Aromatase Inhibitors

An alternative strategy for achieving antiestrogenic effects is the inhibition of aromatase, the enzyme responsible for the biosynthesis of estradiol and estrone from androgens.18 In principle, this strategy has the advantage over the use of antiestrogens of blocking the two pathways involved in the generation of tumors by the estrogenic hormones, which were discussed in Section 2, namely ER activation and the generation of carcinogenic metabolites (Fig. 3.13).

Aromatase catalyzes the loss of the C-19 methyl group as a formic acid molecule, allowing the creation of the aromatic A ring that is characteristic of estrogens (Fig. 3.14). Aromatase inhibitors are employed for the therapy of breast cancer in postmenopausal women, for whom the primary estrogen source is aromatase activity in adipose tissues in the breast, bone, vascular endothelium, and central nervous system and aromatase levels are not under gonadotropin regulation. In premeno-pausal women, the use of aromatase inhibitors leads to incomplete estrogen suppression and increased gonadal stimulation due to the feedback regulatory mechanism that increases luteinizing hormone and follicle-stimulating hormone after aromatase inhibition (see also Section 3.9). This complication is not observed in postmenopausal women.

Aromatase inhibition, specially by third-generation drugs, results in near-complete estrogen deprivation and for this reason some of the drugs discussed below have improved clinical outcomes over tamoxifen in breast cancer treatment. This difference is probably related to the previously mentioned estrogenic agonistic effects of tamoxifen and to the genotoxicity of the estradiol metabolites, specially its quinones, since aromatase inhibitors prevent the generation of estradiol while antiestrogens do not (Fig. 3.13).20 The combination of aromatase inhibitors

Aromatase inhibitors


Proliferation of mutated cells

Proliferation of mutated cells

Androstenedione Testosterone


Estrone Estradiol



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