Mechanism of Action of Aromatase Inhibitors
Aromatase inhibitors block the aromatase enzyme, which catalyzes the final step of estrogen biosynthesis by converting androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) in peripheral tissues. 1, 2, 3
Biochemical Mechanism
Aromatase inhibitors suppress estrogen production by inhibiting the cytochrome P450 enzyme complex (aromatase) that converts adrenal androgens to estrogens in peripheral tissues including adipose tissue, muscle, liver, and breast tissue itself. 2, 3, 4
In postmenopausal women, the ovaries no longer produce significant estrogen, so peripheral aromatization of adrenal androgens becomes the primary source of circulating estrogens—this is why AIs are only effective in postmenopausal women. 1, 2
AIs cannot adequately suppress ovarian estrogen synthesis in premenopausal women with functioning ovaries, making them absolutely contraindicated in this population unless combined with ovarian suppression. 1, 2
Two Classes with Distinct Mechanisms
Nonsteroidal Aromatase Inhibitors (Anastrozole, Letrozole)
Nonsteroidal AIs (anastrozole and letrozole) competitively and reversibly bind to the aromatase enzyme, blocking the active site and preventing androgen-to-estrogen conversion. 2, 3, 5
These agents cause profound suppression of both circulating and intratumoral estrogen levels, with letrozole demonstrating superior estrogen suppression compared to anastrozole in direct comparisons. 2, 3
Steroidal Aromatase Inhibitor (Exemestane)
Exemestane is a steroidal AI that binds irreversibly to the aromatase enzyme through mechanism-based inactivation (also called "suicide inhibition"), causing permanent enzyme destruction. 6, 3
The irreversible binding of exemestane offers a distinct mechanism from nonsteroidal agents, which may explain why switching between steroidal and nonsteroidal AIs can be beneficial when patients experience intolerance. 6
Downstream Effects on Hormone Receptor-Positive Breast Cancer
By markedly suppressing estrogen levels, AIs cause decreased immunoexpression of proliferation markers (such as Ki67) in hormone receptor-positive breast cancer tissue, leading to reduced tumor cell proliferation and growth. 2, 7
The profound estrogen suppression deprives estrogen receptor-positive breast cancer cells of the hormonal stimulus required for proliferation and survival. 2, 4
Because androgens remain unconverted when aromatase is blocked, androgen levels may actually increase relative to estrogen during AI therapy. 2
Clinical Implications of the Mechanism
The mechanism explains why AIs demonstrate superior disease-free survival compared to tamoxifen (which blocks estrogen receptors but does not reduce estrogen levels) in postmenopausal women with hormone receptor-positive breast cancer. 1, 3
The profound estrogen suppression also accounts for mechanism-related adverse effects including accelerated bone resorption and increased fracture risk, as estrogen is critical for maintaining bone mineral density. 2, 7, 4
Estrogen suppression in the brain (where aromatase converts androgens to estradiol locally) may contribute to cognitive impairment and decreased density of dendritic spines on synapses. 2
The mechanism also explains reduced rates of endometrial cancer and thromboembolic events compared to tamoxifen, since AIs do not have the estrogen agonist effects on the endometrium and coagulation system that tamoxifen possesses. 8, 1