A genetic basis for functional hypothalamic amenorrhea
Open accessAbstract
BACKGROUND: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. METHODS: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. RESULTS: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. CONCLUSIONS: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
A genetic contribution to HA has been described, with mutations in genes affecting GnRH neuronal integrity identified in some women with HA.
“Furthermore, a genetic contribution to HA has been described, with mutations in genes affecting GnRH neuronal integrity identified in some women with HA (5).”
From Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History (2019) · cites this paper as [5]
Genetic variants in genes related to GnRH neuronal ontogeny are enriched in patients with HA.
“It has been previously shown that genetic variants in genes related to GnRH neuronal ontogeny are enriched in patients with HA (5).”
From Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History (2019) · cites this paper as [5]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Eating Attitudes Test: psychometric features and clinical correlates
Garner, D. M., Olmsted, M., Bohr, Y., & Garfinkel, P. (1982) · Psychological Medicine · doi:10.1017/s0033291700049163 · Cited by 4,902 · see citing works
The <i>GPR54</i> Gene as a Regulator of Puberty
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S., Shagoury, J. K., Bo-Abbas, Y., Kuohung, W., Schwinof, K. M., Hendrick, A. G., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa035322 · Cited by 2,557 · see citing works
Self-citationHypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834399100 · Cited by 2,431 · see citing works
Frisch, R. E., & McArthur, J. W. (1974) · Science · doi:10.1126/science.185.4155.949 · Cited by 1,412 · see citing works
Recombinant human leptin in women with hypothalamic amenorrhea
Welt, C. K., Chan, J. L., Bullen, J., Murphy, R., Smith, P., DePaoli, A. M., Karalis, A., & Mantzoros, C. S. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040388 · Cited by 908 · see citing works
Self-citationLoucks, A. B., & Thuma, J. R. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020369 · Cited by 760 · see citing works
The Effects of Exercise on Pubertal Progression and Reproductive Function in Girls*
Warren, M. P. (1980) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-51-5-1150 · Cited by 617 · see citing works
Schwanzel-Fukuda, M., Bick, D., & Pfaff, D. W. (1989) · Molecular Brain Research · doi:10.1016/0169-328x(89)90076-4 · Cited by 616 · see citing works
de Roux, N., Young, J., Misrahi, M., Genet, R., Chanson, P., Schaison, G., & Milgrom, E. (1997) · New England Journal of Medicine · doi:10.1056/nejm199711273372205 · Cited by 518 · see citing works
Induction of Menstrual Disorders by Strenuous Exercise in Untrained Women
Bullen, B. A., Skrinar, G. S., Beitins, I. Z., von Mering, G., Turnbull, B. A., & McArthur, J. W. (1985) · New England Journal of Medicine · doi:10.1056/nejm198505233122103 · Cited by 484 · see citing works
Loucks, A. B., Mortola, J. F., GIRTON, L., & Yen, S. S. C. (1989) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-68-2-402 · Cited by 476 · see citing works
Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2
Dodé, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., et al. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020175 · Cited by 457 · see citing works
Seminara, S. B., Hayes, F. J., & Crowley, W. F. (1998) · Endocrine Reviews · doi:10.1210/edrv.19.5.0344 · Cited by 412 · see citing works
Self-citationReversal of Idiopathic Hypogonadotropic Hypogonadism
Raivio, T., Falardeau, J. L., Dwyer, A. A., Quinton, R., Hayes, F. J., HUGHES, V. A., Cole, L. W., Pearce, S. H. S., Lee, H., Boepple, P. A., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa066494 · Cited by 410 · see citing works
Self-citationDecreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice
Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34538 · Cited by 397 · see citing works
