title: Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54.
abstract: The G protein coupled receptor, GPR54, is a key regulator of puberty and reproductive function. Despite its prismatic role, few patients with mutations in GPR54 and the phenotype of hypogonadotropic hypogonadism have been described. This report explores the neuroendocrine, gonadal, placental and obstetric phenotypes of patients with idiopathic hypogonadotropic hypogonadism (IHH) carrying missense (L148S), nonsense (R331X), and nonstop (X399R) mutations in GPR54. A male patient harboring the mutations R331X and X399R demonstrated (1) increased sensitivity to exogenous pulsatile GnRH compared to a cohort of IHH patients undergoing similar therapy and (2) steady increases in testicular volume, spermatogenesis, and fertility while on long-term GnRH therapy. A female patient homozygous for the L148S mutation had (1) intact responses to exogenous GnRH and gonadotropins, (2) multiple conceptions, (3) two uncomplicated pregnancies of healthy children, suggesting grossly intact placental function, (4) spontaneous initiation of uterine contractions, and (5) lactation for several months post-partum. Taken together, these observations help to tease apart the neuroendocrine and gonadal phenotypes of patients bearing mutations in GPR54.
authors.affiliation: Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: J Carl
authors.initials: JC
authors.lastname: Pallais
authors.forename: Yousef
authors.initials: Y
authors.lastname: Bo-Abbas
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
mesh_terms: D000328:Adult; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000097:blood / Q000627:therapeutic use; D006066:Gonads / Q000033:anatomy & histology; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy / Q000235:genetics*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009154:Mutation; D009490:Neurosecretory Systems / Q000033:anatomy & histology; D010375:Pedigree; D010641:Phenotype; D010920:Placenta / Q000033:anatomy & histology; D011247:Pregnancy; D021122:Protein Subunits / Q000097:blood; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000074502:Receptors, Kisspeptin-1; D012741:Sexual Maturation / Q000235:genetics
chemical_list: C118688:KISS1R protein, human; D021122:Protein Subunits; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone