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Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
Open accessAbstract
Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.
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“loss-of-function mutations in the kisspeptin receptor cause GnRH deficiency in humans and mice (16-18).”
From Kisspeptin Overcomes GnRH Neuronal Suppression Secondary to Hyperprolactinemia in Humans (2022) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“both humans and rodents with inactivating mutations in kisspeptin or its receptor fail to progress through puberty or show normal pulsatile LH secretion (Seminara et al., 2003;de Roux et al., 2003;Kaiser, 2015).”
From The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach (2019) · cites this paper as de Roux et al., 2003
Experimental — accuracy not yet measuredIn the citing paper
“The discovery of the kisspeptin system as a crucial component for pubertal activation of the hypothalamic-pituitary-gonadal axis occurred in 2003, when loss-of-function mutations of the KISS1R (previously known as GPR54) gene were identified in individuals with isolated hypogonadotropic hypogonadism, establishing KISS1R inactivation as a cause of this disorder (table, figure 2).42,43”
From Pubertal development and regulation (2016) · cites this paper as [42]
In the citing paper
“Two of the most important excitatory components of the GnRH network were identified with the demonstration that the genetic loss of such inputs results in failure to initiate the GnRH pulse generator at the expected time of puberty, resulting in isolated hypogonadotropic hypogonadism.42–45”
From Pubertal development and regulation (2016) · cites this paper as [42]
In the citing paper
“Although studies in animals have led to identification of regulators of GnRH such as catecholamines, GABA, and glutamate, genetic studies of patients with pubertal disorders have resulted in the identification of a major regulatory hub for the GnRH neurons—ie, the hypothalamic neurons expressing kisspeptin and neurokinin B.42–44”
From Pubertal development and regulation (2016) · cites this paper as [42]
In the citing paper
“The reproductive roles of the G-protein-coupled KiSS-1 receptor (also known as GPR54, encoded by KISS1R) and its endogenous ligand, kisspeptin 1 (encoded by KISS1) were revealed in 2003 when inactivating mutations in the KiSS-1 receptor were found in the homozygous state in members of two large, consanguineous families with a history of normosmic IHH.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [34]
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“Like mutations in the genes encoding NKB or NK3R, inactivating mutations of KISS1R are associated with nHH in humans (de Roux et al., 2003; Seminara et al., 2003), and this phenotype is also observed in mice carrying inactivating mutations of Kiss1 or Kiss1r genes (Seminara et al., 2003;…”
BackgroundA Multi-Oscillatory Circadian System Times Female Reproduction
Simonneaux, V., & Bahougne, T. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00157 · Cited by 68
“The preeminent phenotypes of impaired reproduction (abnormal sexual maturation, small uterus, ovaries without mature follicles, no estrous cycles) often arise from mutations in Kiss1 (36, 37) and Kiss1R (16, 38, 39), which suggest that the Kiss1/Kiss1R complex is essential for the central regulation of the gonadotropi…”
BackgroundInfluentialMapping neuronal inputs to Kiss1 neurons in the arcuate nucleus of the mouse
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“Althoughmonogenic mutations affecting genes such asGNRHR (Bedecarrats and Kaiser, 2007), GPR54 (de Roux et al., 2003; Seminara et al., 2003), KiSS1 (Lapatto et al., 2007; Topaloglu et al., 2012), TAC3 and TACR3 (Topaloglu et al., 2008), result in the absence of pubertal development, the combined…”
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“The hypothesis that disruption of the kisspeptin system during critical windows of development may shift age at puberty is plausible given that the hypothalamic kisspeptin system was fi rst recognized by the discovery that humans with a mutated form of KISS1R are hypogonadal and fail to undergo puberty [ 123 , 124 ].”
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“01) (Figure 4A), which was recently described as a major determinant of pubertal onset [39,40].”
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“Then studies on patients with idiopathic hypogonadotropic hypogonadism (IHH) (de Roux et al., 2003; Marchese et al., 1994; Seminara et al., 2003) found that mutations in a particular orphan GPCR, GPR54, were responsible for the phenotype.”
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“Recently, kisspeptin (kiss-1), a tumor suppressing peptide, and its receptor GPR54 have been identified as major actors of the regulation of GnRH secretion (de Roux et al., 2003; Seminara and Kaiser, 2005).”
