There was a time when the classification or sex hormones was simple. Androg
ens were male and estrogens female. What remains true today is that in youn
g adults androgen levels are higher in males and estrogen levels higher in
females. More recently we have learned that estrogens are necessary in male
s for regulation of male sexual behavior, maintenance of the skeleton and t
he cardiovascular system, and for normal function of the testis and prostat
e. The importance of androgen in females was never in doubt, it is after al
l the precursor of estrogen as the substrate for aromatase, the enzyme that
produces estrogen. In addition, the tissue distribution of androgen recept
ors suggests that androgens themselves are important in the ovary, uterus,
breast, and brain.
New information promises to clarify some of the complex issues of the physi
ological roles of estrogen and the contribution of estrogen to the developm
ent of neoplastic diseases in humans. The discovery of the second estrogen
receptor, the creation of mutant mice defective in both estrogen receptors
and in the aromatase gene, the solution of the structures of the ligand-bin
ding domains of estrogen receptor alpha (ER alpha) and estrogen receptor be
ta (ER beta), the finding of novel routes through which estrogen receptors
can modulate transcription, and the identification of a man with a bi-allel
ic disruptive mutation of the ER alpha gene are but some of the milestones.
This review focuses on the mechanistic aspects of signal transduction medi
ated by ERs and on the physiological consequences of deficiency of estrogen
or estrogen receptor in the available mouse models.