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.
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.
Lanfranco
Fabio
F
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Italy.
Zirilli
Lucia
L
Baldi
Matteo
M
Pignatti
Elisa
E
Corneli
Ginevra
G
Ghigo
Ezio
E
Aimaretti
Gianluca
G
Carani
Cesare
C
Rochira
Vincenzo
V
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
D004967:Estrogens; D004958:Estradiol; D001141:Aromatase