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Kisspeptins: Regulators of Metastasis and the Hypothalamic‐Pituitary‐Gonadal Axis
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“In 2003, inactivating mutations in the KISS1R gene from idiopathic hypogonadotropic hypogonadism patients were reported as well as the murine phenotype of defective onset of puberty in mice lacking the Kiss1r gene (7, 8).”
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“This finding is consistent with the earlier observation of hypogonadotropism and hypogonadism in KiSS1R deficient patients of pubertal and postpubertal age [1,30], and supports the notion that kisspeptin input to the GnRH neuronal network in the hypothalamus of the infant is necessary for the robust GnRH pulsatility d…”
BackgroundResultBeck, B. H., Fuller, S. A., Peatman, E., McEntire, M. E., Darwish, A., & Freeman, D. W. (2012) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2012.03.019 · Cited by 59
“labrax), Felip et al. (2009) found that both KISS1 and KISS2 decapeptides induced some level of FSH and LH secretion within 1–2 h post-injection, but KISS2 exhibited superior effects.”
BackgroundRecent Discoveries on the Control of Gonadotrophin‐Releasing Hormone Neurones in Nonhuman Primates
Terasawa, E., Kurian, J. R., Guerriero, K. A., Kenealy, B. P., Hutz, E. D., & Keen, K. L. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.02027.x · Cited by 60
Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback
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“Kisspeptin signalling is obligatory for normal puberty, as evidenced by a failure to progress through puberty in individuals with mutations in genes encoding kisspeptin and its receptor, GPR54 (de Roux et al., 2003; Seminara et al., 2003; Topaloglu et al., 2012).”
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“4) coding exons and intron–exon junctions were amplified by PCR and sequenced as described previously (de Roux et al., 2003; Brioude et al., 2013).”
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“Loss of KISS1 gene function is reported to be associated with hypogonadotropic hypogonadism in humans and animal models [5, 6].”
Pituitary Physiology and Diagnostic Evaluation
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“Inactivating mutations of KISS1R cause hypogonadotropic hypogonadism [7–9]; conversely, activating mutations cause precocious puberty [1,7,10].”
BackgroundSkorupskaite, K., George, J. T., Veldhuis, J. D., Millar, R. P., & Anderson, R. A. (2020) · Human Reproduction · doi:10.1093/humrep/deaa104 · Cited by 59
Kobayashi Award 2019: The neuroendocrine regulation of the mammalian reproduction
Tsukamura, H. (2021) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2021.113755 · Cited by 59
Mlyczyńska, E., Kieżun, M., Kurowska, P., Dawid, M., Pich, K., Respekta, N., Daudon, M., Rytelewska, E., Dobrzyń, K., Kamińska, B., et al. (2022) · Cells · doi:10.3390/cells11060957 · Cited by 67
“The loss of function due to the mutation of GPR54 leads to hypogonadotropic hypogonadism characterized by a deficiency in LH and FSH secretion, infertility, and a lack of puberty onset [263,264].”
BackgroundObesity and male infertility: multifaceted reproductive disruption
Chaudhuri, G. R., Das, A., Kesh, S. B., Bhattacharya, K., Dutta, S., Sengupta, P., & Syamal, A. K. (2022) · Middle East Fertility Society Journal · doi:10.1186/s43043-022-00099-2 · Cited by 62
“observed that maturation of kisspeptin receptor genes is associated with decreased sex steroid levels along with LH and FSH levels (hypogonadotropic hypogonadism) [78].”
BackgroundSushil Kumar, K., & Kaur, G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0052416 · Cited by 57
“Mutation in GPR-54 receptor causes hypogonadotrophic hypogonadism in rodents and humans [57].”
BackgroundKurian, J. R., Keen, K. L., Guerriero, K. A., & Terasawa, E. (2012) · Endocrinology · doi:10.1210/en.2012-1221 · Cited by 57
“In humans, mutations of the GPR54 gene are related to atypical pubertal timing or the absence of puberty (5, 6).”
BackgroundGonadal and Nongonadal Regulation of Sex Differences in Hypothalamic Kiss1 Neurones
Kauffman, A. S. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.02030.x · Cited by 57
“The Kiss1 system was first implicated in regulating reproduction in 2003, when several groups independently reported that humans and mice with mutations in the kisspeptin receptor exhibit prominent deficits in reproductive function and puberty onset [42,43].”
