Mechanism of Aromatase Inhibitors in Breast Cancer
Core Mechanism of Action
Aromatase inhibitors block the enzyme aromatase, which is responsible for converting adrenal androgens (androstenedione and testosterone) into estrogens (estrone and estradiol) in peripheral tissues of postmenopausal women. 1, 2 This is the principal source of circulating estrogens after menopause, since ovarian estrogen production has ceased. 1, 2
Two Classes of Aromatase Inhibitors
Nonsteroidal (Competitive) Inhibitors:
- Anastrozole and letrozole are selective, reversible competitive inhibitors that bind to the aromatase enzyme active site. 2
- Anastrozole reduces serum estradiol by approximately 70% within 24 hours and 80% after 14 days of daily dosing, with suppression maintained for up to 6 days after cessation. 2
- These agents achieve 85-95% suppression of plasma estrogens at the standard 25 mg daily dose. 1
Steroidal (Irreversible) Inhibitors:
- Exemestane is structurally related to androstenedione and acts as a "false substrate" for aromatase. 1
- It binds irreversibly to the enzyme's active site, causing permanent inactivation through "suicide inhibition." 1
- Exemestane reduces whole body aromatization by 98% in postmenopausal women with breast cancer. 1
- Maximal estrogen suppression occurs 2-3 days after a single dose and persists for 4-5 days. 1
Physiologic Rationale
In postmenopausal women, the aromatase enzyme in peripheral tissues (fat, muscle, liver) and within breast tumor tissue itself converts adrenal androgens to estrogens, which then stimulate hormone receptor-positive breast cancer growth. 1, 2, 3 By blocking this conversion, aromatase inhibitors achieve profound estrogen deprivation that halts tumor progression. 3
Selectivity Profile
- Aromatase inhibitors have no detectable effect on adrenal corticosteroid or aldosterone biosynthesis, eliminating the need for glucocorticoid or mineralocorticoid replacement therapy. 1, 2
- They do not affect other steroidogenic enzymes at therapeutic concentrations. 1
- Anastrozole and exemestane do not affect cortisol or aldosterone secretion at baseline or in response to ACTH stimulation. 1, 2
Critical Limitation: Premenopausal Women
Aromatase inhibitors are absolutely contraindicated in premenopausal women because aromatization of adrenal androgens is not a significant source of estradiol when ovarian function is intact. 2, 4 The ovaries remain the dominant estrogen source in premenopausal women, rendering aromatase inhibitors ineffective and potentially promoting ovarian function recovery. 4
Verification of Menopausal Status
- For women who become amenorrheic after chemotherapy, serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to confirm true postmenopausal status before initiating aromatase inhibitor therapy. 5
- Aromatase inhibitors may paradoxically promote recovery of ovarian function in women with residual ovarian activity, leading to therapeutic failure or unexpected pregnancy. 4
Additional Mechanisms Beyond Estrogen Suppression
Aromatase inhibitors also unmask the inhibitory effect of androgens acting via the androgen receptor (AR), providing a dual mechanism of tumor growth suppression. 6 With estrogen depleted, the remaining androgens can exert anti-proliferative effects through AR signaling. 6
Potential Resistance Mechanisms
- Under profound estrogen deprivation, breast cancer cells may upregulate alternative steroidogenic enzymes that metabolize androgens to estrogen-like steroids (such as 5α-androstane-3β,17β-diol) that can activate estrogen receptors independently of aromatase. 7
- Some resistant tumors develop constitutive ER activation or ER-independent growth signaling pathways. 6