Estrogen, bone, growth and sex: a sea change in conventional wisdom.

The discovery of a man with a homozygous mutation in the estrogen receptor alpha gene, which results in estrogen-receptor alpha resistance, and of males and females with autosomal recessive mutations in the CYP19 gene encoding aromatase, which leads to a failure to synthesize estrogens, has challenged conventional wisdom about the 'unimportant' role of estrogen in the male. For example, in the male, estrogen (not androgen) derived from direct testicular secretion (approximately 20%) and from extragonadal aromatization of testosterone and androstenedione (approximately 80%), is the critical sex hormone in the pubertal growth spurt, skeletal maturation, accrual of peak bone mass, and the maintenance of bone mass in the adult. Estrogen stimulates chondrogenesis in the epiphyseal growth plate increasing pubertal linear growth. At puberty, estrogen promotes skeletal maturation and the gradual, progressive closure of the epiphyseal growth plate, possibly as a consequence of both estrogen-induced vascular and osteoblastic invasion and the termination of chondrogenesis. In addition, during puberty and into the third decade, estrogen has an anabolic effect on the osteoblast and an apoptotic effect on the osteoclast, increasing bone mineral acquisition in axial and appendicular bone. In the adult, estrogen is important in maintaining the constancy of bone mass through its effects on remodeling and bone turnover. Establishing a role for estrogen does not exclude a direct action of testosterone on bone in the human male (especially on cortical bone), but this action is less characterized than thought in the past and is relatively minor in comparison with the major effect of estrogen in the male.