Recent developments have advanced our knowledge of the role of
estrogen in the male. Studies of the mutations in
CYP19, the gene encoding
aromatase, in six females and two males and a mutant
estrogen receptor alpha in a man are described. These observations provide illuminating new insights into the critical role of
estrogen in the male (as well as female) in the pubertal growth spurt and skeletal maturation, and in the importance of
estrogen sufficiency in the accrual and maintenance of bone mass. The weight of evidence supports 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 growth and skeletal maturation and the accrual of bone mass and density.
Estrogen synthesis by the testis is limited before puberty, and
estrogen deficiency does not affect the age of pubertal onset.
Estrogen deficiency in men leads to hypergonadotropism, macroorchidism, and increased
testosterone levels.
Estrogen lack has a significant effect on
carbohydrate and lipid metabolism, and
estrogen resistance was associated with evidence of premature
coronary 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 and
estrogen resistance (alpha) does not seem to affect gender identity or psychosexual development. The clinical repercussions of mutations in
CYP19 on the fetal-placental unit have highlighted the major role of placental
aromatase in the protection of the female fetus from
androgen excess, thus preventing
androgen-induced pseudohermaphrodism and
virilization of the mother. These features are compared with the
virilization that occurs in utero in the female spotted hyena. The novel features of the
aromatase deficiency syndrome in the affected female--in the fetus, during childhood, and at puberty--are discussed, including
virilization at puberty and development of polycystic ovaries. The severity of the syndrome correlates with the severity of impairment of
aromatase formation in expression systems. Finally, the structural consequences of missense mutations in
CYP19 are described in accordance with a model of the structure of human
aromatase.