Letrozole, sold by Novartis as Femara and as generics, is an oral aromatase inhibitor: a drug that blocks the enzyme that turns androgens into estrogens. The FDA approved it in July 1997. All of its approved uses are in hormone receptor-positive breast cancer in postmenopausal women.
Letrozole is a very potent aromatase inhibitor. At its labeled 2.5 mg dose it blocked more than 99% of whole-body aromatization in a head-to-head study, slightly more than anastrozole at 1 mg. Off-label, it is widely used to induce ovulation in polycystic ovary syndrome, where trials found more live births than with clomiphene. It has also been studied in men with low testosterone, male infertility and short stature. It is also used to lower estradiol during anabolic steroid use, a setting with no controlled trials.
This page summarizes what the FDA label, clinical trials and anti-doping rules report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Nonsteroidal (triazole) aromatase inhibitor |
| Brand / approval | Femara (Novartis), NDA 020726, approved July 25, 1997; generics available |
| Route | Oral tablet, with or without food |
| Strength and labeled dose | 2.5 mg tablet; 2.5 mg once daily (every other day in cirrhosis or severe liver impairment) |
| Half-life (label) | About 2 days; steady state after 2–6 weeks of daily dosing |
| Estrogen suppression (label) | Estradiol, estrone and estrone sulfate down 75–95% within 2–3 days, in postmenopausal women |
| Approved use | Hormone receptor-positive early or advanced breast cancer in postmenopausal women |
| US status | Prescription only; not a controlled substance |
| WADA status | Prohibited at all times (class S4.1, aromatase inhibitors; specified substance) |
What it is
Letrozole’s chemical name is 4,4’-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile: formula C₁₇H₁₁N₅, molecular weight 285.3 g/mol (FDA label; PubChem). It is not a steroid. The label describes it as a competitive inhibitor that binds the heme group of aromatase, a cytochrome P450 enzyme.
Aromatase converts androstenedione to estrone and testosterone to estradiol. After menopause, this conversion of adrenal androgens in tissues outside the ovaries is the main source of estrogen. The label reports that letrozole does not affect cortisol, aldosterone or thyroid hormone production at doses of 0.1–5 mg/day, so no steroid replacement is needed.
The three aromatase inhibitors differ in structure and how they bind the enzyme (half-lives from the Femara, Arimidex and Aromasin labels):
| Drug | Type | Labeled dose | Label half-life | Library page |
|---|---|---|---|---|
| Letrozole | Nonsteroidal, reversible (competitive) | 2.5 mg/day | About 2 days | This page |
| Anastrozole | Nonsteroidal, reversible (competitive) | 1 mg/day | About 50 h | Arimidex (anastrozole) |
| Exemestane | Steroidal, irreversible (“suicide” inhibitor) | 25 mg/day | About 24 h | Aromasin (exemestane) |
Aromatase inhibitors lower estrogen production. Selective estrogen receptor modulators (SERMs) such as tamoxifen and clomiphene instead act at the estrogen receptor and leave estrogen levels unchanged or higher.
How strongly it blocks aromatase
A randomized crossover study gave 12 postmenopausal women with metastatic breast cancer letrozole 2.5 mg/day and anastrozole 1 mg/day for 6 weeks each, and measured whole-body aromatization with isotope tracers (Geisler et al., J Clin Oncol 2002):
| Measure | Letrozole 2.5 mg | Anastrozole 1 mg |
|---|---|---|
| Whole-body aromatization inhibited | Over 99.1% in every patient | 97.3% (mean) |
| Fall in estradiol | 87.8% | 84.9% |
| Fall in estrone | 84.3% | 81.0% |
| Fall in estrone sulfate | 98.0% | 93.5% |
The differences in estrone and estrone sulfate suppression were statistically significant. Whether this small biochemical edge matters clinically was later tested in the FACE trial (see below).
