.

    • cites Sandoval-Guzmán et al., 2004 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    In the majority of menopausal women, estrogen withdrawal causes hot flushes.

    “In the majority of menopausal women, estrogen withdrawal causes hot flushes (also known as hot flashes), a disorder of hypothalamic thermoregulation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Kisspeptin and neurokinin B are essential for pubertal development and fertility in humans.

    “Moreover, two of the peptides in the hypertrophied neurons, kisspeptin and neurokinin B, are essential for pubertal development and fertility in the human (Chan et al., 2011; Topaloglu et al., 2009, 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chan et al., 2011 source

      Not checked in the free run.

    • cites Topaloglu et al., 2009 source

      Not checked in the free run.

    • cites Topaloglu et al., 2012 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The etiology of hot flushes remains unknown.

    “Despite affecting millions of individuals, the etiology of hot flushes remains unknown.”
    • Also stated in: § 1. Introduction · plain
      “Despite the millions of individuals affected, there has been limited basic research on the physiology of hot flushes and their etiology has remained an enigma (Kronenberg, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kronenberg, 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most postmenopausal women eventually acclimate to the low estrogen level and the flushes disappear.

    “Eventually, most (but not all) postmenopausal women will acclimate to the low estrogen level, and the flushes will disappear (Kronenberg, 1990).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kronenberg, 1990 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Withdrawal of gonadal steroids induces flushes in women treated with tamoxifen, women with premature ovarian failure, aging men with diminished testosterone, and men with prostate carcinoma undergoing androgen ablation therapy.

    “Withdrawal of gonadal steroids induces flushes in a variety of patients: women treated with tamoxifen for breast cancer, women with premature ovarian failure, aging men with diminished testosterone, and men with prostate carcinoma undergoing androgen ablation therapy (Santoro, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Santoro, 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    KNDy neurons have been identified in multiple experimental animals.

    “Because KNDy neurons have been identified in multiple experimental animals, information on the role of these neurons in LH secretion is accumulating at a rapid pace (Kinsey-Jones et al., 2012; Lehman et al., 2010; Mittelman-Smith et al., 2012b; Rance et al., 2010; Wakabayashi et al., 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kinsey-Jones et al., 2012 source

      Not checked in the free run.

    • cites Lehman et al., 2010 source

      Not checked in the free run.

    • cites Mittelman-Smith et al., 2012b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hot flushes are characterized by a transient and intense sensation of heat accompanied by activation of heat-loss effectors including skin vasodilatation, sweating, and cold-seeking behavior.

    “Hot flushes are characterized by a transient and intense sensation of heat accompanied by the activation of heat-loss effectors including skin vasodilatation, sweating, and cold-seeking behavior (Fig. 3) (Freedman, 2001; Kronenberg, 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Freedman, 2001 source

      Not checked in the free run.

    • cites Kronenberg, 2010 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    It is not the absolute level of estrogens, but the rate of estrogen withdrawal that determines the onset of flushes.

    “It is not the absolute level of estrogens, but the rate of estrogen withdrawal that determines the onset of flushes (Kronenberg, 2010; Santoro, 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kronenberg, 2010 source

      Not checked in the free run.

    • cites Santoro, 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Flushes often begin during the perimenopausal period when there are wide fluctuations in serum estrogen.

    “Flushes often begin during the perimenopausal period when there are wide fluctuations in serum estrogen (Burger et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Burger et al., 2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Complete coexpression of kisspeptin, NKB and dynorphin is not always found.

    “Complete coexpression of kisspeptin, NKB and dynorphin is not always found (Hrabovszky et al., 2012; Navarro et al., 2011), but this issue is complicated by limitations in the sensitivity of detection (Ruka et al., 2013) and differential expression depending on developmental stage (Gill et al., 2012) or physiological state of the animal (Foradori et al., 2005; Navarro et al., 2011; Rance and Bruce”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hrabovszky et al., 2012 source

      Not checked in the free run.

