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, oligoand 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 receptormediated 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. Clomiphene citrate, the first clinically available antiestrogen, was approved by the U.S. Food and Drug Administration (FDA) in 1967 and used for ovulation induction as well as for treatment of endocrine-dependent breast cancer. In the mid-1970s, tamoxifen gained approval for use in the United States as a treatment for breast cancer and later, toremiphene, a close cousin. Raloxifene is used for treatment of osteopenia and osteoporosis and is undergoing trial for breast cancer prevention. All four of these medications exert strong estrogen antagonist effects on certain tissues and partial estrogen agonistic activity on others and thus are considered selective ER modulators (SERMs). More recently, pure antiestrogens that lack agonistic properties have been developed and are undergoing extensive clinical testing (2). Investigators first developed the concept of using aromatase inhibitors for treatment of a variety of estrogendependent processes in the 1960s. Later, clinical trials with the first-generation aromatase inhibitor, aminoglutethimide, provided practical proof that aromatase inhibitors could be used for treatment of hormone-dependent breast cancer. Direct clinical comparisons with the antiestrogen, tamoxifen, demonstrated equal efficacy for this indication (3). However, aminoglutethimide produced substantial side effects and toxicity, which diminished its usefulness. Over the last 30 yr, more potent and selective but less toxic aromatase inhibitors evolved (1). The third-generation agents, now approved for use worldwide, are nearly completely selective for the aromatase enzyme, 1,000to 10,000-fold more potent than aminoglutethimide, and much better tolerated. These new inhibitors comprise two categories with respect to mechanism of action: 1) the competitive inhibitors that bind to the active site of the aromatase enzyme and block estradiol formation, and 2) the inactivators that are modified by the catalytic effects of aromatase to form reactive compounds that bind covalently to the active site of the enzyme and irreversibly destroy its enzymatic action. The latter are called suicide or mechanism-based inactivators. The FDA has now approved three third-generation aromatase inhibitors for use in the United States: the competitive inhibitors anastrozole and letrozole and the inactivator exemestane. During the process of sequential development and testing in breast cancer patients, the second-generation (i.e. fadrozole, 4-hydroxy androstenedione) inhibitors demonstrated equal but not superior clinical efficacy when compared with the antiestrogens (1). Consequently, it came as a surprise to investigators in the field that third-generation aromatase inhibitors appear to be superior to tamoxifen for treatment of advanced hormone-dependent breast cancer (4–11). Preliminary evidence also suggests superiority in the adjuvant and neoadjuvant setting for breast cancer prevention and perhaps also for ovulatory dysfunction in infertile women (12–14). Direct head-to-head studies of tamoxifen and the thirdgeneration aromatase inhibitors provided substantial power for assessing relative efficacy. Five recent trials compared tamoxifen with a third-generation aromatase inhibitor as the first hormonal treatment of recurrent or advanced breast cancer (Table 1; Refs. 6–8, 10). Each comprised a large multicenter study with randomization of patients and use of double-blind methodology. The largest trial, involving 907 women, compared the third-generation inhibitor, letrozole, with tamoxifen (7). Planned study end points included clinical benefit (defined as complete objective regression, partial Abbreviations: ATAC, Arimidex, tamoxifen, alone or in combination; ER, estrogen receptor; SERM, selective ER modulators. 0013-7227/02/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 87(7):3007–3012 Printed in U.S.A. Copyright © 2002 by The Endocrine Society