Self-citationBOYAR, R. M., Katz, J. L., Finkelstein, J. W., Kapen, S., Weiner, H., Weitzman, E. D., & HELLMAN, L. (1974) · New England Journal of Medicine · doi:10.1056/nejm197410242911701 · Cited by 394 · see citing works
Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism
Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29884 · Cited by 379 · see citing works
Self-citationThe genetic and molecular basis of idiopathic hypogonadotropic hypogonadism
Bianco, S. D. C., & Kaiser, U. B. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.177 · Cited by 336 · see citing works
Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans
Cheng, C. K., & Leung, P. C. K. (2005) · Endocrine Reviews · doi:10.1210/er.2003-0039 · Cited by 298 · see citing works
Matsumoto, S.-I., Yamazaki, C., Masumoto, K.-H., Nagano, M., Naito, M., Soga, T., Hiyama, H., Matsumoto, M., Takasaki, J., Kamohara, M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508881103 · Cited by 281 · see citing works
Pitteloud, N., Zhang, C., Pignatelli, D., Li, J.-D., Raivio, T., Cole, L. W., Plummer, L., Jacobson-Dickman, E. E., Mellon, P. L., Zhou, Q.-Y., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707173104 · Cited by 264 · see citing works
Self-citationSANTORO, N., FILICORI, M., & CROWLEY, W. F. (1986) · Endocrine Reviews · doi:10.1210/edrv-7-1-11 · Cited by 255 · see citing works
Self-citationBeranova, M., Oliveira, L. M. B., Bédécarrats, G. Y., Schipani, E., Vallejo, M., Ammini, A. C., Quintos, J. B., Hall, J. E., Martin, K. A., Hayes, F. J., et al. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.4.7395 · Cited by 251 · see citing works
Oliveira, L. M. B., Seminara, S. B., Beranova, M., Hayes, F. J., Valkenburgh, S. B., Schipani, E., Costa, E. M. F., Latronico, A. C., Crowley, W. F., & Vallejo, M. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.4.7420 · Cited by 210 · see citing works
Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., et al. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2654 · Cited by 208 · see citing works
Self-citationAdult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility
Nachtigall, L. B., Boepple, P. A., Pralong, F. P., & Crowley, W. F. (1997) · New England Journal of Medicine · doi:10.1056/nejm199702063360604 · Cited by 199 · see citing works
Self-citationClassification of eating disorders: toward DSM-V.
Wilfley, D. E., Bishop, M. E., Wilson, G., & Agras, W. (2007) · International Journal of Eating Disorders · doi:10.1002/eat.20436 · Cited by 188 · see citing works
Adult-onset amenorrhea: A study of 262 patients
Reindollar, R. H., Novak, M., Tho, S. P. T., & McDonough, P. G. (1986) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(86)90274-7 · Cited by 176 · see citing works
Seminara, S. B. (1998) · Endocrine Reviews · doi:10.1210/er.19.5.521 · Cited by 171 · see citing works
Self-citationMiller, K. K., Parulekar, M. S., Schoenfeld, E., Anderson, E. J., Hubbard, J. L., Klibanski, A., & Grinspoon, S. K. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.7.4975 · Cited by 166 · see citing works
Pitteloud, N., Acierno, J. S., Meysing, A. U., Dwyer, A. A., Hayes, F. J., & Crowley, W. F. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1361 · Cited by 160 · see citing works
Self-citationCognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison
Giles, D. E., & Berga, S. L. (1993) · Fertility and Sterility · doi:10.1016/s0015-0282(16)56165-2 · Cited by 136 · see citing works
PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity
Monnier, C., Dodé, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., & Rondard, P. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddn318 · Cited by 123 · see citing works
Chung, W. C. J., Moyle, S. S., & Tsai, P. (2008) · Endocrinology · doi:10.1210/en.2007-1634 · Cited by 112 · see citing works
Raivio, T., Sidis, Y., Plummer, L., Chen, H., Ma, J., Mukherjee, A., Jacobson-Dickman, E. E., Quinton, R., Vliet, G. V., Lavoie, H. B., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0179 · Cited by 98 · see citing works
Self-citationSun, H. D., Malabunga, M., Tonra, J. R., DiRenzo, R., Carrick, F. E., Zheng, H., Berthoud, H., McGuinness, O. P., Shen, J., Böhlen, P., et al. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00089.2006 · Cited by 95 · see citing works
