Mechanism of Action of Anastrozole
Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol by specifically inhibiting the aromatase enzyme in peripheral tissues. 1
Molecular Mechanism
Anastrozole binds reversibly to the heme group of the aromatase enzyme, distinguishing it from steroidal aromatase inhibitors like exemestane that bind irreversibly to the catalytic site. 2
The drug achieves its therapeutic effect by preventing the final step of estrogen biosynthesis in postmenopausal women, where aromatase converts adrenal androgens into estrogens. 1
This mechanism is highly selective—anastrozole significantly lowers serum estradiol concentrations without detectable effects on formation of adrenal corticosteroids, aldosterone, thyroid function, or other steroid hormones. 1
Pharmacodynamic Effects
Anastrozole 1 mg daily reduces estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of continuous dosing. 1
The drug suppresses plasma estrogen levels by 84-94% and inhibits in vivo aromatization by 96-97%. 3
Intratumoral estrogen suppression is equally profound: tissue levels of estradiol, estrone, and estrone sulfate are reduced by 89%, 83.4%, and 72.9% respectively after 15 weeks of treatment. 3
Suppression of serum estradiol is maintained for up to 6 days after cessation of daily dosing. 1
Critical Population Restriction
Anastrozole is only effective in postmenopausal women because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women. 4, 1
In premenopausal women, the ovaries remain the primary source of estrogen production, rendering aromatase inhibition ineffective and potentially harmful. 4
Serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to confirm true postmenopausal status before initiating therapy. 4
Selectivity Profile
Anastrozole demonstrates high selectivity for the aromatase enzyme with no direct progestogenic, androgenic, or estrogenic activity. 1
The drug does not affect cortisol or aldosterone secretion at baseline or in response to ACTH stimulation, eliminating the need for glucocorticoid or mineralocorticoid replacement therapy. 1
No increase in thyroid-stimulating hormone occurs during anastrozole administration. 1
Clinical Implications of Mechanism
By depleting both circulating and intratumoral estrogen levels, anastrozole causes decreased immunoexpression of proliferation markers Ki67 and pS2 in estrogen receptor-positive breast cancers. 3
The profound estrogen suppression explains the drug's superior efficacy in hormone receptor-positive breast cancer but also accounts for its adverse effects on bone metabolism, leading to increased bone resorption and fracture risk. 2
Maximum plasma concentrations occur within 2 hours of oral dosing, with steady-state levels achieved after approximately 7 days of once-daily administration. 1