Clinical review 78: Aromatase deficiency in women and men: would you have predicted the phenotypes?

T HE PHYSIOLOGICAL roles of estrogens in women include the development of secondary sexual characteristics, follicular maturation, regulation of gonadotropin secretion for ovulation, preparation of tissues for progesterone response, maintenance of bone mass, regulation of lipoprotein synthesis, prevention of urogenital atrophy, and possibly regulation of insulin responsiveness (1). However, the important physiological roles of estrogens in men were largely unanticipated until recently, when estrogen was found to be necessary for fusion of epiphyses and prevention of bone loss (2,3). Estrogen deficiency manifested by sexual infantilism in a 46,Xx individual can be caused by an inherited enzymatic defect. Any of the ovarian steroidogenic enzymes can be affected, but the common feature is absent negative feedback inhibition of estrogen on pituitary gonadotropin secretion. The clinical manifestations are the consequences of both deficient synthesis of estrogen and excessive secretion of precursor steroids that are synthesized before the defective step. Aromatase catalyzes the final reaction of this pathway in the ovary and converts C,, steroids to estrogens (4). It is also expressed in the human placenta, testis, adipose tissue, and brain (4). MacDonald et aI. (5) demonstrated that in men, estrogens are formed primarily by aromatization of plasma precursors in extraglandular sites. It is currently believed that the adipose tissue is the primary site for estrogen production in men (6). There have been several recent reports in the world literature describing aromatase deficiency, following the first description in 1991 of a Japanese newborn girl with an aromatase P450 (P450arom) gene defect (7,8). Until then, aromatase deficiency had been considered incompatible with life, and this dogma may have undermined the efforts of investigators to entertain this diagnosis in suspected cases. It should be noted that Mango et