Mercader, J. M., Ribasés, M., Gratacòs, M., González, J. R., Bayés, M., de Cid, R., Badia, A. M. T. I., Fernández‐Aranda, F., & Estivill, X. (2007) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00301.x · Cited by 95 · see citing works
Kisspeptin and GPR54: Discovery of a Novel Pathway in Reproduction
Seminara, S. B., & Crowley, W. F. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01731.x · Cited by 90 · see citing works
Self-citationKim, S. ‐., Hu, Y., Cadman, S., & Bouloux, P. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2007.01627.x · Cited by 87 · see citing works
Thome, J. L., & Espelage, D. L. (2006) · Eating Behaviors · doi:10.1016/j.eatbeh.2006.11.009 · Cited by 80 · see citing works
Hayes, F. J., McNicholl, D. J., Schoenfeld, D., Marsh, E. E., & Hall, J. E. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.3.5579 · Cited by 70 · see citing works
Perkins, R. B., Hall, J. E., & Martin, K. A. (2001) · Human Reproduction · doi:10.1093/humrep/16.10.2198 · Cited by 69 · see citing works
Self-citationProkineticin 2 Is a Hypothalamic Neuropeptide That Potently Inhibits Food Intake
Gardiner, J., Bataveljic, A., Patel, N. A., Bewick, G. A., Roy, D., Campbell, D., Greenwood, H. C., Murphy, K. G., Hameed, S., Jethwa, P. H., et al. (2009) · Diabetes · doi:10.2337/db09-1198 · Cited by 66 · see citing works
Mercader, J. M., Saus, E., Agüera, Z., Bayés, M., Boni, C., Carreras, A., Cellini, E., de Cid, R., Dierssen, M., Escaramís, G., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn013 · Cited by 56 · see citing works
Canto, P., Munguía, P., Söderlund, D., Castro, J. J., & Méndez, J. P. (2008) · Journal of Andrology · doi:10.2164/jandrol.108.005314 · Cited by 51 · see citing works
Centeno, M. ‐., Sanchez, R. L., Cameron, J. L., & Bethea, C. L. (2007) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2007.01566.x · Cited by 27 · see citing works
Flagged first, then by citations
3 of the 49 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline
Gordon, C. M., Ackerman, K. E., Berga, S. L., Kaplan, J. R., Mastorakos, G. P., Misra, M., Murad, M. H., Santoro, N. F., & Warren, M. P. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-00131 · Cited by 634 · see citing works
Control of puberty onset and fertility by gonadotropin-releasing hormone neurons
Herbison, A. E. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.70 · Cited by 515 · see citing works
Clinical Management of Congenital Hypogonadotropic Hypogonadism
Young, J., Xu, C., Papadakis, G. E., Acierno, J. S., Maione, L., Hietamäki, J., Raivio, T., & Pitteloud, N. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00116 · Cited by 407 · see citing works
Self-citationOligogenic basis of isolated gonadotropin-releasing hormone deficiency
Sykiotis, G. P., Plummer, L., HUGHES, V. A., Au, M., Durrani, S., Nayak-Young, S., Dwyer, A. A., Quinton, R., Hall, J. E., Gusella, J. F., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009622107 · Cited by 356 · see citing works
Self-citationThe endocrine manifestations of anorexia nervosa: mechanisms and management
Haines, M. S., & Miller, K. K. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.175 · Cited by 322 · see citing works
Harrington, J., & Palmert, M. R. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1598 · Cited by 226 · see citing works
Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era
Fang, Q., George, A. S., Brinkmeier, M. L., Mortensen, A. H., Gergics, P., Cheung, L., Daly, A. Z., Ajmal, A., Millan, M. I. P., Ozel, A. B., et al. (2016) · Endocrine Reviews · doi:10.1210/er.2016-1101 · Cited by 208 · see citing works
Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism
Stamou, M. I., & Georgopoulos, N. A. (2017) · Metabolism · doi:10.1016/j.metabol.2017.10.012 · Cited by 194 · see citing works
Endocrine disorders & female infertility
Unuane, D., Tournaye, H. J., Velkeniers, B., & Poppe, K. G. (2011) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2011.08.001 · Cited by 187 · see citing works
Cangiano, B., Swee, D. S., Quinton, R., & Bonomi, M. (2020) · Human Genetics · doi:10.1007/s00439-020-02147-1 · Cited by 182 · see citing works
