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 de!ciency in a man of 26 years of age andpresent the results of !ve year follow-up during trandermal estradiol (tE2) substitution, focusing on bonegrowth and mineralization. The lack of patient's compliance to tE2 treatment, resulting in low but detectableserum estradiol levels, provides helpful information about the physiological estradiol needed in serum toguarantee a complete bone maturation and mineralization.Design: Clinical case report study.Methods: Genetic, biochemical and hormonal evaluations and the study of bone health were performedbefore 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 slightlyabove the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compoundheterozygosity due to 23 bp deletion in exon IV and a point mutation in the !rst nucleotide of intron IX of theCYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and boneturnover markers, and the improvement of insulin levels were reached during tE2 only when serum estradiolraised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy.Conclusions: This new case of aromatase de!ciency underlines the role of estrogen on skeletal maturation,BMD, metabolic abnormalities and gonadal axis. It provides evidence on the need not only of a continuousestrogen replacement, but also of ensuring adequate estradiol levels in serum in order to ensure a completebone maturation and mineralization and to prevent the worsening of body skeletal proportions. Thecomprehension of this physiological aspect has relevant clinical signi!cance especially for the developmentof new therapeutic strategies useful to treat growth disorders by targeting serum estradiol in men