CLINICAL DIVERSIFICATION OF AROMATASE INHIBITORS BEYOND ONCOLOGY: SEX-BASED PHYSIOLOGY, BENEFITS, AND ADVERSE EFFECTS

Abstract

Aromatase inhibitors (AIs) are potent endocrine agents that suppress estrogen biosynthesis by inhibiting aromatase, the enzyme catalyzing the conversion of androgens to estrogens. Originally developed for hormone receptor–positive breast cancer in postmenopausal women, their use has expanded to male endocrine disorders, including hypogonadism, infertility, and conditions with altered testosterone–estrogen balance. Due to fundamental differences in hormonal regulation, tissue-specific aromatase expression, and estrogen-dependent physiology, AIs produce distinct systemic responses in males and females. In women, AI-mediated estrogen suppression exerts therapeutic benefit in breast cancer but is associated with adverse skeletal, cardiovascular, metabolic, and neurocognitive effects during long-term therapy. In men, aromatase inhibition enhances gonadotropin secretion and testosterone synthesis; however, prolonged estradiol depletion may impair bone integrity, lipid metabolism, and cardiovascular function. This review synthesizes the pharmacology, clinical benefits, and sex-specific risks of AIs across generations and highlights the need for precision-based dosing and selective aromatase modulation to optimize efficacy while minimizing systemic toxicity in both sexes