Self-citationRaivio, T., Stefanija, M. A., McCabe, M. J., Romero, C. J., Dwyer, A. A., Tommiska, J., Sykiotis, G. P., Gregory, L. C., Diaczok, D., Tziaferi, V., et al. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2938 · Cited by 165 · see citing works
Self-citationBone Health in Endurance Athletes
Scofield, K. L., & Hecht, S. S. (2012) · Current Sports Medicine Reports · doi:10.1249/jsr.0b013e3182779193 · Cited by 164 · see citing works
Approach to the patient with hypogonadotropic hypogonadism
Silveira, L. F. G., & Latronico, A. C. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3550 · Cited by 161 · see citing works
Williams, N. I., Leidy, H. J., Hill, B. R., Lieberman, J. L., Legro, R. S., & Souza, M. J. D. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00386.2013 · Cited by 156 · see citing works
Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory
Mitchell, A. L., Dwyer, A. A., Pitteloud, N., & Quinton, R. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.03.002 · Cited by 150 · see citing works
Self-citationNeuroendocrine Causes of Amenorrhea—An Update
Fourman, L. T., & Fazeli, P. K. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3344 · Cited by 144 · see citing works
Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism
Jayasena, C. N., Anderson, R. A., Llahana, S., Barth, J. H., MacKenzie, F., Wilkes, S., Smith, N., Sooriakumaran, P., Minhas, S., Wu, F. C. W., et al. (2022) · Clinical Endocrinology · doi:10.1111/cen.14633 · Cited by 147 · see citing works
Self-citationTRANSITION IN ENDOCRINOLOGY: Induction of puberty
Dunkel, L., & Quinton, R. (2014) · European Journal of Endocrinology · doi:10.1530/eje-13-0894 · Cited by 150 · see citing works
Self-citationJayasena, C. N., Abbara, A., Veldhuis, J. D., Comninos, A. N., Ratnasabapathy, R., Silva, A. D., Nijher, G. M. K., Ganiyu‐Dada, Z., Mehta, A., Todd, C., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1569 · Cited by 138 · see citing works
Howard, S. R., Guasti, L., Ruiz‐Babot, G., Mancini, A., David, A., Storr, H. L., Metherell, L., Sternberg, M. J. E., Cabrera, C., Warren, H. R., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606250 · Cited by 137 · see citing works
Self-citationAdolescent Anovulation: Maturational Mechanisms and Implications
Rosenfield, R. L. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1770 · Cited by 139 · see citing works
Delayed Puberty—Phenotypic Diversity, Molecular Genetic Mechanisms, and Recent Discoveries
Howard, S. R., & Dunkel, L. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00248 · Cited by 114 · see citing works
A Shared Genetic Basis for Self-Limited Delayed Puberty and Idiopathic Hypogonadotropic Hypogonadism
Zhu, J., Choa, R., Guo, M. H., Plummer, L., Buck, C. L., Palmert, M. R., Hirschhorn, J. N., Seminara, S. B., & Chan, Y.-M. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1080 · Cited by 110 · see citing works
Self-citationAmenorrhea: an approach to diagnosis and management.
Klein, D. A., & Poth, M. (2013) · PubMed · Cited by 109 · see citing works
Bonomi, M., Vezzoli, V., Krausz, C. G., Guizzardi, F., Vezzani, S., Simoni, M., Bassi, I., Duminuco, P., Iorgi, N. D., Giavoli, C., et al. (2017) · European Journal of Endocrinology · doi:10.1530/eje-17-0065 · Cited by 103 · see citing works
Female infertility of endocrine origin
Weiss, R. V., & Clapauch, R. (2014) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/0004-2730000003021 · Cited by 104 · see citing works
Sultan, C., Gaspari, L., Maı̈moun, L., Kalfa, N., & Paris, F. (2017) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2017.11.004 · Cited by 102 · see citing works
Exercise, Training, and the Hypothalamic-Pituitary-Gonadal Axis in Men and Women
Sokoloff, N. C., Misra, M., & Ackerman, K. (2016) · Frontiers of Hormone Research · doi:10.1159/000445154 · Cited by 83 · see citing works
Morrison, A., Fleming, S., & Levy, M. J. (2020) · Clinical Endocrinology · doi:10.1111/cen.14399 · Cited by 101 · see citing works
Messina, A., Ferraris, N., Wray, S., Cagnoni, G., Donohue, D. E., Casoni, F., Kramer, P. R., Derijck, A. A. H. A., Adolfs, Y., Fasolo, A., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr403 · Cited by 91 · see citing works