Pharmacokinetics
From the FDA label:
| Parameter | Value |
|---|---|
| Absorption | Rapid and complete; not affected by food |
| Terminal half-life | About 2 days |
| Steady state | Reached in 2–6 weeks; levels 1.5–2 times higher than predicted from a single dose (slight non-linearity), without continued accumulation |
| Protein binding and distribution | Weakly protein bound; volume of distribution ≈1.9 L/kg |
| Metabolism | CYP3A4 and CYP2A6 convert it to an inactive carbinol metabolite |
| Excretion | About 90% of a radiolabeled dose recovered in urine, mostly as the glucuronide of the carbinol metabolite; 6% unchanged |
| Kidney impairment | No effect at creatinine clearance 9–116 mL/min |
| Liver impairment | AUC 37% higher in moderate impairment; about 2× higher in cirrhosis with severe impairment (hence the every-other-day dose) |
Estrogen suppression is fast even though steady state takes weeks: maximal suppression came within 2–3 days in postmenopausal women. The roughly 2-day half-life is close to anastrozole’s and about twice exemestane’s.
Approved medical use
The label approves letrozole 2.5 mg once daily for postmenopausal women with:
- hormone receptor-positive early breast cancer, as adjuvant treatment after surgery;
- early breast cancer after 5 years of adjuvant tamoxifen (“extended adjuvant” treatment);
- hormone receptor-positive or receptor-unknown advanced breast cancer, as first-line treatment;
- advanced breast cancer that has progressed on antiestrogen therapy.
There is no labeled use in men, children or premenopausal women. The label states that safety and effectiveness in children have not been established.
What the research shows
Breast cancer
Letrozole’s approval rests on several large randomized trials:
| Trial | Design | Main result |
|---|---|---|
| P025, first-line advanced disease (label; Mouridsen et al., J Clin Oncol 2003) | 916 women; letrozole 2.5 mg vs tamoxifen 20 mg | Median time to progression 9.4 vs 6.0 months (HR 0.72, 95% CI 0.62–0.83); response rate 32% vs 21%; overall survival not significantly different |
| BIG 1-98, initial adjuvant (Thürlimann et al., NEJM 2005) | 8,010 women; 5 years of letrozole, tamoxifen, or a switch between them | Disease-free survival HR 0.81 (95% CI 0.70–0.93) at a median 25.8 months |
| BIG 1-98, long-term (Ruhstaller et al., J Clin Oncol 2019) | Same trial, median 12.6 years | Disease-free survival HR 0.91 (95% CI 0.81–1.01) for letrozole vs tamoxifen |
| MA.17, extended adjuvant (Goss et al., NEJM 2003) | 5,187 women after 5 years of tamoxifen; letrozole vs placebo | 4-year disease-free survival 93% vs 87%; trial stopped early for benefit |
| MA.17R, extension to 10 years (Goss et al., NEJM 2016) | 1,918 women who had completed about 5 years of an aromatase inhibitor; 5 more years of letrozole vs placebo | 5-year disease-free survival 95% vs 91% (HR 0.66); overall survival 93% vs 94% (HR 0.97) |
A consistent pattern runs through these trials: letrozole reduces recurrence, but overall survival differences have been small or not significant.
Letrozole vs anastrozole (FACE)
FACE randomized 4,136 postmenopausal women with hormone receptor-positive, node-positive early breast cancer to letrozole 2.5 mg or anastrozole 1 mg daily for 5 years (Smith et al., J Clin Oncol 2017):
| Outcome | Letrozole | Anastrozole | Hazard ratio (95% CI) |
|---|---|---|---|
| 5-year disease-free survival | 84.9% | 82.9% | 0.93 (0.80–1.07) |
| 5-year overall survival | 89.9% | 89.2% | 0.98 (0.82–1.17) |
| Joint pain (arthralgia), all grades | 48.2% | 47.9% | — |
Letrozole’s stronger estrogen suppression did not translate into better outcomes or a different side-effect profile. The investigators concluded that it was not superior in either efficacy or safety.
Ovulation induction in polycystic ovary syndrome
This is the most-studied off-label use. In a double-blind NIH trial, 750 women with polycystic ovary syndrome (PCOS) took letrozole (2.5 mg/day, raised to a maximum of 7.5 mg/day, for 5 days per cycle) or clomiphene for up to five cycles (Legro et al., NEJM 2014):
| Outcome | Letrozole | Clomiphene |
|---|---|---|
| Cumulative live births | 27.5% | 19.1% (rate ratio 1.44, 95% CI 1.10–1.87) |
| Ovulation, per treatment cycle | 61.7% | 48.3% |
| Twin pregnancy | 3.4% | 7.4% (not significant) |
| Major congenital anomalies | 4 | 1 (p = 0.65) |
A 2022 Cochrane review of 41 randomized trials (6,522 women) found higher live birth rates with letrozole than with SERMs followed by timed intercourse (OR 1.72, 95% CI 1.40–2.11; high-certainty evidence), with no difference in ovarian hyperstimulation, miscarriage or multiple pregnancy (Franik et al., Cochrane 2022).
