Human prepubertal aromatase deficiency: Physiological and pathophysiological lessons learned from this experiment of nature.

BELGOROSKY, A; RIVAROLA MA.,

Endocrinología Molecular

Treballs de la Societat Catala

Año: 2005 vol. 56 p. 147 - 158

0212-3037

HUMAN PREPUBERTAL AROMATASE DEFICIENCY: PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL LESSONS LEARNED FROM THIS EXPERIMENT OF NATURE Alicia Belgorosky, MD and Marco A. Rivarola Research Laboratory Hospital de Pediatria Garrahan Buenos Aires, Argentina Address correspondence to: A.      Belgorosky, MD Research Laboratory Combate de los Pozos 1881 Buenos Aires, Argentina ABSTRACT Studies of patients with complete cP450arom deficiency have contributed considerably to the analysis of the importance cP450arom activity on sexual differentiation, the pattern of gonadotropin secretion, reproductive capacity, lipid metabolism and insulin sensitivity, as well as growth and skeletal maturation, in the two sexes. In humans, cP450arom appears to be the product of a single gene (CYP19 gene), located in chromosome 15q21.1. The protein coding sequence is contained within 9 exons (exon 2-10). There are multiple untranslated first exons that are involved in tissue-specific expression, but  the protein sequence is conserved in all tissues. In the placenta, the aromatase gene is specifically expressed in syncytiotrophoblasts, and it is under the regulation of a placental-specific enhancer. In this organ, the active aromatization of androgens protects the female fetus and the mother from the virilizing actions of fetal androgens. Indeed, 46, XX neonates with complete aromatase deficiency are born with ambiguous external genitalia. Since 1992 , 11 well documented cases of complete aromatase deficiency secondary to mutations of the CYP19 gene have been reported in 10 families. The pattern of serum hormones is characterized by very low estrogens and high androgens, FSH, and sometimes LH, depending on age and sex. In girls, gonadotropins and androgens are high in newborns and early infants, there is a temporary decrease during childhood, but with serum FSH higher than in normal girls, and a subsequent increase in adolescence and adulthood. In boys, after the newborn period, both serum FSH and LH are normal during infancy and childhood, indicating a sexual dimorphism of the role of estrogens in the regulation of gonadotropins. The study of these patients has been useful to illustrate the essential role of estrogens in skeletal development, epiphysial maturation and in the pubertal growth spurt, in the two sexes. Excessive final height has been reported, particularly in men. These patients are at risk of developing ovarian cysts, even before puberty. Low-dose estrogen treatment has been indicated in prepubertal girls to enhance bone calcification and to prevent cyst formation. However, more experience is necessary to assess the long term effect of estrogens in prepubertal girls. Estrogens have also been used to induce epiphyseal fusion in adult men. Finally, estrogen therapy is clearly indicated to induce sexual development at puberty in girls, as well as to maintain cyclical estrogen stimulation later on.