    • cites Navarro et al., 2011 source

      Not checked in the free run.

    • cites Ruka et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    KNDy neurons could contribute to the generation of flushes.

    “We hypothesized that KNDy neurons could contribute to the generation of flushes (Rance and Young, 1991) because estrogen withdrawal leads to such remarkable changes in cell size and gene expression in the hypothalamus of postmenopausal women (Abel et al., 1999; Rance and Young, 1991; Rometo et al., 2007; Sandoval-Guzmán et al., 2004).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Rance and Young, 1991

      Not checked in the free run.

    • cites Abel et al., 1999

      Not checked in the free run.

    • cites Rometo et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hot flushes occur in response to ovariectomy in young women and are effectively treated by estrogen replacement.

    “Hot flushes occur in response to ovariectomy in young women and are effectively treated by estrogen replacement (Santoro, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Santoro, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GnRH does not cause flushes, as estrogen withdrawal produces hot flushes in women who lack hypothalamic GnRH neurons due to Kallman's syndrome.

    “Similarly, GnRH does not cause the flushes, as estrogen withdrawal produces hot flushes in women who lack hypothalamic GnRH neurons due to Kallman’s syndrome (Gambone et al., 1984; Schwanzel-Fukuda et al., 1989).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gambone et al., 1984 source

      Not checked in the free run.

    • cites Schwanzel-Fukuda et al., 1989 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hot flushes can be triggered by thermal, chemical, or other stimuli including increased ambient temperature, hot beverages, caffeine, spicy food, stress or anxiety.

    “Hot flushes can be triggered by a variety of stimuli including thermal (increased ambient temperature or hot beverages), chemical (caffeine or spicy food) or other (stress or anxiety) (Archer et al., 2011; Freedman, 2001).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Archer et al., 2011 source

      Not checked in the free run.

    • cites Freedman, 2001 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Even in women who acclimate, hot flushes may reoccur if estrogens are administered and then withdrawn.

    “However, even in these women, hot flushes may reoccur if estrogens are administered and then withdrawn (Jensen and Christiansen, 1983).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jensen and Christiansen, 1983

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ovariectomy decreased dynorphin gene expression in the arcuate nucleus of the ewe, but ovariectomized mice exhibited increased dynorphin mRNA compared to estrogen treated mice.

    “In parallel to the findings in postmenopausal women, ovariectomy decreased dynorphin gene expression in the arcuate nucleus of the ewe (Foradori et al., 2005), but ovariectomized mice exhibited increased dynorphin mRNA, compared to estrogen treated mice (Navarro et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Foradori et al., 2005 source

      Not checked in the free run.

    • cites Navarro et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preoptic warm-sensitive neurons are GABAergic, and activation of these neurons inhibits the rostral raphe pallidus, resulting in cutaneous vasodilatation.

    “The preoptic warm-sensitive neurons are GABAergic (Eberwine and Bartfai, 2011), and activation of these neurons inhibits the rostral raphe pallidus, resulting in cutaneous vasodilatation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Eberwine and Bartfai, 2011

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    KNDy neurons could also be involved in the generation of flushes.

    “Emerging evidence that KNDy neurons are an important part of the GnRH pulse generator (Lehman et al., 2010; Rance et al., 2010; Wakabayashi et al., 2010) strongly supports the hypothesis that they could also be involved in the generation of flushes.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lehman et al., 2010 source

      Not checked in the free run.

    • cites Rance et al., 2010 source

      Not checked in the free run.

    • cites Wakabayashi et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with mutations in the genes encoding NKB or its receptor NK3R are infertile and do not transition through puberty.

    “The significance of this line of inquiry became apparent with the discovery that individuals with mutations in the genes encoding NKB or its receptor (NK3R) are infertile and do not transition through puberty (Gianetti et al., 2010; Topaloglu et al., 2009; Young et al., 2010).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gianetti et al., 2010 source

      Not checked in the free run.

