Letrozole Mechanism and Clinical Implications

Estrogen Suppression and Anti-Tumor Effects

The American College of Physicians notes that letrozole markedly suppresses both circulating and intratumoral estrogen levels, causing decreased immunoexpression of proliferation markers in hormone receptor-positive breast cancer 1
Letrozole only works effectively in postmenopausal women because in this population, estrogens are mainly derived from peripheral aromatization of adrenal androgens rather than ovarian production, as supported by the National Institute for Health and Care Excellence 1
The drug blocks aromatase-dependent synthesis of estradiol but cannot adequately suppress ovarian estrogen synthesis in premenopausal women with functioning ovaries, according to the British Medical Journal 2
The British Medical Journal also reports that letrozole causes impaired conversion of androgen to estradiol in the brain and decreased density of dendritic spines on synapses, potentially contributing to cognitive impairment 2

The American College of Physicians states that the profound estrogen suppression accounts for adverse effects on bone metabolism, leading to increased bone resorption and fracture risk 1
Letrozole causes impaired conversion of androgen to estradiol in the brain and decreased density of dendritic spines on synapses, potentially contributing to cognitive impairment, as reported by the British Medical Journal 3

Letrozole is a nonsteroidal aromatase inhibitor that blocks the enzyme responsible for converting androgens to estrogens, according to the National Comprehensive Cancer Network 4, 5
The American College of Clinical Oncology notes that letrozole inhibits aromatase-dependent synthesis of estradiol but leaves androgens unconverted, which means androgen levels may actually increase relative to estrogen 6, 7, 8

The American Society of Clinical Oncology reports that the most common adverse effects of letrozole include hot flashes (38-54% of patients), arthralgia/joint pain (53-69% of patients), myalgia/muscle pain (28-37% of patients), and fatigue (36-45% of patients) 6, 8
The National Comprehensive Cancer Network guidelines state that letrozole may increase the risk of bone-related events, including fractures (14% vs 9% with placebo) and new osteoporosis (11% vs 6% with placebo) 7
The American College of Clinical Oncology notes that letrozole may also increase the risk of cardiovascular events, with a trend toward increased risk 7

The National Comprehensive Cancer Network considers all three selective aromatase inhibitors (anastrozole, letrozole, exemestane) to have similar toxicity profiles, and notes that even exemestane does not cause hirsutism as a recognized adverse effect 4, 5

The American Society of Clinical Oncology notes that aromatase inhibitors demonstrate superior disease-free survival compared to tamoxifen in postmenopausal women with hormone receptor-positive breast cancer, due to their ability to reduce estrogen levels 9