Arends, J., Cheung, M.-Y. C., Barrack, M., & Nattiv, A. (2012) · International Journal of Sport Nutrition & Exercise Metabolism · doi:10.1123/ijsnem.22.2.98 · Cited by 91 · see citing works
Stamou, M. I., Cox, K. H., & Crowley, W. F. (2015) · Endocrine Reviews · doi:10.1210/er.2015-1045 · Cited by 91 · see citing works
Self-citationRetractedPROKR2 Variants in Multiple Hypopituitarism with Pituitary Stalk Interruption
Reynaud, R., Jayakody, S. A., Monnier, C., Saveanu, A., Bouligand, J., Guedj, A. M., Simonin, G., Lecomte, P., Barlier, A., Rondard, P., et al. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3056 · Cited by 87 · see citing works
New understandings of the genetic basis of isolated idiopathic central hypogonadism
Bonomi, M., Libri, D. V., Guizzardi, F., Guarducci, E., Maiolo, E., Pignatti, E., Asci, R., & Persani, L. (2011) · Asian Journal of Andrology · doi:10.1038/aja.2011.68 · Cited by 84 · see citing works
Phylactou, M., Clarke, S. A., Patel, B., Baggaley, C., Jayasena, C. N., Kelsey, T., Comninos, A. N., Dhillo, W. S., & Abbara, A. (2020) · Clinical Endocrinology · doi:10.1111/cen.14402 · Cited by 77 · see citing works
MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism
Dwyer, A. A., Raivio, T., & Pitteloud, N. (2016) · European Journal of Endocrinology · doi:10.1530/eje-15-1033 · Cited by 71 · see citing works
Self-citationGenetics of Isolated Hypogonadotropic Hypogonadism: Role of GnRH Receptor and Other Genes
Karges, B., Joseph, N., de Roux, N., & Karges, W. (2011) · International Journal of Endocrinology · doi:10.1155/2012/147893 · Cited by 70 · see citing works
O'Donnell, E., Goodman, J., & Harvey, P. (2011) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2011-1223 · Cited by 2 · see citing works
Seppä, S., Kuiri‐Hänninen, T., Holopainen, E., & Voutilainen, R. (2021) · European Journal of Endocrinology · doi:10.1530/eje-20-1487 · Cited by 78 · see citing works
Balasubramanian, R., & Crowley, W. F. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.07.012 · Cited by 68 · see citing works
Self-citationGnRH-Deficient Phenotypes in Humans and Mice with Heterozygous Variants in<i>KISS1</i>/<i>Kiss1</i>
Chan, Y.-M., Broder-Fingert, S., Paraschos, S., Lapatto, R., Au, M., Hughes, V., Bianco, S. D. C., Min, L., Plummer, L., Cerrato, F., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0518 · Cited by 68 · see citing works
Self-citationPuberty and its disorders in the female
Rosenfield, R. L., Cooke, D. W., & Radovick, S. (2014) · Elsevier eBooks · doi:10.1016/b978-1-4557-4858-7.00024-x · Cited by 67 · see citing works
Current understanding of hypothalamic amenorrhoea
Roberts, R., Farahani, L., Webber, L., & Jayasena, C. (2020) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018820945854 · Cited by 59 · see citing works
Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders
Tusset, C., Noel, S. D., Trarbach, E. B., Silveira, L. F. G., Jorge, A. A. L., Brito, V. N., Cukier, P., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., et al. (2012) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302012000900008 · Cited by 65 · see citing works
Self-citationThe Genetic Basis of Delayed Puberty
Howard, S. R., & Dunkel, L. (2017) · Neuroendocrinology · doi:10.1159/000481569 · Cited by 62 · see citing works
Williams, N., Statuta, S. M., & Austin, A. V. (2017) · Clinics in Sports Medicine · doi:10.1016/j.csm.2017.05.003 · Cited by 51 · see citing works
Variations inPROKR2, But NotPROK2, Are Associated With Hypopituitarism and Septo-optic Dysplasia
McCabe, M. J., Gaston‐Massuet, C., Gregory, L. C., Alatzoglou, K. S., Tziaferi, V., Sbai, O., Rondard, P., Masumoto, K., Nagano, M., Shigeyoshi, Y., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3067 · Cited by 60 · see citing works
Self-citationRaivio, T., & Miettinen, P. J. (2019) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2019.101316 · Cited by 63 · see citing works
Where Have the Periods Gone? The Evaluation and Management of Functional Hypothalamic Amenorrhea