    • cites Topaloglu et al., 2009 source

      Not checked in the free run.

    • cites Young et al., 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Thermosensitive neurons receive information related to gonadal hormones, including estrogen.

    “Thermosensitive neurons also receive information related to blood pressure, osmolarity, pyrogens, glucose concentration, and gonadal hormones, including estrogen (Boulant, 2000; Silva and Boulant, 1986).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Boulant, 2000 source

      Not checked in the free run.

    • cites Silva and Boulant, 1986

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Convergence of information on warm-sensitive neurons provides a mechanism to modulate the activation of thermoregulatory effectors, based on the physiological state of the animal.

    “Thus, convergence of information on warm-sensitive neurons provides a mechanism to modulate the activation of thermoregulatory effectors, based on the physiological state of the animal.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    KNDy neurons play a role in the mechanism of flushes.

    “Based on the marked changes in hypothalamic kisspeptin, neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lesions that include the MnPO result in hyperthermia, supporting a role for this nucleus in the control of heat-defense effectors.

    “Finally, lesions that include the MnPO result in hyperthermia, supporting a role for this nucleus in the control of heat-defense effectors (Almeida et al., 2006b; Romanovsky et al., 2003; Yoshida et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Almeida et al., 2006b

      Not checked in the free run.

    • cites Romanovsky et al., 2003 source

      Not checked in the free run.

    • cites Yoshida et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Excitation of the heat-defense pathway by skin warming inhibits the activity of sympathetic vasoconstrictor neurons, resulting in tail skin vasodilatation.

    “Excitation of the heat-defense pathway by skin warming inhibits the activity of sympathetic vasoconstrictor neurons, resulting in tail skin vasodilatation (Nakamura and Morrison, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nakamura and Morrison, 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tail skin temperature is increased by ovariectomy and reduced by estrogen treatment of ovariectomized rats.

    “Tail skin temperature is increased by ovariectomy (Berendsen et al., 2001; Kobayashi et al., 1995; Opas et al., 2004) and reduced by estrogen treatment of ovariectomized rats (Berendsen et al., 2001; Bowe et al., 2006; Dacks and Rance, 2010; Hosono et al., 2001; Kobayashi et al., 1995).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Berendsen et al., 2001 source

      Not checked in the free run.

    • cites Kobayashi et al., 1995 source

      Not checked in the free run.

    • cites Opas et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Thermosensitive neurons that participate in physiological thermoregulation are predominantly warm-sensitive cells located mostly in the preoptic hypothalamus.

    “Thermosensitive neurons that do participate in physiological thermoregulation are predominantly warm-sensitive cells located mostly in the preoptic hypothalamus (Boulant, 2000; Nakayama et al., 1961).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Boulant, 2000 source

      Not checked in the free run.

    • cites Nakayama et al., 1961 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The thermoneutral zone for the same animal varies widely depending on the experimental setup.

    “Therefore, the thermoneutral zone for the same animal varies widely, depending on the experimental setup (Romanovsky et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Romanovsky et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Estrogen replacement of ovariectomized rats improves the maintenance of core temperature during heat stress, similar to postmenopausal women.

    “Thus, similar to postmenopausal women (Tankersley et al., 1992), estrogen replacement of ovariectomized rats improves the maintenance of core temperature during heat stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tankersley et al., 1992 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Core temperature has been reported to be increased, decreased, or unaffected by estrogen treatment of ovariectomized rats.

    “Core temperature has been reported to be increased (Hosono et al., 1997a; Marrone et al., 1976), decreased (Wilkinson et al., 1980) or unaffected by estrogen treatment of ovariectomized rats (Hosono et al., 2001; Laudenslager et al., 1980; Williams et al., 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hosono et al., 1997a

      Not checked in the free run.

    • cites Wilkinson et al., 1980 source

      Not checked in the free run.

    • cites Hosono et al., 2001 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These data show a vasodilator effect of NK3R MnPO neuron activation in neutral ambient temperatures, that is suppressed in the subneutral environment.