BackgroundHeppner, K. M., Baquero, A. F., Bennett, C. M., Lindsley, S. R., Kirigiti, M. A., Bennett, B. J., Bosch, M. A., Mercer, A. J., Rønnekleiv, O. K., True, C. A., et al. (2017) · eNeuro · doi:10.1523/eneuro.0198-16.2016 · Cited by 58
“Kisspeptin (Kiss1)-expressing neurons are positive regulators of gonadotropin-releasing hormone (GnRH) release, and Kiss1 signaling through its receptor (Kiss1r) is essential for fertility (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundEmerging Genetic and Epigenetic Mechanisms Underlying Pubertal Maturation in Adolescence
Aylwin, C. F., Toro, C. A., Shirtcliff, E. A., & Lomniczi, A. (2019) · Journal of Research on Adolescence · doi:10.1111/jora.12385 · Cited by 60
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“The structure of the current analysis is a model of an efficient strategy for ongoing investigation of other potential modifiers of the reproductive endocrine axis, such as leptin, -aminobutyric acid, glutamate, neuropeptide Y, fibroblast growth factor receptor 1, and G protein-coupled receptor 54 (53, 54, 56, 57) as…”
BackgroundZhang, C., Bosch, M. A., Rønnekleiv, O. K., & Kelly, M. J. (2013) · Endocrinology · doi:10.1210/en.2013-1180 · Cited by 58
Estrogen Regulation of the Molecular Phenotype and Active Translatome of AVPV Kisspeptin Neurons
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Treatments targeting neuroendocrine dysfunction in polycystic ovary syndrome (PCOS)
Garg, A., Patel, B., Abbara, A., & Dhillo, W. S. (2022) · Clinical Endocrinology · doi:10.1111/cen.14704 · Cited by 61
“Loss of function of the kisspeptin receptor in both humans and mouse models results in a failure of GnRH secretion and in hypogonadotrophic hypogonadism.(23,24) Various forms of kisspeptin (KP‐54, KP‐14, KP‐13, and KP‐10) have been characterized based on their amino‐acid length, with KP54 and KP10 being the most widel…”
BackgroundImmortalized neurons for the study of hypothalamic function
Dalvi, P. S., Nazarians-Armavil, A., Tung, S., & Belsham, D. D. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00649.2010 · Cited by 56
“The discovery that human patients deficient in the kisspeptin receptor Kiss1r exhibit hypogonadotropic hypogonadism and that this same phenotype is observed in knockout mice lacking the Kiss1 or Kiss1r gene firmly established kisspeptin as a key player in reproductive development and pubertal onset (55, 57, 84, 102, 2…”
BackgroundBeale, K., Kinsey‐Jones, J. S., Gardiner, J., Harrison, E., Thompson, E. L., Hu, M., Sleeth, M., Sam, A. H., Greenwood, H. C., McGavigan, A. K., et al. (2013) · Endocrinology · doi:10.1210/en.2013-1544 · Cited by 55
Impact of psychosocial stress on gonadotrophins and sexual behaviour in females: role for cortisol?
Ralph, C. R., Lehman, M. N., Goodman, R. L., & Tilbrook, A. J. (2016) · Reproduction · doi:10.1530/rep-15-0604 · Cited by 56
Physiology and Disorders of Puberty
Styne, D. M., & Grumbach, M. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-29738-7.00025-3 · Cited by 55
Seminara, S. B. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0139 · Cited by 57
“In 2003, however, multiple groups, using the human disease model of IHH and targeted mouse mutagenesis, converged on the conclusion that G-protein-coupled receptor 54 and metastin have key roles in this process”
BackgroundSmith, J. T. (2012) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2011.11.003 · Cited by 55
“In 2003, genetic studies discovered that idiopathic hypogonadotropin hypogonadism was caused by disabling mutations in Kiss1R [5,6].”
