Kisspeptin antagonists: Unraveling the role of kisspeptin in reproductive physiology
Abstract
Kisspeptin has recently been identified as a key neuroendocrine gatekeeper of reproduction and is essential for the initiation of human puberty and maintenance of adult reproduction. Kisspeptin neurons appear to be integrative sensors, as they respond to changes in numerous internal and external factors including nutrient and fat status, stress and sex steroids, thus providing a link between these factors and reproduction. We have pioneered the development of kisspeptin antagonists as powerful tools for interrogating the role of kisspeptin in reproductive physiology and pathology, and as potential treatments for hormone-dependent disease. This article summarizes their development and key findings to date. These demonstrate an essential role for kisspeptin in GnRH neuron firing, GnRH pulsatile secretion, negative feedback by gonadal steroids, the onset of puberty, and the ovulatory LH surge. These studies establish that kisspeptin antagonists are powerful investigative tools and set the scene for more extensive physiological and pathophysiological studies as well as therapeutic intervention.
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Activation of arcuate nucleus kisspeptin neurons directly influences pulsatile GnRH release.
“In contrast, activation of kisspeptin neurons in the arcuate nucleus has been shown to directly influence the regulation of pulsatile GnRH release (Han et al., 2005; Millar et al., 2010).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Millar et al., 2010
Cites
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Oyola, M. G., & Handa, R. J. (2017) · Stress · doi:10.1080/10253890.2017.1369523 · Cited by 710 · see citing works
“In contrast, activation of kisspeptin neurons in the arcuate nucleus has been shown to directly influence the regulation of pulsatile GnRH release (Han et al., 2005; Millar et al., 2010).”
BackgroundInactivating<i>KISS1</i>Mutation and Hypogonadotropic Hypogonadism
Topaloglu, A. K., Tello, J. A., Kotan, L. D., Ozbek, M. N., Yilmaz, M. B., Erdogan, S., Gurbuz, F., Temiz, F., Millar, R. P., & Yuksel, B. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1111184 · Cited by 467 · see citing works
Self-citationKisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men
George, J. T., Veldhuis, J. D., Roseweir, A. K., Newton, C. L., Faccenda, E., Millar, R. P., & Anderson, R. A. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0089 · Cited by 186 · see citing works
Self-citationGranata, L., Gildawie, K. R., Ismail, N., Brenhouse, H. C., & Kopec, A. M. (2022) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2022.101143 · Cited by 15 · see citing works
- Authors
- Millar, R. P., Roseweir, A. K., Tello, J. A., Anderson, R. A., George, J. T., Morgan, K., & Pawson, A. J.
- Affiliations
- Medical Research Council (GB)
- Corresponding author
- Millar, Robert P.
- ORCID
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 1364
- Pages
- 81-89
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2032263844
- Cited by
- 69
- References
- 10
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 6 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 8 · 2015: 7 · 2014: 2 · 2013: 5 · 2012: 14
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- 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
- kisspeptin, reproductive physiology, puberty onset, GnRH neurons, luteinizing hormone surge, ovulation, neuroendocrine regulation of reproduction
- MeSH terms
- Animals, Blood-Brain Barrier, Female, Humans, Gonadotropin-Releasing Hormone, Male, Neurons, Puberty, Reproduction, Feedback, Physiological, Tumor Suppressor Proteins, Electrophysiological Phenomena, Kisspeptins
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