title: Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women.
abstract: Women harbouring inactivating mutations in luteinizing hormone (LH) beta subunit (LHB) or LH receptor (LHCGR) genes have similar clinical manifestations characterized by female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligo-amenorrhea and infertility. Oestradiol and progesterone levels are normal for the early to midfollicular phase, but do not reach ovulatory or luteal phase levels, confirming lack of ovulation. Notably, serum LH levels are low in patients with LHB mutations and high in those with LHCGR mutations, whereas follicle-stimulating hormone levels are normal or only slightly increased. Pelvic ultrasound has demonstrated a small or normal uterus and normal or enlarged ovaries with cysts. Women with LHB mutations may be treated with hCG (human chorionic gonadotropin) or LH, whereas those with mutations in LHCGR are resistant. Lhb and Lhcgr knockout female mice are close phenocopies of the respective human mutations, and confirm that early follicular development, low levels of oestrogen production and theca cell development are independent of LH action, which is necessary for ovulation. Although inactivating mutations in LHB and LHCGR are rare in comparison to other genetic and non-genetic causes of hypogonadism, they should be considered in the differential diagnosis of oligo-amenorrhea and infertility.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, LIM/42, Divisão de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. iarnhold@usp.br
authors.forename: Ivo Jorge
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Adriana
authors.initials: A
authors.lastname: Lofrano-Porto
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D000568:Amenorrhea / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D006063:Chorionic Gonadotropin / Q000627:therapeutic use; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D007247:Infertility, Female / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics* / Q000627:therapeutic use; D008597:Menstrual Cycle / Q000097:blood / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011974:Receptors, LH / Q000235:genetics* / Q000378:metabolism
chemical_list: D006063:Chorionic Gonadotropin; D037101:Luteinizing Hormone, beta Subunit; D011974:Receptors, LH