To Block Estrogen's Synthesis or Action: That Is the Question

Several disorders in patients require estradiol to produce clinical manifestations, and abrogation of the effects of this sex steroid ameliorates the related signs or symptoms. Included in this list are hyperplasia and neoplasia of the breast and endometrium as well as gynecomastia, premature thelarche, precocious and delayed puberty, mastodynia, oligo- and anovulation, leiomyomata uteri, and endometriosis. Two separate treatment strategies, available for at least three decades, can reduce the target organ effects of estrogen. One is designed to block estrogen action with antiestrogens that bind to the estrogen receptor and interfere with receptor-mediated transcriptional events. The other uses aromatase inhibitors to block the rate-limiting step in synthesis of estradiol involving the conversion of androgens to estrogens (1). Aromatase inhibitors lower the concentrations of estradiol in plasma and tissue and reduce the amount of estrogen available to stimulate estrogen receptor (ER)-mediated transcription. The major question is whether one strategy is superior to the other. Very recent evidence suggests the superiority of aromatase inhibitors over the anti-estrogens for certain indications. This article will review the background surrounding this issue, outline the evidence available, and discuss the potential mechanistic basis for the favorable effects of the aromatase inhibitors.