Hormone Action

Estrogen

Estrogens are steroid hormones that are primarily synthesized in the ovary and testis and to a lesser extent, in peripheral tissues. The three forms of endogenous estrogens are estradiol, estrone, and estriol. Estrogens have biological effects on mammalian tissues that are essential for many physiological processes to occur. Although estrogens have been traditionally connected with female reproduction, the importance of these hormones in the male reproductive system and non-reproductive processes such as cardiovascular health and bone formation has also been established. In addition, the gastrointestinal tract and the immune system are now considered to be among the "estrogen targets".

Estrogen receptor (ER) molecules are members of the nuclear receptor superfamily, a group made up of ligand-inducible transcription factors that are activated by small lipophilic molecules (i.e. estrogens). Two distinct estrogen receptor molecules exist: the ERa and ERß. Although these receptors share a similar domain structure, they have different localizations and concentrations within the body. Both ER molecules consist of several subdivisions: a growth factor binding domain (AF-1), a ligand-binding domain (AF-2), and a DNA-binding domain (DBD) that binds at estrogen response elements on the chromosome. When complexed with estrogen, the ERa and ERß signal in opposite ways; estrogen appears to inhibit gene transcription when bound to ERß whereas transcription is activated when estrogen is bound to ERa.

Technological advances have allowed for the production of in vitro and transgenic animal models for the purpose of studying the physiological roles of ERa and ERß. In mice with disrupted ERa (aERKO), ERß (ßERKO), or both ERa and ERß, the most significant effects are observed in the reproductive systems of these animals. In particular, male and female aERKO are completely infertile, whereas the ßERKO males are fertile and the fertility of ßERKO females is decreased. Within the female reproductive system, estrogen withdrawal prevents the down-regulation of luteinizing hormone ß (LHß) gene transcription thus increasing serum LH concentrations and disrupting the regulation of gonadotropin production. With respect to male reproduction, both sperm deficiency and dilation of the seminiferous tubules have been observed in aERKO males.

Decreasing estrogen production may also have adverse effects on the cardiovascular system. The vascular cells in postmenopausal women tend to proliferate at a faster rate than those in pre-menopausal women, and this is though to increase the risk of developing atherosclerosis, a vascular disease in which blood vessels become blocked due to plaque build-up. Estrogen may exert a cardio-protective role by inhibiting this cell proliferation in the vascular system.

Lack of estrogen may also accelerate bone loss in postmenopausal women which can lead to the development of osteoporosis. Bone remodeling, the process whereby new bone is formed and existing bone is removed (resorption), is affected by changes in estrogen production. Under normal conditions, osteoclast cells make resorption possible by continuously removing microscopic portions of bone and osteoblast cells fill in the holes by producing new bone. However, estrogen loss enhances the efficiency of osteoclasts leading to a more rapid rate of bone loss than bone formation, and thus more fragile bones.