Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Mini Review Horm Res 2009;71:75–82 DOI: 10.1159/000183895 Inactivating Mutations of Luteinizing Hormone -Subunit or Luteinizing Hormone Receptor Cause Oligo-Amenorrhea and Infertility in Women Ivo Jorge Arnhold a Adriana Lofrano-Porto b Ana Claudia Latronico a a 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, and b Unidade de Endocrinologia, Hospital Universitário de Brasília, Faculdade de Medicina da Universidade de Brasília, Brasília, Brazil 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. Copyright © 2009 S. Karger AG, Basel Introduction Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are pituitary gonadotropins directly in- volved in the integrated series of events that regulate nor- mal sexual maturation and fertility. They belong to the family of glycoprotein hormones, which also includes thyroid-stimulating hormone and human chorionic go- nadotropin (hCG) [1]. These hormones are heterodimers composed of a common -subunit and a specific -sub- unit, each encoded by a separate gene [2]. The human LH -subunit gene (LHB) is located within a cluster of 7 highly homologous sequences in chromosome 19q13.3, including 5 non-coding pseudogenes [2]. It encodes a peptide that contains 121 amino acids, which is 82% ho- mologous to -hCG. Both LH and hCG bind to the same G-protein-coupled receptor, characterized by 7 trans- membrane domains with a long extracellular length [1] . Key Words Luteinizing hormone  Amenorrhea  Hypogonadism  Infertility  Puberty 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, con- firming 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 dem- onstrated a small or normal uterus and normal or enlarged ovaries with cysts. Women with LHB mutations may be treat- ed with hCG (human chorionic gonadotropin) or LH, where- as 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 follicu- lar development, low levels of oestrogen production and theca cell development are independent of LH action, which Received: May 8, 2008 Accepted after revision: September 9, 2008 Published online: January 8, 2009 HORMONE RESEARCH Dr. Ivo Jorge Arnhold, Laboratório de Hormônios e Genética Molecular – LIM/42 Disciplina de Endocrinologia, Departamento de Clínica Médica, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av. Enéas de Carvalho Aguiar 155 – PAMB – 2º andar – Bloco 6, São Paulo, SP, CEP 05403–900 (Brasil) Tel. +55 11 3069 7512, Fax +55 11 3069 7519, E-Mail iarnhold@usp.br © 2009 S. Karger AG, Basel 0301–0163/09/0712–0075$26.00/0 Accessible online at: www.karger.com/hre