Menopause and the human hypothalamus: Evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback

Rance, Naomi E.

doi:10.1016/j.peptides.2008.05.016

Cited by 238Hypothalamic control of reproductive hormonesNeuropeptides and Animal PhysiologyReproductive Biology and Fertility

Menopause and the human hypothalamus: Evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback

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Rance, Naomi E.·2009·Peptides

DOI 10.1016/j.peptides.2008.05.016PMC PMC2632595

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Abstract

Menopause is characterized by depletion of ovarian follicles, a reduction of ovarian hormones to castrate levels and elevated levels of serum gonadotropins. Rather than degenerating, the reproductive neuroendocrine axis in postmenopausal women is intact and responds robustly to the removal of ovarian hormones. Studies in both human and non-human primates provide evidence that the gonadotropin hypersecretion in postmenopausal women is secondary to increased gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. In addition, menopause is accompanied by hypertrophy of neurons in the infundibular (arcuate) nucleus expressing KiSS-1, neurokinin B (NKB), substance P, dynorphin and estrogen receptor alpha (ERalpha) mRNA. Ovariectomy in experimental animals induces nearly identical findings, providing evidence that these changes are a compensatory response to ovarian failure. The anatomical site of the hypertrophied neurons, as well as the extensive data implicating kisspeptin, NKB and dynorphin in the regulation of GnRH secretion, provide compelling evidence that these neurons are part of the neural network responsible for the increased levels of serum gonadotropins in postmenopausal women. We propose that neurons expressing KiSS-1, NKB, substance P, dynorphin and ERalpha mRNA in the infundibular nucleus play an important role in sex-steroid feedback on gonadotropin secretion in the human.

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NKB is co-expressed with kisspeptin in neurons in the arcuate nucleus of the hypothalamus.
“given the co-expression of NKB with kisspeptin in neurons in the arcuate nucleus of the hypothalamus.64”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [64]
The mechanism by which NKB and NKR regulate reproduction probably involves regulation of GnRH secretion, perhaps via interactions with the kisspeptin 1-KiSS-1 receptor system.
“While the underlying mechanism has not been established, it probably involves the regulation of GnRH secretion, perhaps via interactions with the kisspeptin 1–KiSS-1 receptor system given the co-expression of NKB with kisspeptin in neurons in the arcuate nucleus of the hypothalamus.64”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [64]
The rise in serum LH in postmenopausal women is likely mediated by increased GnRH secretion from the hypothalamus.
“Therefore, the rise in serum LH in postmenopausal women is likely mediated by increased GnRH secretion from the hypothalamus (Rance, 2009).”
From 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 (2013) · cites this paper as Rance, 2009

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“While it is well recognized that GnRH neurons are influenced by multiple converging inputs, studies of GPR54 mutations in humans [16,93] and transgenic mice emphasize the essential nature of this circuitry in the regulation of reproduction.”
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Perimenopause: The Complex Endocrinology of the Menopausal Transition
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Menopausal Increases in Pulsatile Gonadotropin-Releasing Hormone Release in a Nonhuman Primate (Macaca mulatta)
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Effects of ovariectomy on the neuroendocrine axes regulating reproduction and energy balance in young cynomolgus macaques
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Serum Gonadotropin Responses to Estrogen and Progestogen in Recently Castrated Human Females
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Proopiomelanocortin gene expression is decreased in the infundibular nucleus of postmenopausal women
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Sex steroid modulation of neurokinin B gene expression in the arcuate nucleus of adult male rats
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Neuropeptide Y Gene Expression Is Increased in the Hypothalamus of Older Women
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Ovarian Control of Gonadotropin Hormone-Releasing Hormone Pulse Generator Activity in the Rhesus Monkey: Duration of the Associated Hypothalamic Signal
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Impaired Estrogen-Induced Luteinizing Hormone Release in Young Women with Anovulatory Dysfunctional Uterine Bleeding*
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Research works printed but not linked: 5

[24]Escobar CM, Krajewski SJ, Sandoval-Guzmán T, Voytko ML, Rance NE. Neuropeptide Y gene expression is increased in the infundibular nucleus of postmenopausal women. J Clin Endocrinol Metab. 2004;89:2338–2343. doi: 10.1210/jc.2003-031899. [DOI] [PubMed] [Google Scholar] · DOI
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TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction
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Minireview: Kisspeptin/Neurokinin B/Dynorphin (KNDy) Cells of the Arcuate Nucleus: A Central Node in the Control of Gonadotropin-Releasing Hormone Secretion
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Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat
Wakabayashi, Y., Nakada, T., Murata, K., Ohkura, S., Mogi, K., Navarro, V. M., Clifton, D. K., Mori, Y., Tsukamura, H., Maeda, K.-I., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5848-09.2010 · Cited by 597 · see citing works
“These anatomical observations suggest that kisspeptin/NKB/Dyn neurons in the ARC comprise an oscillatory feedback loop interconnected through collaterals that synchronize their activity, as previously proposed (Burke et al., 2006; Foradori et al., 2006; Rance, 2009; Navarro et al., 2009).”
Background
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Authors: Rance, N. E.
Affiliations: University of Arizona (US)
Corresponding author: Rance, Naomi E.
ORCID: Rance, Naomi E.
Venue: Peptides
Publisher: Elsevier BV
Published: 2009-01
Volume: 30
Issue: 1
Pages: 111-122
ISSN: 0196-9781 (ISSN-L)
DOI: 10.1016/j.peptides.2008.05.016
PMC: PMC2632595
OpenAlex: W2092614270
Cited by: 237
References: 114
Citations by year: 2026: 4 · 2025: 11 · 2024: 15 · 2023: 4 · 2022: 7 · 2021: 11 · 2020: 6 · 2019: 10 · 2018: 12 · 2017: 12 · 2016: 12 · 2015: 17 · 2014: 18 · 2013: 21 · 2012: 18
FWCI: 22.44
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Peptides (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (AG09214, R56AG009214, R01AG009214)
Topics: Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords: menopause, hypothalamus, kisspeptin, neurokinin B, estrogen negative feedback, gonadotropin secretion, gonadotropin-releasing hormone, arcuate nucleus, ovariectomy, estrogen receptor alpha, dynorphin, substance P, postmenopausal women, ovarian failure
MeSH terms: Aging, Animals, Dynorphins, Estrogens, Female, Humans, Hypothalamus, Menopause, Middle Aged, Neurons, Neurosecretory Systems, Ovary, Substance P, Neurokinin B, Feedback, Physiological, Tumor Suppressor Proteins, Rats, Kisspeptins

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Menopause and the human hypothalamus: Evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback

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