title: Aromatase deficiency in a Chinese adult man caused by novel compound heterozygous CYP19A1 mutations: effects of estrogen replacement therapy on the bone, lipid, liver and glucose metabolism.
abstract: OBJECTIVE
  Aromatase deficiency is a rare disorder resulting in estrogen insufficiency in humans. It has been reported in remarkably few men with loss-of-function mutations in the CYP19A1 gene encoding the aromatase, a cytochrome P450 enzyme that plays a crucial role in the biosynthesis of estrogens from androgens. We investigated a non-consanguineous family including an adult man with clinical features of aromatase deficiency, and studied the effects of estrogen replacement in the man.
  
  
  METHODS
  We investigated the clinical and biochemical phenotype, performed CYP19A1 mutational analysis in the family and 50 unrelated persons, studied the effects of CYP19A1 mutations on aromatase protein structure, functionally characterized the mutations by cell-based aromatase activity assays, and studied the effects of estrogen replacement on the bone, lipid, liver and glucose metabolism.
  
  
  RESULTS
  The man with clinical features of aromatase deficiency had novel compound heterozygous CYP19A1 mutations (Y81C and L451P) that were not found in 50 unrelated persons. Three-dimensional modeling predicted that Y81C and L451P mutants disrupted protein structure. Functional studies on the basis of in vitro expression showed that Y81C and L45P mutants significantly decreased the aromatase activity and catalytic efficiency. Estrogen replacement in the man increased bone mineral density, accelerated bone maturation, improved lipid profile and liver steatosis, and improved glucose levels but not insulin resistance.
  
  
  CONCLUSIONS
  We have identified two novel CYP19A1 missense mutations in an aromatase-deficient man. Estrogen replacement in the man shows great impact on recovering the impairments in the bone, lipid, liver and glucose metabolism, but fails to improve insulin resistance.
authors.affiliation: Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
authors.forename: Zhike
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Ou
authors.initials: O
authors.lastname: Wang
authors.affiliation: Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Nie
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Elison
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
authors.forename: Dujin
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Weibo
authors.initials: W
authors.lastname: Xia
authors.affiliation: Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xunwu
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States. Electronic address: schen@coh.org.
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. Electronic address: xingxp2006@126.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xing
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D001141:Aromatase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000627:therapeutic use*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006177:Gynecomastia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007248:Infertility, Male / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary
chemical_list: D004967:Estrogens; D001141:Aromatase; C561410:CYP19A1 protein, human; D005947:Glucose
keywords: Aromatase; Aromatase deficiency; CYP19A1; Estrogen replacement; Insulin resistance; Metabolic syndrome