Anastrozole and letrozole stop the synthesis of estrogens in the same way, but their pharmacokinetics, interactions with other drugs and the depth of estradiol inhibition are different. It is these details that determine which side effects occur and how severe they are. The editors analyze the mechanism of action of the two drugs and systematize their unwanted effects based on clinical research data and official instructions.
Molecular mechanism: how aromatase "turns off"
Aromatase is an enzyme that converts the A ring of androgen into the aromatic ring of estrogen in three successive oxidation reactions. For this, it needs molecular oxygen and NADPH, and the catalytic center is an iron atom in the composition of heme.
Anastrozole and letrozole contain a triazole ring, the nitrogen atom of which is coordinated to the heme iron. At the same time, the rest of the molecule occupies the place where the natural substrate — androstenedione or testosterone — should have gone. Thus, the drug competitively and reversibly blocks the enzyme: as long as the inhibitor molecule is in the active center, aromatization does not occur.
Reversibility means that the effect depends on the constant presence of the drug in the blood. After withdrawal, when the concentration decreases, aromatase gradually resumes its work, and the level of estrogens returns to the original. In this way, non-steroidal inhibitors fundamentally differ from the steroid exemestane, which destroys the enzyme irreversibly.
Letrozole has a higher affinity for aromatase and in studies inhibits whole-body aromatization somewhat more fully: according to Geisler et al. (2002) — about 99% versus about 97% for anastrozole. Plasma estradiol and estrone levels were also lower on letrozole.
Pharmacokinetics and drug interactions
Both drugs are well absorbed when taken orally, and food does not significantly affect overall exposure. The half-life of anastrozole is about 50 hours, letrozole — about two days or more; steady-state concentration is reached within several weeks of daily administration, slightly longer for letrozole.
Metabolic pathways are different. Anastrozole mainly undergoes N-dealkylation, hydroxylation and glucuronidation in the liver; its main metabolites are inactive. Letrozole is metabolized mainly by CYP3A4 and CYP2A6 enzymes to an inactive carbinol metabolite. In addition, letrozole itself inhibits CYP2A6 and moderately CYP2C19, which theoretically can affect the metabolism of other drugs.
Practically significant interaction for both drugs — with tamoxifen and estrogens. Concomitant use of tamoxifen with anastrozole in the ATAC study did not provide an advantage over tamoxifen alone, and tamoxifen decreased plasma concentrations of letrozole. Estrogen-containing drugs, in turn, reduce the effect of aromatase inhibitors.
With severe liver failure, the exposure of letrozole increases significantly, which the instructions take into account separately. For anastrozole, data on severe liver damage are limited.
Consequences of profound estrogen suppression
Virtually all specific side effects of aromatase inhibitors are consequences of estrogen deficiency. Estrogens support bone mineral density, the condition of articular cartilage and synovial membranes, thermoregulation, mood, lipid metabolism, and the condition of mucous membranes.
The most well-known effect is loss of bone mass and increased risk of fractures. In large oncology studies, the incidence of fractures on aromatase inhibitors was higher than on tamoxifen, which, let's remember, partially protects bones. Therefore, densitometry and, if necessary, antiresorptive therapy are recommended for women on long-term therapy.
The second characteristic effect is the so-called musculoskeletal pain syndrome: arthralgia, stiffness, myalgia. It is one of the most frequent reasons for stopping treatment. The mechanism is not fully elucidated, but it is associated precisely with a sharp decrease in estrogens.
Since letrozole reduces estrogens somewhat more deeply, it would be logical to expect more pronounced side effects. However, in a head-to-head FACE comparison, the safety profiles of the two drugs appeared to be very similar, with no clinically significant difference in the main categories.
Side effects: comparative table
The following is a generalization based on guidelines and large studies in postmenopausal women. Frequencies are not reported because they vary significantly between studies and populations.
| Category | Anastrozole | Letrozole |
|---|---|---|
| Hot flashes, sweating | Often | Often |
| Arthralgia, myalgia, stiffness | Common; a frequent reason for discontinuation | Common; a frequent reason for discontinuation |
| Osteopenia, fractures | Increased risk, densitometry required | Increased risk, densitometry required |
| Lipids | Possible increase in cholesterol | Hypercholesterolemia is listed among frequent phenomena |
| Fatigue, headache, sleep disturbance | Possible | Possible |
| Carpal tunnel syndrome, tendinitis | Described | Described |
| Thromboembolism, endometrial cancer | Less often than on tamoxifen | Less often than on tamoxifen |
Among rare but important events, the guidelines mention allergic reactions, increased liver enzymes, mood changes, and depression. In a number of studies on aromatase inhibitors, the rate of cardiovascular events was slightly higher than on tamoxifen, but whether this is harm from the inhibitors or a protective effect of tamoxifen is not conclusively determined.
Practical conclusion for the patient: the vast majority of side effects of the two drugs are the same in nature, so switching one for the other sometimes helps with tolerability, but does not eliminate the problem completely.
Use in men and monitoring
In men, aromatase inhibitors reduce estradiol and, due to the removal of inhibition from the pituitary gland, increase LH and testosterone. However, estradiol performs indispensable functions in the male body. A study by Finkelstein et al. (2013) showed that estradiol deficiency in men is associated with increased fat mass and impaired sexual function even with normal testosterone.
- Bone: One year of anastrozole administration in elderly men reduced bone mineral density (Burnett-Bowie et al., 2009).
- Lipids: Decreased estradiol may worsen the lipid profile, particularly lowering HDL.
- Sexual function and mood: decreased libido, fatigue, depressed mood with excessively low estradiol.
- Joints: Pain and stiffness similar to those described in women.
Control of therapy, if the doctor considers it appropriate, includes estradiol (preferably by a sensitive method), testosterone, LH, lipid panel, and with long-term use - densitometry. The goal is not to maximally reduce estradiol, but to maintain it within physiological limits.
For people using anabolic steroids, the editorial notes that over-suppressing estrogen with a stronger drug like letrozole only adds to the risks already present. Both drugs are banned by WADA (Class S4) at any time.
Editorial conclusions
Anastrozole and letrozole are competitive reversible aromatase inhibitors that bind to the heme of the enzyme. Letrozole inhibits aromatization slightly more fully and has different metabolic pathways and the potential for interactions through CYP2A6 and CYP2C19.
Side effects of both drugs are mostly the consequences of estrogen deficiency: hot flashes, arthralgias, bone loss, lipid changes. In a head-to-head comparison, their safety profiles were found to be similar.
In men, these effects are also real, so reducing estradiol "as a precaution" is harmful, and any use requires medical indications and control.
We also recommend reading "Anastrozole vs Letrozole: What's the Difference", "Anastrozole vs Exemestane: Comparison of Mechanism of Action and Side Effects" and our article on densitometry and bone health in athletes.
References
- Geisler J, Haynes B, Anker G, et al. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002;20(3):751–757.
- Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348(24):2431–2442.
- Smith I, Yardley D, Burris H, et al. Comparative efficacy and safety of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor-positive, node-positive early breast cancer: final results of the randomized phase III FACE trial. J Clin Oncol. 2017;35(10):1041–1048.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341–1352.
- Burnett-Bowie SA, McKay EA, Lee H, Leder BZ. Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab. 2009;94(12):4785–4792.
- Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011–1022.
- U.S. Food and Drug Administration. Prescribing information: Arimidex (anastrozole) tablets; Femara (letrozole) tablets.
