title: Use of genetic models of idiopathic hypogonadotrophic hypogonadism in mice and men to understand the mechanisms of disease.
abstract: Mutations in the genes encoding the neuropeptides kisspeptin and neurokinin B, as well as their receptors, are associated with gonadotrophin-releasing hormone (GnRH) deficiency and a failure to initiate and/or progress through puberty. Although the total number of patients studied to date is small, mutations in the kisspeptin pathway appear to result in lifelong GnRH deficiency. Mice with mutations in kisspeptin and the kisspeptin receptor, Kiss1(-/-) and Kiss1r(-/-), respectively, appear to be phenocopies of the human with abnormal sexual maturation and infertility. In contrast, mutations in the neurokinin B pathway lead to a more variable adult reproductive phenotype, with a subset of hypogonadotrophic individuals demonstrating paradoxical recovery of reproductive function later in life. While 'reversal' remains poorly understood, the ability to recover reproductive function indicates that neurokinin B may play different roles in the initiation of sexual maturation compared with the maintenance of adult reproductive function. Mice with mutations in the gene encoding the neurokinin B receptor, Tacr3, have abnormal oestrous cycles and subfertility but, similar to their human counterparts, appear less severely affected than mice with kisspeptin deficiency. Further investigations into the interaction between the kisspeptin and neurokinin B pathways will reveal key insights into how GnRH neuronal modulation occurs at puberty and throughout reproductive life.
authors: Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. sseminara@partners.org.
authors: Margaret F
authors: MF
authors: Lippincott
authors: Cadence
authors: C
authors: True
authors: Stephanie B
authors: SB
authors: Seminara
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000503:physiopathology*; D059648:Kisspeptins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D015287:Neurokinin B / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: C106628:KISS1 protein, human; D059648:Kisspeptins; D007987:Gonadotropin-Releasing Hormone; D015287:Neurokinin B
references: N Engl J Med. 2007 Aug 30;357(9):863-73
references: 17761590
references: Eur J Endocrinol. 2012 Aug;167(2):209-16
references: 22619348
references: J Clin Endocrinol Metab. 2011 Nov;96(11):E1771-81
references: 21880801
references: J Neurosci. 2005 Dec 7;25(49):11349-56
references: 16339030
references: J Comp Neurol. 2005 Aug 29;489(3):372-86
references: 16025449
references: J Mater Sci Mater Med. 2004 Apr;15(4):419-22
references: 15332610
references: J Neurosci. 2010 Feb 24;30(8):3124-32
references: 20181609
references: Horm Res Paediatr. 2010;73(6):477-81
references: 20395662
references: Endocrinology. 2012 Feb;153(2):825-36
references: 22166978
references: J Clin Endocrinol Metab. 2010 May;95(5):2276-80
references: 20237166
references: N Engl J Med. 2003 Oct 23;349(17):1614-27
references: 14573733
references: Endocrinology. 2013 Aug;154(8):2750-60
references: 23744641
references: Brain Res. 2004 Nov 12;1026(2):307-12
references: 15488494
references: Brain Res. 2010 Dec 10;1364:72-80
references: 20816945
references: Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E202-10
references: 21045176
references: Biochem Biophys Res Commun. 2003 Dec 26;312(4):1357-63
references: 14652023
references: Endocrinology. 2010 Sep;151(9):4494-503
references: 20573725
references: J Clin Endocrinol Metab. 2007 Mar;92(3):1137-44
references: 17164310
references: Endocrinology. 2011 Nov;152(11):4265-75
references: 21914775
references: J Physiol. 2004 Dec 1;561(Pt 2):379-86
references: 15486019
references: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2129-34
references: 15684075
references: J Neurosci. 2012 Feb 15;32(7):2388-97
references: 22396413
references: Pharmacol Res. 2004 Dec;50(6):611-5
references: 15501700
references: Nat Genet. 2009 Mar;41(3):354-358
references: 19079066
references: Endocrinology. 2012 Oct;153(10):4894-904
references: 22903614
references: Neuroendocrinology. 2010;92(2):81-99
references: 20606386
references: Neuroendocrinology. 2011;94(3):237-45
references: 21832818
references: Endocrinology. 2012 Mar;153(3):1498-508
references: 22253416
references: Endocrinology. 2012 Jan;153(1):307-15
references: 22109887
references: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10714-9
references: 17563351
references: Front Endocrinol (Lausanne). 2012 Apr 02;3:48
references: 22649420
references: Endocrinology. 2007 Oct;148(10):4927-36
references: 17595229
references: PLoS One. 2011;6(10):e25614
references: 22031817
references: N Engl J Med. 2008 Feb 14;358(7):709-15
references: 18272894
references: Endocrinology. 2006 Jun;147(6):2864-78
references: 16527840
references: Endocrinology. 2012 Oct;153(10):4818-29
references: 22822161
references: Reproduction. 2006 Apr;131(4):623-30
references: 16595713
references: J Neuroendocrinol. 2009 Dec;21(12):1015-23
references: 19840236
references: N Engl J Med. 2012 Feb 16;366(7):629-35
references: 22335740
references: Neuroendocrinology. 2013;97(2):193-202
references: 22377698
references: J Clin Endocrinol Metab. 2010 Jun;95(6):2857-67
references: 20332248
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10972-6
references: 12944565
references: PLoS One. 2013;8(1):e53896
references: 23349759
references: PLoS One. 2012;7(9):e44344
references: 23028524