Sophie Gibson, M. E., Fleming, N., Zuijdwijk, C., & Dumont, T. (2020) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2019.2019.s0178 · Cited by 61 · see citing works
Neuroendocrine control of ovulation
Berga, S. L., & Naftolin, F. N. (2012) · Gynecological Endocrinology · doi:10.3109/09513590.2012.651929 · Cited by 60 · see citing works
Butz, H., Nyírő, G., Kurucz, P. A., Likó, I., & Patócs, A. (2020) · Human Genetics · doi:10.1007/s00439-020-02148-0 · Cited by 60 · see citing works
The Genetic Basis of Delayed Puberty
Howard, S. R. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00423 · Cited by 59 · see citing works
Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis
Saadedine, M., Kapoor, E., & Shufelt, C. (2023) · Mayo Clinic proceedings · doi:10.1016/j.mayocp.2023.05.027 · Cited by 52 · see citing works
Beneduzzi, D., Trarbach, E. B., Min, L., Jorge, A. A. L., Garmes, H. M., Renck, A. C., Fichna, M., Fichna, P., Arantes, K. A., Costa, E. M. F., et al. (2014) · Fertility and Sterility · doi:10.1016/j.fertnstert.2014.05.044 · Cited by 57 · see citing works
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 · see citing works
Gianetti, 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 · see citing works
Self-citationStress, 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 58 · see citing works
Molecular Plasticity of Male and Female Murine Gonadotropes Revealed by mRNA Sequencing
Qiao, S., Nordström, K. J. V., Muijs, L., Gasparoni, G., Tierling, S., Krause, E., Walter, J., & Boehm, U. (2015) · Endocrinology · doi:10.1210/en.2015-1836 · Cited by 49 · see citing works
Faienza, M. F., Urbano, F., Moscogiuri, L. A., Chiarito, M., Santis, S. D., & Giordano, P. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1019468 · Cited by 50 · see citing works
Pharmacology of medications used for ovarian stimulation
Quaas, A. M., & Legro, R. S. (2018) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2018.10.002 · Cited by 48 · see citing works
Beyond hormone replacement: quality of life in women with congenital hypogonadotropic hypogonadism
Dzemaili, S., Tiemensma, J., Quinton, R., Pitteloud, N., Morin, D., & Dwyer, A. A. (2017) · Endocrine Connections · doi:10.1530/ec-17-0095 · Cited by 47 · see citing works
Self-citationRanganathan, P., Kumar, R. G., Davis, K., McCullough, E. H., Berga, S. L., & Wagner, A. K. (2016) · Brain Injury · doi:10.3109/02699052.2016.1144081 · Cited by 45 · see citing works
Reversible male hypogonadotropic hypogonadism due to energy deficit
Wong, H. K., Hoermann, R., & Grossmann, M. (2019) · Clinical Endocrinology · doi:10.1111/cen.13973 · Cited by 43 · see citing works
Dwyer, A. A., Chavan, N. R., Lewkowitz-Shpuntoff, H., Plummer, L., Hayes, F. J., Seminara, S. B., Crowley, W. F., Pitteloud, N., & Balasubramanian, R. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02697 · Cited by 41 · see citing works
Self-citationAbreu, A. P., Noel, S. D., Xu, S., Carroll, R. S., Latronico, A. C., & Kaiser, U. B. (2012) · Molecular Endocrinology · doi:10.1210/me.2012-1102 · Cited by 40 · see citing works
An ancient founder mutation in PROKR2 impairs human reproduction
Stefanija, M. A., Jeanpierre, M., Sykiotis, G. P., Young, J., Quinton, R., Abreu, A. P., Plummer, L., Au, M., Balasubramanian, R., Dwyer, A. A., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds264 · Cited by 38 · see citing works
Self-citationCangiano, B., Duminuco, P., Vezzoli, V., Guizzardi, F., Chiodini, I., Corona, G., Maggi, M., Persani, L., & Bonomi, M. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8010126 · Cited by 39 · see citing works
Neuroendocrine mechanisms in athletes
Misra, M. (2014) · Handbook of clinical neurology · doi:10.1016/b978-0-444-59602-4.00025-3 · Cited by 38 · see citing works
Prokineticins and their G protein-coupled receptors in health and disease
Zhao, Y., Wu, J., Wang, X., Jia, H., Chen, D., & Li, J. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2018.09.006 · Cited by 40 · see citing works
Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism
Jayasena, C. N., Devine, K., Barber, K., Comninos, A. N., Conway, G. S., Crown, A. L., Davies, M. C., Ewart, A., Seal, L., Smyth, A., et al. (2024) · Clinical Endocrinology · doi:10.1111/cen.15097 · Cited by 39 · see citing works