    “Because vasodilatation in the rat is accomplished by inhibiting vasoconstriction (O’Leary et al., 1985), these data show a vasodilator effect of NK3R MnPO neuron activation in neutral ambient temperatures, that is suppressed in the subneutral environment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites O’Leary et al., 1985 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The reduction in tail skin temperature by estrogen is part of the normal estrous cycle and physiologically relevant.

    “These data provide evidence that the reduction in tail skin temperature by estrogen is part of the normal estrous cycle and physiologically relevant (Williams et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Williams et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In guinea pigs, core temperature is increased by ovariectomy and reduced by treatment with estrogen or a ligand for a membrane-associated estrogen receptor.

    “In guinea pigs, core temperature is increased by ovariectomy and reduced by treatment with estrogen or a ligand for a membrane-associated estrogen receptor (Roepke et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Roepke et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NKB signaling from KNDy neurons could influence heat-defense effectors through projections to NK3R-expressing MnPO neurons or NK3R-expressing warm-sensitive neurons in the medial preoptic area.

    “Therefore, NKB signaling (from KNDy neurons) could influence heat-defense effectors through projections to NK3R-expressing MnPO neurons or NK3R-expressing warm-sensitive neurons in the medial preoptic area.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    KNDy neurons may play a role in this pathway because estrogen strongly suppresses kisspeptin and neurokinin B gene expression, as well as LH pulses and flushes.

    “KNDy neurons may play a role in this pathway because estrogen strongly suppresses kisspeptin and neurokinin B gene expression, as well as LH pulses and flushes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    These data provide the first evidence that KNDy neurons promote cutaneous vasodilatation and participate in estrogen modulation of body temperature in the rat.

    “These data provide the first evidence that KNDy neurons promote cutaneous vasodilatation and participate in estrogen modulation of body temperature in the rat (Mittelman-Smith et al., 2012a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mittelman-Smith et al., 2012a

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Estrogen-responsive KNDy neurons play a role in body temperature regulation and may activate thermoregulatory vasodilatation through projections to preoptic regions expressing NK3R.

    “In this review, we summarize the evidence gained in a rat model that estrogen-responsive KNDy neurons play a role in body temperature regulation and may activate thermoregulatory vasodilatation through projections to preoptic regions expressing NK3R.”
    Quote in the paperSubstantial claim
47 of 47

  • The paper relies on this without support.

    There was virtually no information on the role of KNDy neurons in thermoregulation in any species before the authors' studies.

    “There was, however virtually no information on the role of KNDy neurons in thermoregulation in any species.”

  • The paper relies on this without support.

    Findings about KNDy neurons and thermoregulation in the rat are relevant to the mechanism of hot flushes in women.

    “To address this issue, we established methods in our laboratory to examine how estrogen modulates thermoregulation and related neural pathways in the rat (Dacks et al., 2011b; Dacks and Rance, 2010; Williams et al., 2010).”

  • The paper relies on this without support.

    Hot flushes are a manifestation of a central (hypothalamic) disorder of thermoregulation.

    “One of the most prominent symptoms of menopause is the hot flush, a manifestation of a central (hypothalamic) disorder of thermoregulation.”

  • The paper relies on this without support.

    Cutaneous vasodilatation is a cardinal sign of a hot flush.

    “Because cutaneous vasodilatation is a cardinal sign of a hot flush, these data support the hypothesis that KNDy neurons could play a role in the generation of flushes.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Ablation of KNDy neurons reduces cutaneous vasodilatation.

    “There is considerable interest in this group of neurons because they are thought to be involved in triggering hot flashes in peri- and post-menopausal women: KNDy neurons are hypertrophied post-menopause after estrogen withdrawal and ablation of these neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation [169].”

