Anastrozole and letrozole are commonly referred to as the "twins": both are third-generation non-steroidal aromatase inhibitors, both are taken as a once-daily pill and are used in the treatment of breast cancer. However, there are differences between them in the strength of action, duration of stay in the body and in additional areas of application. The editors explain what exactly distinguishes these drugs and why these differences are important.
What are aromatase inhibitors
Aromatase is an enzyme of the cytochrome P450 family (CYP19A1), which converts androgens into estrogens: testosterone into estradiol, androstenedione into estrone. In postmenopausal women, when the ovaries no longer produce estrogens, it is peripheral aromatization in adipose tissue, muscle, skin, and breast tissue that is the main source of estrogens.
Aromatase inhibitors block this enzyme and reduce the level of estrogens in the blood by an order of magnitude. For hormone-dependent breast cancer, whose cells "feed" on estrogens, this is a key therapeutic mechanism.
Anastrozole and letrozole belong to non-steroidal (type II) inhibitors: they contain a triazole ring that reversibly binds to the heme iron atom of the enzyme. The third drug of this generation is the steroid exemestane, which works in a different way - we write about it in separate materials.
Approved breast-cancer doses in the prescribing information are 1 mg of anastrozole and 2.5 mg of letrozole per day. These doses are chosen to provide near-maximal aromatase inhibition, so a direct milligram-for-milligram comparison does not make practical sense.
| Characteristics | Anastrozole | Letrozole |
|---|---|---|
| Class | Nonsteroidal aromatase inhibitor | Nonsteroidal aromatase inhibitor |
| Binding type | Reversible | Reversible |
| Approved breast-cancer dose | 1 mg/day | 2.5 mg/day |
| Half-life | ≈ 2 days | ≈ 2–4 days |
| Inhibition of aromatization (Geisler et al., 2002) | ≈ 97% | ≈ 99% |
| Additional areas of application | Few | Ovulation induction (outside the instructions in many countries) |
Oncology: Is there a winner
Anastrozole became the first aromatase inhibitor that, in a large ATAC study, convincingly showed advantages over tamoxifen in the adjuvant treatment of breast cancer in postmenopausal women. Letrozole demonstrated a similar benefit in the BIG 1-98 study (Thürlimann et al., 2005). The EBCTCG (2015) individual-level meta-analysis confirmed that aromatase inhibitors as a class reduce the risk of relapse compared to tamoxifen.
Since letrozole suppresses aromatization more strongly, the logical question was: does this translate into better treatment outcomes? The answer came from the FACE study, which directly compared letrozole and anastrozole in women with lymph node involvement. There was no significant difference in disease-free survival between the groups.
Thus, for oncological indications, these drugs are both established options; the absence of a significant difference in FACE does not prove equivalence in every setting. The choice between them is often determined by tolerability, physician experience, availability, and cost. If one drug is poorly tolerated, the oncologist can replace it with another aromatase inhibitor.
Anastrozole has also been studied for prevention: in the IBIS-II trial (Cuzick et al., 2014), it reduced the incidence of breast cancer in high-risk postmenopausal women. This indication is reflected in some clinical guidelines.
Letrozole in reproductive medicine
The most notable practical difference between the two drugs is the use of letrozole to stimulate ovulation. The mechanism is similar to the action of SERMs: a short-term decrease in estrogen "takes off the brakes" from the hypothalamus, FSH increases, and the follicle matures in the ovary.
In a large randomized trial, Legro et al. (2014) in women with polycystic ovary syndrome, letrozole provided a higher live birth rate than clomiphene. After that, a number of professional societies began to consider letrozole as a first-line drug for ovulation induction in PCOS, although in the instructions of many countries such an indication is formally absent.
Anastrozole in this role has been studied much less, so in reproductive medicine these drugs are not equivalent: letrozole has an evidence base, anastrozole lacks a comparable evidence base.
- Ovulation induction schemes are short and carried out under ultrasound control.
- The drug is contraindicated during pregnancy, so the appointment requires careful planning.
- Independent application for the purpose of "stimulation" is dangerous and ineffective without monitoring.
Aromatase inhibitors in men
In men, aromatase converts part of testosterone into estradiol, and estradiol inhibits the pituitary gland. Therefore, aromatase inhibitors can increase the level of LH and testosterone. In a study by Leder et al. (2004) anastrozole in elderly men with low or borderline testosterone increased its level. However, in the subsequent work of the same group (Burnett-Bowie et al., 2009), annual use of anastrozole was accompanied by a decrease in bone mineral density of the spine.
These data illustrate well the main problem: estradiol in men is needed for bone, lipid metabolism, libido and body composition. A study by Finkelstein et al. (2013) showed that some of the effects traditionally attributed to testosterone (fat accumulation, sexual function) are actually dependent on estradiol.
In clinical practice, aromatase inhibitors are used in men outside of the instructions and only in certain situations — for example, in some forms of infertility with a low ratio of testosterone to estradiol. Endocrine Society guidelines do not recommend them as a treatment for hypogonadism.
Letrozole, as a stronger inhibitor, is able to reduce estradiol even more deeply in men, which theoretically increases the risk of the consequences of estrogen deficiency. This is why the notion that "letrozole is just stronger anastrozole and that's fine" is a dangerous oversimplification.
Sport, doping and risks of self-medication
Both drugs are listed in section S4 of the WADA Prohibited List (aromatase inhibitors) and are prohibited at all times. In athletes of any sex, their detection is considered a violation of anti-doping rules, regardless of the purpose of administration, if there is no permission for therapeutic use.
Among anabolic steroid users, aromatase inhibitors are used independently in an attempt to prevent gynecomastia and fluid retention. The editors draw attention to the risk of "overpressing" estradiol: pain in the joints, fatigue, decreased libido, deterioration of the lipid profile and loss of bone mass. This happens especially easily with the stronger letrozole.
Another problem is laboratory diagnostics. Standard immunoassays for estradiol in men can be inaccurate at low concentrations, and more accurate methods (liquid chromatography with mass spectrometry) are not widely available. It is risky to focus on "feelings" or inaccurate analysis.
Finally, on the "gray" market, anastrozole and letrozole are often sold in the form of solutions or tablets without a confirmed composition, which makes any control of the effect impossible.
Editorial conclusions
Anastrozole and letrozole are nonsteroidal reversible aromatase inhibitors with a similar mechanism. Letrozole suppresses aromatization a little more strongly and stays in the body longer, but in oncology, according to the FACE study, it did not demonstrate superior disease-free survival.
The real difference is in reproductive medicine, where letrozole has a high-quality evidence base for ovulation induction in PCOS.
In men, both drugs can increase testosterone, but at the cost of reducing estradiol, which is necessary for bones and metabolism; they are prohibited in sports.
We recommend also reading "Anastrozole vs Letrozole: Comparison of Mechanism of Action and Side Effects", "Anastrozole or Exemestane: What's the Difference" and our material on the role of estradiol in the male body.
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.
- Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):2747–2757.
- 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.
- 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 Femara Versus Anastrozole Clinical Evaluation (FACE) trial. J Clin Oncol. 2017;35(10):1041–1048.
- Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(2):119–129.
- Leder BZ, Rohrer JL, Rubin SD, et al. Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. J Clin Endocrinol Metab. 2004;89(3):1174–1180.
- 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.
- Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014;383(9922):1041–1048.