BackgroundKisspeptin antagonists: Unraveling the role of kisspeptin in reproductive physiology
Millar, R. P., Roseweir, A. K., Tello, J. A., Anderson, R. A., George, J. T., Morgan, K., & Pawson, A. J. (2010) · Brain Research · doi:10.1016/j.brainres.2010.09.044 · Cited by 69
The Emerging Therapeutic Potential of Kisspeptin and Neurokinin B
Patel, B., Koysombat, K., Mills, E., Tsoutsouki, J., Comninos, A. N., Abbara, A., & Dhillo, W. S. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad023 · Cited by 64
Milestones on Steroids and the Nervous System: 10 Years of Basic and Translational Research
Panzica, G., Balthazart, J., Frye, C. A., García‐Segura, L. M., Herbison, A. E., Mensah‐Nyagan, A. G., McCarthy, M. M., & Melcangi, R. C. (2011) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02265.x · Cited by 58
Jacobi, J. S., Martin, C., Nava, G., Jeziorski, M. C., Clapp, C., & de la Escalera, G. M. (2007) · Neuroendocrinology · doi:10.1159/000107770 · Cited by 55
“Kisspeptin, the peptide product of the KiSS-1 gene and the endogenous agonist for the GRP54 receptor, has recently been shown to be vital to reproductive axis function, since GPR54 mutations can result in hypogonadotropic hypogonadism in humans [”
BackgroundOhga, H., Fujinaga, Y., Selvaraj, S., Kitano, H., Nyuji, M., Yamaguchi, A., & Matsuyama, M. (2013) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2013.07.016 · Cited by 54
Anatomy of the kisspeptin systems in teleosts
Ogawa, S., & Parhar, I. S. (2012) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2012.08.023 · Cited by 55
Serum Kisspeptin Levels in Korean Girls with Central Precocious Puberty
Rhie, Y., Lee, K. H., Eun, S. H., Choi, B. M., Chae, H. W., Kwon, A., Lee, W. J., Kim, J. H., & Kim, H.-S. (2011) · Journal of Korean Medical Science · doi:10.3346/jkms.2011.26.7.927 · Cited by 56
“The kisspeptin, the peptide product of KISS1 gene and its putative receptor G protein coupled receptor-54 (GPR54) signaling complex has recently emerged as essential gatekeeper of pubertal activation of GnRH neurons and the reproductive axis, and it has been the focus of intense study by investigators (3-7).”
BackgroundDirect Regulation of Gonadotropin Release by Neurokinin B in Tilapia (Oreochromis niloticus)
Biran, J., Golan, M., Mizrahi, N., Ogawa, S., Parhar, I. S., & Levavi‐Sivan, B. (2014) · Endocrinology · doi:10.1210/en.2013-2114 · Cited by 57
Kottler, M., Chou, Y., Chabre, O., Richard, N., Polge, C., Brailly‐Tabard, S., Chanson, P., Guiochon‐Mantel, A., Huhtaniemi, I. T., & Young, J. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0648 · Cited by 55
Wahab, F., Shahab, M., & Behr, R. (2015) · Journal of Endocrinology · doi:10.1530/joe-14-0688 · Cited by 55
Kisspeptin signalling in the physiology and pathophysiology of the urogenital system
Wahab, F., Atika, B., Shahab, M., & Behr, R. (2015) · Nature Reviews Urology · doi:10.1038/nrurol.2015.277 · Cited by 58
Kisspeptin across the human lifespan:evidence from animal studies and beyond
Clarke, S. A., & Dhillo, W. S. (2016) · Journal of Endocrinology · doi:10.1530/joe-15-0538 · Cited by 56
GnIH Control of Feeding and Reproductive Behaviors
Tsutsui, K., & Ubuka, T. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00170 · Cited by 55
The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function
Owens, L. A., Abbara, A., Lerner, A., O'Floinn, S., Christopoulos, G., Khanjani, S., Islam, R., Hardy, K., Hanyaloglu, A. C., Lavery, S. A., et al. (2017) · Human Reproduction · doi:10.1093/humrep/dex357 · Cited by 55
“It regulates the hypothalamo–pituitary–gonadal (HPG) axis by acting on kisspeptin receptors (KISS1R) on GnRH neurons to stimulate GnRH, and consequently gonadotropin release (Seminara et al., 2003; de Roux et al., 2003; Kirilov et al., 2013).”