    From Temperature regulation in women: Effects of the menstrual cycle (2020) · cites this paper as [169]

  • Estradiol can affect central thermoregulatory pathways via actions on estrogen-sensitive arcuate neurons that co-express kisspeptin, neurokinin B, and dynorphin (KNDy neurons) involved in the regulation of GnRH secretion.

    “There is growing evidence from Rance and colleagues [169] showing that estradiol can also affect central thermoregulatory pathways via actions on a group of estrogen-sensitive arcuate neurons that co-express kisspeptin, neurokinin B, and dynorphin (KNDy neurons) involved in the regulation of GnRH secretion.”

    From Temperature regulation in women: Effects of the menstrual cycle (2020) · cites this paper as [169]

  • KNDy neurons are hypertrophied post-menopause after estrogen withdrawal.

    “There is considerable interest in this group of neurons because they are thought to be involved in triggering hot flashes in peri- and post-menopausal women: KNDy neurons are hypertrophied post-menopause after estrogen withdrawal and ablation of these neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation [169].”

    From Temperature regulation in women: Effects of the menstrual cycle (2020) · cites this paper as [169]

  • Ablation of KNDy neurons partially blocks the effects of estrogen on thermoregulation.

    “There is considerable interest in this group of neurons because they are thought to be involved in triggering hot flashes in peri- and post-menopausal women: KNDy neurons are hypertrophied post-menopause after estrogen withdrawal and ablation of these neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation [169].”

    From Temperature regulation in women: Effects of the menstrual cycle (2020) · cites this paper as [169]

  • Several physiological systems exhibit ultradian rhythms in the 1-3 h range, including the HPG axis, HPA axis, and suprachiasmatic nucleus.

    “Several physiological systems exhibit ultradian rhythms (URs) in the 1–3 h range, including the HPG axis60–65, the HPA axis66–72, and the suprachiasmatic nucleus73, 74 – the principal orchestrating brain area for circadian rhythms.”

    From Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice (2017) · cites this paper as [63]

Cites

Flagged first, then by citations

2 of the 205 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Wiley, 2005

Cited by

Sorted by citations

Related

Authors
Rance, N. E., Dacks, P. A., Mittelman-Smith, M. A., Romanovsky, A. A., & Krajewski-Hall, S. J.
Affiliations
  • University of Arizona (US)
  • Alzheimer's Drug Discovery Foundation (US)
  • St. Joseph's Hospital and Medical Center (US)
Corresponding author
Rance, Naomi E.
ORCID
Venue
Frontiers in Neuroendocrinology
Publisher
Elsevier BV
Published
2013-08
Volume
34
Issue
3
Pages
211-227
ISSN
0091-3022 (ISSN-L)
DOI
10.1016/j.yfrne.2013.07.003
PMC
PMC3833827
OpenAlex
W2061642929
Semantic Scholar
7043397029ae60ac9040a754434a6e725779bcdf
Cited by
380
References
205
Citations by year
2026: 45 · 2025: 52 · 2024: 46 · 2023: 41 · 2022: 28 · 2021: 35 · 2020: 22 · 2019: 24 · 2018: 28 · 2017: 27 · 2016: 10 · 2015: 15 · 2014: 7
FWCI
1.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (R01 NS41233)
  • National Institute on Aging (R01 AG032315)
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
hot flashes, KNDy neurons, kisspeptin, neurokinin B, dynorphin, hypothalamus, thermoregulation, estrogen, postmenopausal women, neurokinin-3 receptor, median preoptic nucleus, cutaneous vasodilation, luteinizing hormone secretion, arcuate nucleus
MeSH terms
Animals, Body Temperature Regulation, Dynorphins, Estradiol, Female, Humans, Hypothalamus, Luteinizing Hormone, Models, Biological, Neurons, Ovariectomy, Preoptic Area, Skin, Tail, Vasodilation, Neurokinin B, Signal Transduction, Postmenopause, Receptors, Neurokinin-3, Hot Flashes, Estrous Cycle, Rats, Kisspeptins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review