Selective estrogen receptor modulators

Abstract

It is a remarkable irony that the advent of a new agent designed to prevent the consequences of falling to earth should have had its origin in mankind's desire to voyage free in interplanetary space. It was predicted theoretically, and then confirmed in practice, that spaceflight withdrew from bone the protection supplied by the ceaseless stimulation from those muscles whose push and pull constantly adjust the position of the skeleton in conditions of earth gravity. What had not been anticipated was the degree of calcium loss and, ultimately, osteoporosis that was caused by prolonged weightlessness. In the USA, the National Aeronautical and Space Administration (NASA) investigated, jointly with Baylor University in Houston, the means whereby bone loss might be arrested. In 1984, this group reported that clomiphene citrate, an antiestrogen used in infertility, prevented bone loss in the oophorectomized rat1. However, clomiphene is not a pure compound. It is a mixture of two geometric isomers: enclomiphene which has both estrogen agonistic and antagonistic activities and zuclomiphene which is a pure agonist. The effects of true anti-estrogens were examined by Jordan and colleagues2, who reported that tamoxifen and keoxi-fene (now renamed raloxifene) not only helped to protect bone mineral density in intact rats, but also acted to maintain it in ovariectomized animals. This was a remarkable observation. Since estrogen was known to arrest bone loss in this animal model, an antiestrogen would have been expected to enhance such loss rather than promote gain. It was a defining moment. What was being reported did not accord with our current knowledge and understanding of the antiestrogens, an understanding which would now have to be revised. That revision has now progressed to the clinical advent of an agent, raloxifene, which was recently licensed by the Food and Drug Administration (FDA) for bone loss prevention, in the United States. This development heralds a new chapter for postmenopausal women and their gynecologists, since raloxifene will undoubtedly be only the first in a series of compounds which reproduce the agonistic effects of estrogen on tissues outside the reproductive system which acting as estrogen antagonists on the key sites of breast and endometrium. They are, thus, selective estrogen receptor modulators (SERMs). This class of drugs has an interesting pedigree. Their development proceeded as noted above from careful observation of the activities of certain antiestrogens such as clomiphene and also tamoxifen. Development of SERMs has also coincided with the unravelling of the complexities of the estrogen receptor function which, in the future, should enable heightened tissue selectivity.