title: A novel mutation in the human aromatase gene: insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment.
abstract: OBJECTIVE
  Here we report on a new case of human aromatase deficiency in a man of 26 years of age and present the results of five year follow-up during trandermal estradiol (tE2) substitution, focusing on bone growth and mineralization. The lack of patient's compliance to tE2 treatment, resulting in low but detectable serum estradiol levels, provides helpful information about the physiological estradiol needed in serum to guarantee a complete bone maturation and mineralization.
  
  
  METHODS
  Clinical case report study.
  
  
  METHODS
  Genetic, biochemical and hormonal evaluations and the study of bone health were performed before and during estrogen treatment.
  
  
  RESULTS
  Eunuchoid body proportions, unfused epiphyses, tall stature, osteopenia, increase fasting insulin, mild astenozoospermia and a history of right cryptorchidism were present. Baseline serum FSH was slightly above the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compound heterozygosity due to 23 bp deletion in exon IV and a point mutation in the first nucleotide of intron IX of the CYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and bone turnover markers, and the improvement of insulin levels were reached during tE2 only when serum estradiol raised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy.
  
  
  CONCLUSIONS
  This new case of aromatase deficiency underlines the role of estrogen on skeletal maturation, BMD, metabolic abnormalities and gonadal axis. It provides evidence on the need not only of a continuous estrogen replacement, but also of ensuring adequate estradiol levels in serum in order to ensure a complete bone maturation and mineralization and to prevent the worsening of body skeletal proportions. The comprehension of this physiological aspect has relevant clinical significance especially for the development of new therapeutic strategies useful to treat growth disorders by targeting serum estradiol in men.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Lanfranco
authors.forename: Lucia
authors.initials: L
authors.lastname: Zirilli
authors.forename: Matteo
authors.initials: M
authors.lastname: Baldi
authors.forename: Elisa
authors.initials: E
authors.lastname: Pignatti
authors.forename: Ginevra
authors.initials: G
authors.lastname: Corneli
authors.forename: Ezio
authors.initials: E
authors.lastname: Ghigo
authors.forename: Gianluca
authors.initials: G
authors.lastname: Aimaretti
authors.forename: Cesare
authors.initials: C
authors.lastname: Carani
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Rochira
mesh_terms: D000328:Adult; D001141:Aromatase / Q000172:deficiency; D015992:Body Mass Index; D015519:Bone Density; D001847:Bone Diseases / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology*; D004958:Estradiol / Q000097:blood / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000378:metabolism; D005877:Gigantism / Q000175:diagnosis / Q000188:drug therapy; D006579:Heterozygote; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation
chemical_list: D004967:Estrogens; D004958:Estradiol; D001141:Aromatase