Journal of Steroid Biochemistry & Molecular Biology 95 (2005) 75–81 Endocrine effects of aromatase inhibitors and inactivators in vivo: Review of data and method limitations  J¨ urgen Geisler * , Per Eystein Lønning Department of Medicine, Section of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway Abstract The so-called “third-generation” aromatase inhibitors/inactivators have become standard first-line endocrine therapy for postmenopausal women in the metastatic setting. In addition, these compounds, administered as monotherapy or in sequence with tamoxifen, are likely to become standard adjuvant therapy in most countries in the near future. In contrast to the SERMs, aromatase inhibitors may be assessed for their biochemical efficacy in vivo either by measuring their ability to suppress plasma and tissue estrogen levels or, alternatively, by measuring their ability to inhibit the conversion of tracer-labelled androstenedione into estrone. While contemporary methods for estrogen measurement (with the exception of estrone sulphate) lack the sensitivity to measure plasma estrogen levels during treatment with the most potent compounds, in vivo aromatase inhibition can be determined with a much better sensitivity. Thus, in a joint program conducted by the Royal Marsden Hospital, London and our team in Bergen, we were able to reveal profound differences between first- and second-generation aromatase inhibitors, causing 50–90% aromatase inhibition, and the three third-generation compounds, causing >98% inhibition of total body aromatization. © 2005 Elsevier Ltd. All rights reserved. Keywords: Aromatase inhibitors; Estrogens; Breast cancer; Anastrozole; Letrozole; Exemestane 1. Introduction The aromatase reaction is the final and limiting step in the synthesis of estrogens in postmenopausal women. As many breast cancer cells are at least partly depending on estrogen stimulation, the first aromatase inhibitor that came into gen- eral clinical practise, aminoglutethimide, was successfully introduced for breast cancer treatment about three decades ago [1]. However, due to its lack of specificity inhibiting several enzymes involved in adrenal steroid synthesis in addi- tion to its aromatase inhibition and side-effects (see [2] for references), much effort has been spent on developing more selective, less toxic and more potent compounds. Thus, sev- eral “second-generation” drugs were developed. In general, these compounds had little effects on enzymes other than the aromatase in vivo; further, they revealed a better toxicity  Presented at the VIIth International Aromatase Conference: AROMATASE 2004, Edinburgh, Scotland, UK, 6–8 September 2004. * Corresponding author. Tel.: +47 55 97 2010; fax: +47 55 97 2046. E-mail address: jurgen.geisler@helse-bergen.no (J. Geisler). profile. However, similar to aminoglutethimide [3], they inhibited in vivo aromatization by 90% or less [4–7] and did not improve clinical outcome when compared to tamoxifen or megestrol acetate as first- or second-line therapy, respec- tively, for metastatic breast cancer (see [8] for references). In contrast, the “third generation” compounds, anas- trozole, exemestane and letrozole, all caused about 98% aromatase inhibition or better [9–12]. Most importantly, clinical studies revealed improved efficacy for these drugs when compared to megestrol as well as tamoxifen but also aminoglutethimide and the second-generation aromatase inhibitor fadrozole in advanced breast cancer [8,13,14]. In addition, results from a neoadjuvant study showed signifi- cant differences in response rates comparing tamoxifen and letrozole in ER-positive, ErbB-1 and/or ErbB-2-positive tumors, favoring the concept of aromatase inhibition [15]. A fourth compound belonging to the triazole class, vorozole that revealed potent estrogen suppression and aromatase inhibition [16,17], was withdrawn by the manufacturer for marketing reasons. Finally, early results from three large phase III studies now suggest anastrozole, exemestane and 0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.04.015