Aromatase Deficiency and Its Consequences
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New developments have challenged long-held concepts of the role of estrogen in the human male and prenatally in the conceptus, have uncovered widespread effects of estrogen in diverse tissues in the male and female, and have emphasized the role of extraglandular estrogen synthesis and paracrine and intracrine actions. Three illuminating developments are mainly responsible for the challenge to conventional wisdom: (1) description of a man with a homozygous null mutation in the ERα (estrogen receptor α) gene that led to estrogen resistance (ERαR) and the detection of 7 men and an infant boy, and 11 prepubertal or pubertal age females with severe estrogen deficiency as a consequence of a variety of homozygous and compound heterozygous mutations in the CYP19 gene, the gene that encodes aromatase (P450 aromatase), the enzyme responsible for the last and irreversible step in estrogen synthesis from androgens by the gonads and extragonadal tissues, and which has a wide tissue distribution in the human; (2) the concurrent development of mice that lack the gene encoding ERα (αERKO mice) and the gene encoding aromatase (Arko mice); and (3) the discovery of a second widely distributed estrogen receptor ERβ and the development of ERβ knockout mice (βERKO), and later of mice in which the gene encoding each receptor has been disrupted (αβERKO). Estrogen deficiency or resistance in the men led to tall stature without a pubertal growth spurt, eunuchoid proportions, delayed skeletal maturation, and severe osteopenia despite high testosterone levels. In the aromatase-deficient men but not the ERαR man, low-dose E replacement induced within 6–7 months rapid epiphyseal fusion and cessation of growth and by 3 years of E Rx striking improvement in bone mass and repair of the osteoporosis without inducing gynecomastia.