BackgroundGianetti, E., Hall, J. E., Au, M. G., Kaiser, U. B., Quinton, R., Stewart, J. A., Metzger, D. L., Pitteloud, N., Mericq, V., Merino, P. M., et al. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1264 · Cited by 53
The Role of Kisspeptin in the Onset of Puberty and in the Ovulatory Mechanism: A Mini-review
Cortés, M. E., Carrera, B., Rioseco, H., Río, J. P. D., & Pilar Vigil, P. (2014) · Journal of Pediatric and Adolescent Gynecology · doi:10.1016/j.jpag.2014.09.017 · Cited by 57
An updated model to describe the neuroendocrine control of reproduction in chickens
Bédécarrats, G. Y., Baxter, M. F. A., & Sparling, B. A. T. E. (2015) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2015.09.023 · Cited by 54
Donato, J., Lee, C., Ratra, D. V., Franci, C. R., Canteras, N. S., & Elias, C. F. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.03.013 · Cited by 54
“As kisspeptin neurons are key players in reproductive physiology (de Roux et al., 2003; Seminara et al., 2003; Clarkson et al., 2008, 2010; Oakley et al., 2009; Pineda et al., 2010), we assessed the expression of Kiss1 mRNA by in situ hybridization in the AVPV and the anterior PeN of PMV-lesioned…”
Amstalden, M., Cardoso, R. C., Alves, B. R. C., & Williams, G. L. (2014) · Journal of Animal Science · doi:10.2527/jas.2014-7808 · Cited by 55
“…role of kisspeptin in the control of reproductive function was first characterized in studies in which mutations in the gene encoding the kisspeptin receptor (KISS1R) identified in humans were associated with disruption of normal pubertal development (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundRuka, K. A., Burger, L. L., & Moenter, S. M. (2015) · Endocrinology · doi:10.1210/en.2015-1688 · Cited by 52
Oxytocin Facilitates Female Sexual Maturation through a Glia-to-Neuron Signaling Pathway
Parent, A., Rasier, G., Matagne, V., Lomniczi, A., Lebrethon, M.-C., Gérard, A., Ojeda, S. R., & Bourguignon, J. (2007) · Endocrinology · doi:10.1210/en.2007-1054 · Cited by 53
“The neuronal networks involved in the transsynaptic regulation of GnRH secretion mainly comprise neurons that use excitatory and inhibitory amino acids for neurotransmission in addition to the newly discovered kisspeptin-GPR54 signaling system (12, 13).”
BackgroundRather, M. A., Bhat, I. A., Gireesh-Babu, P., Chaudhari, A., Sundaray, J. K., & Sharma, R. (2016) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2016.01.005 · Cited by 54
Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing
Comninos, A. N., & Dhillo, W. S. (2017) · Neuroendocrinology · doi:10.1159/000481137 · Cited by 67
KiSS-1 peptide induces release of LH by a direct effect on the hypothalamus of ovariectomized ewes
Arreguin-Arevalo, J. A., Lents, C. A., Farmerie, T. A., Nett, T. M., & Clay, C. M. (2006) · Animal Reproduction Science · doi:10.1016/j.anireprosci.2006.09.021 · Cited by 52
Bianco, S. D. C. (2012) · Frontiers in Endocrinology · doi:10.3389/fendo.2012.00149 · Cited by 57
Stress, kisspeptin, and functional hypothalamic amenorrhea
Męczekalski, B., Niwczyk, O., Bala, G., & Szeliga, A. (2022) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2022.102288 · Cited by 62
Tena‐Sempere, M. (2009) · Endocrine development · doi:10.1159/000262528 · Cited by 54
Evaluation of kisspeptin levels in obese pregnancy as a biomarker for pre‐eclampsia
Logie, J. J., Denison, F. C., Riley, S. C., Ramaesh, T., Forbes, S., Norman, J. E., & Reynolds, R. M. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04317.x · Cited by 54
Kisspeptin/KISS1R System in Breast Cancer
Cvetković, D., Babwah, A. V., & Bhattacharya, M. M. (2013) · Journal of Cancer · doi:10.7150/jca.7626 · Cited by 55
“Physiologically, the KP/KISS1R signaling system potently triggers gonadotropin-releasing hormone release, thereby, acting a major regulator of the neuroendocrine reproductive axis[22, 23]; negatively regulates trophoblast migration and invasion, thereby, being proposed as a major regulator of placentation and fetal de…”
Guimiot, F., Chevrier, L., Dreux, S., Chevenne, D., Caraty, A., Delezoide, A., & de Roux, N. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-2078 · Cited by 57
The Vasoactive Potential of Kisspeptin-10 in the Peripheral Vasculature
Sawyer, I. A., Smillie, S.-J., Bodkin, J. V., Fernandes, E. S., O'Byrne, K. T., & Brain, S. D. (2011) · PLoS ONE · doi:10.1371/journal.pone.0014671 · Cited by 54
Matsuzaki, T., Iwasa, T., Kinouchi, R., Yoshida, S., Murakami, M., Gereltsetseg, G., Yamamoto, S., Kuwahara, A., Yasui, T., & Irahara, M. (2011) · Endocrine Journal · doi:10.1507/endocrj.k11e-131 · Cited by 52
Organizational and activational effects of sex steroids on kisspeptin neuron development
Poling, M. C., & Kauffman, A. S. (2012) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2012.06.001 · Cited by 54
“The essential role of kisspeptin and Kiss1r in reproductive endocrinology was first reported in 2003 from the characterization of two consanguineous families suffering from then idiopathic hypogonadotropic hypogonadism [29; 126].”
