Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys

Rometo, Adonna M.; Krajewski, Sally J.; Lou Voytko, Mary; Rance, Naomi E.

doi:10.1210/jc.2007-0553

Cited by 396Hypothalamic control of reproductive hormonesRegulation of Appetite and ObesityNeuropeptides and Animal Physiology

Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys

Rometo, Adonna M., Krajewski, Sally J., Lou Voytko, Mary, Rance, Naomi E.·2007·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2007-0553

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Abstract

CONTEXT: Human menopause is characterized by ovarian failure, gonadotropin hypersecretion, and neuronal hypertrophy in the hypothalamic infundibular (arcuate) nucleus. Recent studies have demonstrated a critical role for kisspeptins in reproductive regulation, but it is not known whether menopause is accompanied by changes in hypothalamic kisspeptin neurons. OBJECTIVES: Our objective was to map the location of neurons expressing kisspeptin gene (KiSS-1) transcripts in the human hypothalamus and determine whether menopause is associated with changes in the size and gene expression of kisspeptin neurons. In monkeys, our objective was to evaluate the effects of ovariectomy and hormone replacement on neurons expressing KiSS-1 mRNA in the infundibular nucleus. SUBJECTS: Hypothalamic tissues were collected at autopsy from eight premenopausal and nine postmenopausal women and from 42 young cynomolgus monkeys in various endocrine states. METHODS: We used hybridization histochemistry, quantitative autoradiography, and computer-assisted microscopy. RESULTS: Examination of human hypothalamic sections revealed that KiSS-1 neurons were located predominantly in the infundibular nucleus. In the infundibular nucleus of postmenopausal women, there was a significant increase in the size of neurons expressing KiSS-1 mRNA and the number of labeled cells and autoradiographic grains per neuron. Similar to postmenopausal women, ovariectomy induced neuronal hypertrophy and increased KiSS-1 gene expression in the monkey infundibular nucleus. Conversely, in ovariectomized monkeys, estrogen replacement markedly reduced KiSS-1 gene expression. CONCLUSIONS: The cynomolgus monkey experiments provide strong evidence that the increase in KiSS-1 neuronal size and gene expression in postmenopausal women is secondary to ovarian failure. These studies suggest that kisspeptin neurons regulate estrogen negative feedback in the human.

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Cellular hypertrophy in the postmenopausal infundibular nucleus is accompanied by increased neurokinin B and kisspeptin gene expression.
“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).”
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 Rometo et al., 2007
The hypertrophy and increased kisspeptin and NKB gene expression in postmenopausal women are secondary to estrogen withdrawal.
“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).”
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 Rometo et al., 2007
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).”
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 Rometo et al., 2007
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).”
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 Rometo et al., 2007
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).”
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 Rometo et al., 2007

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Changes in Prodynorphin Gene Expression and Neuronal Morphology in the Hypothalamus of Postmenopausal Women
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Authors: Rometo, A. M., Krajewski, S. J., Lou Voytko, M., & Rance, N. E.
Affiliations: University of Arizona (US)
Department of Pathology (M.L.V.), Section of Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
Corresponding author: Rance, Naomi E.
ORCID: Krajewski, Sally J.
Rance, Naomi E.
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2007-07-01
Volume: 92
Issue: 7
Pages: 2744-2750
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2007-0553
OpenAlex: W2131769837
Cited by: 396
References: 40
Citations by year: 2026: 6 · 2025: 20 · 2024: 14 · 2023: 14 · 2022: 29 · 2021: 23 · 2020: 15 · 2019: 18 · 2018: 23 · 2017: 24 · 2016: 17 · 2015: 22 · 2014: 17 · 2013: 36 · 2012: 27
FWCI: 27.97
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: Frances McClelland Institute for Children, Youth, and Families
National Institutes of Health
National Institute on Aging (AG09214, T32AG007434)
Topics: Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords: kisspeptin, arcuate nucleus, menopause, postmenopausal women, ovariectomy, estrogen replacement therapy, neuronal hypertrophy, ovarian failure, estrogen negative feedback, reproductive control
MeSH terms: Adult, Aged, Aged, 80 and over, Animals, Arcuate Nucleus of Hypothalamus, Estrogens, Female, Humans, Hypertrophy, Macaca fascicularis, Middle Aged, Neurons, Ovariectomy, Pituitary Gland, Posterior, Progesterone, RNA, Messenger, Gene Expression, Estrogen Replacement Therapy, Postmenopause, Feedback, Physiological, Tumor Suppressor Proteins, Kisspeptins

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Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys

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Integrity signals

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