Self-citationFunctional hypothalamic and drug-induced amenorrhea: an overview
Lania, A. G., Gianotti, L., Gagliardi, I., Bondanelli, M., Vena, W., & Ambrosio, M. R. (2019) · Journal of Endocrinological Investigation · doi:10.1007/s40618-019-01013-w · Cited by 38 · see citing works
Koltun, K. J., Souza, M. D. D., Scheid, J., & Williams, N. (2019) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/clinem/dgz030 · Cited by 30 · see citing works
Louden, E. D., Poch, A., Kim, H., Ben‐Mahmoud, A., Kim, S., & Layman, L. C. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111334 · Cited by 34 · see citing works
Witchel, S. F., & Topaloglu, A. K. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-47912-7.00017-2 · Cited by 40 · see citing works
Diagnostic and therapeutic use of oral micronized progesterone in endocrinology
Memi, E., Pavli, P., Papagianni, M., Vrachnis, N., & Mastorakos, G. P. (2024) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-024-09882-0 · Cited by 38 · see citing works
Sirt1-Deficient Mice Have Hypogonadotropic Hypogonadism due to Defective GnRH Neuronal Migration
Sante, G. D., Wang, L., Wang, C., Jiao, X., Casimiro, M. C., Chen, K., Pestell, T. G., Yaman, İ., Rocco, A. D., Sun, X., et al. (2014) · Molecular Endocrinology · doi:10.1210/me.2014-1228 · Cited by 35 · see citing works
Al-Sayed, Y., & Howard, S. R. (2022) · European Journal of Human Genetics · doi:10.1038/s41431-022-01261-0 · Cited by 34 · see citing works
Functional Consequences ofAXLSequence Variants in Hypogonadotropic Hypogonadism
Salian‐Mehta, S., Xu, M., Knox, A. J., Plummer, L., Slavov, D. B., Taylor, M. R. G., Bevers, S. G., Hodges, R. S., Crowley, W. F., & Wierman, M. E. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3426 · Cited by 33 · see citing works
Self-citationStamou, M. I., Cox, K. H., & Crowley, W. F. (2015) · Endocrine Reviews · doi:10.1210/er.2015-1045.2016.1.test · Cited by 32 · see citing works
Self-citationRecovery of menses after functional hypothalamic amenorrhoea: if, when and why
Pape, J., Herbison, A. E., & Leeners, B. (2020) · Human Reproduction Update · doi:10.1093/humupd/dmaa032 · Cited by 31 · see citing works
Update in Hyper- and Hypogonadotropic Amenorrhea
Santoro, N. F. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1419 · Cited by 31 · see citing works
The Metabolic Syndrome in Central Hypogonadotrophic Hypogonadism
Dwyer, A. A., & Quinton, R. (2018) · Frontiers of hormone research · doi:10.1159/000485998 · Cited by 30 · see citing works
Self-citationLoucks, A. B., Stachenfeld, N. S., & DiPietro, L. (2006) · Springer eBooks · doi:10.1007/978-3-032-05988-8_80 · Cited by 30 · see citing works
Męczekalski, B., Niwczyk, O., Battipaglia, C., Troìa, L., Kostrzak, A., Bala, G., Maciejewska-Jeske, M., Genazzani, A. D., & Luisi, S. V. (2023) · Endocrine · doi:10.1007/s12020-023-03619-w · Cited by 33 · see citing works
Functional hypothalamic amenorrhea: Impact on bone and neuropsychiatric outcomes
Pedreira, C. C., Maya, J., & Misra, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.953180 · Cited by 28 · see citing works
Libri, D. V., Kleinau, G., Vezzoli, V., Busnelli, M., Guizzardi, F., Sinisi, A. A., Pincelli, A. I., Mancini, A., Russo, G., Beck‐Peccoz, P., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2431 · Cited by 28 · see citing works
Role of fibroblast growth factor (FGF) signaling in the neuroendocrine control of human reproduction
Miraoui, H., Dwyer, A. A., & Pitteloud, N. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.05.042 · Cited by 28 · see citing works
Self-citationOtt, J., Robin, G., Hager, M., & Dewailly, D. (2024) · Human Reproduction Update · doi:10.1093/humupd/dmae030 · Cited by 27 · see citing works
Strock, N. C. A., Souza, M. J. D., & Williams, N. I. (2020) · Journal of Sports Sciences · doi:10.1080/02640414.2020.1786297 · Cited by 26 · see citing works
Epigenetics of functional hypothalamic amenorrhea
Fontana, L., Garzia, E., Marfia, G., Galiano, V., & Miozzo, M. R. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.953431 · Cited by 29 · see citing works