BackgroundChoi, J., & Yoo, H. (2013) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e32835b7ec7 · Cited by 53
“The KISS1/KISS1R signaling complex was demonstrated as an important regulator of the HPG axis in 2003 by two independent groups reporting deletions and inactivating mutations of KISS1R in patients with hypogonadotropic hypogonadism [9,30].”
BackgroundAncel, C., Inglis, M. A., & Anderson, G. M. (2017) · Endocrinology · doi:10.1210/en.2016-1902 · Cited by 52
The Arg–Phe‐amide peptide 26RFa/glutamine RF‐amide peptide and its receptor: IUPHAR Review 24
Leprince, J., Bagnol, D., Bureau, R., Fukusumi, S., Granata, R., Hinuma, S., Larhammar, D., Primeaux, S. D., Santos, J. S. O., Tsutsui, K., et al. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13907 · Cited by 55
“In humans, loss of function of the GPR54 gene causes idiopathic hypogonadotropic hypogonadism (de Roux et al., 2003; Seminara et al., 2003) indicating that metastin and/or its processed fragments kisspeptins play a pivotal role in the control of the hypothalamo–pituitary–gonadal axis (Pinilla et…”
BackgroundPita, J., Barrios, V., Gavela‐Pérez, T., Martos‐Moreno, G. Á., Muñoz-Calvo, M. T., Pozo, J., Rovira, A., Argente, J., & Soriano‐Guillén, L. (2011) · Peptides · doi:10.1016/j.peptides.2011.07.016 · Cited by 53
Metadata
- Authors
- de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E.
- Affiliations
- Institut National de la Santé et de la Recherche Médicale Unité 135, Unité de Recherches Hormones Gènes et Reproduction, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France; Institut National de la Santé et de la Recherche Médicale Unité 584, Hormone Targets, Faculté de Médecine Necker Enfants Malades, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale Unité 535, Génétique Epidémiologique et Structure des Populations Humaines, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre...
- Hôpital Necker-Enfants Malades (FR)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-08-27
- Volume
- 100
- Issue
- 19
- Pages
- 10972-10976
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC196911
- OpenAlex
- W2143506157
- Cited by
- 2,431
- References
- 29
- Citations by year
- 2026: 36 · 2025: 65 · 2024: 99 · 2023: 78 · 2022: 123 · 2021: 115 · 2020: 130 · 2019: 120 · 2018: 144 · 2017: 121 · 2016: 127 · 2015: 133 · 2014: 137 · 2013: 147 · 2012: 153
- FWCI
- 45.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- isolated hypogonadotropic hypogonadism, GPR54, loss-of-function mutations, chromosome 19p13, consanguineous family, GnRH receptor, orphan G protein-coupled receptor, gonadotropic axis, aberrant splicing, follicle-stimulating hormone, luteinizing hormone
- MeSH terms
- Receptors, Kisspeptin-1, Base Sequence, Consanguinity, Female, Genotype, Humans, Hypogonadism, Male, Pedigree, DNA Primers, Receptors, Neuropeptide, Receptors, G-Protein-Coupled
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