Commentary - Estrogen consequences and implications of human mutations in synthesis and action

Recent developments have advanced our knowledge of the role of estrogen in the male. Studies of the mutations in CYP19, the gene encoding aromatase, i n six females and two males and a mutant estrogen receptor a in a man are d escribed. These observations provide illuminating new insights into the cri tical role of estrogen in the male (as well as female) in the pubertal grow th spurt and skeletal maturation, and in the importance of estrogen suffici ency in the accrual and maintenance of bone mass. The weight of evidence su pports an effect of androgens on the latter processes, but this effect has not been quantitated. There is a discordance in the estrogen-deficient male between skeletal grow th and skeletal maturation and the accrual of bone mass and density. Estrog en synthesis by the testis is limited before puberty, and estrogen deficien cy does not affect the age of pubertal onset. Estrogen deficiency in men le ads to hypergonadotropism, macroorchidism, and increased testosterone level s. Estrogen lack has a significant effect on carbohydrate and Lipid metabol ism, and estrogen resistance was associated with evidence of premature coro nary atherosclerosis in a man. These observations have highlighted the role of extraglandular estrogen synthesis and intracrine and paracrine actions. In the human, in contrast to nonprimate vertebrates, aromatase deficiency a nd estrogen resistance (Lu) does not seem to affect gender identity or psyc hosexual development. The clinical repercussions of mutations in CYP19 on t he fetal-placental unit have highlighted the major role of placental aromat ase in the protection of the female fetus from androgen excess, thus preven ting androgen-induced pseudohermaphrodism and virilization of the mother. T hese features are compared with the virilization that occurs in utero in th e female spotted hyena. The novel features of the aromatase deficiency syndrome in the affected fem ale-in the fetus, during childhood, and at puberty-are discussed, including virilization at puberty and development of polycystic ovaries. The severit y of the syndrome correlates with the severity of impairment of aromatase f ormation in expression systems. Finally, the structural consequences of missense mutations in CYP19 are des cribed in accordance with a model of the structure of human aromatase.