Tommiska, J., Jørgensen, N., Christiansen, P., Juul, A., & Raivio, T. (2012) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2012.04493.x · Cited by 26 · see citing works
Choi, J., Balasubramanian, R., Lee, P. H., Shaw, N. D., Hall, J. E., Plummer, L., Buck, C. L., Kottler, M., Jarząbek, K., Wołczyński, S., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2262 · Cited by 26 · see citing works
Self-citationLomniczi, A., Garcia‐Rudaz, C., Ramakrishnan, R., Wilmot, B., Khouangsathiene, S., Ferguson, B. M., Dissen, G. A., & Ojeda, S. R. (2011) · Endocrinology · doi:10.1210/en.2011-1540 · Cited by 26 · see citing works
Neurobiology of puberty and its disorders
Witchel, S. F., & Plant, T. M. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-820683-6.00033-6 · Cited by 23 · see citing works
Genetic architecture of self-limited delayed puberty and congenital hypogonadotropic hypogonadism
Vezzoli, V., Hrvat, F., Goggi, G., Federici, S., Cangiano, B., Quinton, R., Persani, L., & Bonomi, M. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1069741 · Cited by 24 · see citing works
Self-citationDelaney, A., Burkholder, A., Lavender, C. A., Plummer, L., Verónica Mericq, G., Merino, P. M., Quinton, R., Lewis, K. L., Meader, B. N., Albano, A., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa609 · Cited by 24 · see citing works
Self-citationCöster, M., Wittkopf, D., Kreuchwig, A., Kleinau, G., Thor, D., Krause, G., & Schöneberg, T. (2012) · The FASEB Journal · doi:10.1096/fj.12-203737 · Cited by 22 · see citing works
Hietamäki, J., Hero, M. T., Holopainen, E., Känsäkoski, J., Vaaralahti, K., Iivonen, A.-P., Miettinen, P. J., & Raivio, T. (2017) · PLoS ONE · doi:10.1371/journal.pone.0188750 · Cited by 22 · see citing works
Czajkowska, M., Drosdzol-Cop, A. B., Naworska, B., Gałązka, I., Gogola, C., Rutkowska, M., & Skrzypulec‐Plinta, V. (2020) · Ginekologia Polska · doi:10.5603/gp.2020.0097 · Cited by 21 · see citing works
TNFAIP3 Reduction-of-Function Drives Female Infertility and CNS Inflammation
Zammit, N. W., McDowell, J., Warren, J. A., Muskovic, W., Gamble, J., Shi, Y., Kaczorowski, D. C., Chan, C., Powell, J. E., Ormandy, C. J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.811525 · Cited by 20 · see citing works
- Authors
- Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Martin, K. A., Hall, J. E., & Pitteloud, N.
- Affiliations
- Harvard University (US)
- Newcastle University (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2011-01-20
- Volume
- 364
- Issue
- 3
- Pages
- 215-225
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3045842
- OpenAlex
- W2343831581
- Cited by
- 256
- References
- 49
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 15 · 2023: 11 · 2022: 15 · 2021: 17 · 2020: 18 · 2019: 23 · 2018: 13 · 2017: 14 · 2016: 13 · 2015: 15 · 2014: 15 · 2013: 24 · 2012: 26
- FWCI
- 29.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Harvard Catalyst (1UL1RR025758, 1 UL1 RR 025758‐01, UL1-RR025758, UL1 RR025758-01, RR025758, M01RR01066)
- Newcastle University
- National Institutes of Health (UL1RR02575801)
- National Institute on Aging (R01AG013241)
- National Institute of Child Health and Human Development
- National Center for Research Resources (UL1RR025758, M01RR001066, M01-RR01066)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD015788, R01HD043341, 5R01HD42708, R01HD042708, R01HD056264, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- functional hypothalamic amenorrhea, idiopathic hypogonadotropic hypogonadism, GnRH deficiency, genetic susceptibility, FGFR1, PROKR2, GnRH receptor, KAL1, rare variants, loss-of-function mutations, Kallmann syndrome, reproductive axis
- MeSH terms
- Amenorrhea, Female, Humans, Hypogonadism, Hypothalamic Diseases, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Mutation, Nerve Tissue Proteins, Protein Precursors, Receptors, LHRH, Gene Expression, Extracellular Matrix Proteins, Sequence Analysis, DNA, Receptors, Peptide, Genetic Predisposition to Disease, Receptors, G-Protein-Coupled, Receptor, Fibroblast Growth Factor, Type 1
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.
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