Birth-defect concerns were raised early in this use. A retrospective Canadian study of 911 newborns found congenital malformations in 2.4% after letrozole vs 4.8% after clomiphene, with no significant difference in overall major or minor malformations (Tulandi et al., Fertil Steril 2006). In fertility treatment the drug is given only for a few days early in the cycle, before conception. The label still contraindicates letrozole in pregnancy (see below).
Hormones in men
In men, estradiol helps restrain the pituitary’s release of LH (luteinizing hormone). Blocking aromatase removes part of that brake, so LH and testosterone rise. Letrozole does this strongly:
| Study | Men studied | Regimen | Estradiol | Testosterone |
|---|---|---|---|---|
| T’Sjoen et al., JCEM 2005 | 10 young and 10 older healthy men; placebo-controlled crossover | 2.5 mg/day for 28 days | −46% (young); −62% (older) | +146% (young); +99% (older) |
| de Boer et al., Diabetes Obes Metab 2005 | 10 severely obese men with low LH and testosterone; uncontrolled | 7.5–17.5 mg/week for 6 weeks | 120 → 70 pmol/L (≈33 → 19 pg/mL) | 7.5 → 23.8 nmol/L (≈216 → 686 ng/dL) |
| Loves et al., Eur J Endocrinol 2008 | 12 severely obese men with low LH and testosterone; uncontrolled | 2.5 mg once a week for 6 months | 123 → 58 pmol/L (≈34 → 16 pg/mL) | 5.9 → 19.6 nmol/L (≈170 → 565 ng/dL) |
Several findings are relevant to safety:
- Overshoot is easy. Even once a week, free testosterone rose above the normal range in 7 of 12 men in the Loves study. In the de Boer study, men on 17.5 mg/week had an excessive LH response.
- Lipids and IGF-1 moved the wrong way. In the 28-day crossover, LDL cholesterol rose 14% and IGF-1 fell 15% in young men, and apolipoprotein A1 fell 10% in older men (Lapauw et al., Eur J Endocrinol 2009).
- No outcome data. None of these studies measured muscle, strength, bone or cardiovascular outcomes, and none lasted more than 6 months. The de Boer authors noted that clinical significance “remains to be established.”
Longer trials in men used the related drug anastrozole, including a year-long study of bone density. They are summarized on the anastrozole page.
Male infertility
In a multicenter, open-label, assessor-blinded trial, 296 men with severe sperm production failure (73.6% had no sperm in the ejaculate) received letrozole 2.5 mg/day plus vitamins C and E, or vitamins alone, for 3 months (Sun et al., JAMA Netw Open 2026). More men on letrozole moved up at least one WHO sperm-concentration category: 14.3% vs 5.4% (risk difference 9.2%, 95% CI 2.5–15.8%). Individual semen parameters did not differ significantly between groups, and decreased libido was more common with letrozole (12.2% vs 5.4%).
A 2022 meta-analysis of 10 studies (666 men) found that letrozole or anastrozole raised sperm concentration, LH, FSH and testosterone from baseline. Compared with SERMs or hCG, however, aromatase inhibitors did not improve sperm concentration, motility or morphology (Guo et al., Andrology 2022). Male infertility is not a labeled use.
Growth in boys
Because estrogen closes the growth plates in both sexes, letrozole has been tested to extend growth in short boys. Results are mixed, and a safety signal has emerged:
- Constitutional delay of puberty. In a randomized trial of 17 boys on testosterone enanthate, adding letrozole 2.5 mg/day for 12 months gave a higher near-final height than placebo: 175.8 vs 169.1 cm (p = 0.04) (Hero et al., Clin Endocrinol 2006).
- Vertebral changes. In a follow-up MRI study, mild vertebral body deformities were found in 5 of 11 boys (45%) previously treated with letrozole for idiopathic short stature, and in none on placebo (p = 0.01) (Hero et al., J Bone Miner Res 2010).
- Letrozole vs anastrozole. In a 3-year open-label trial in 79 pubertal boys with idiopathic short stature, letrozole produced higher testosterone and lower estradiol and IGF-1 than anastrozole, but no difference in predicted adult height. The combined gain over 3 years was only +1.3 cm (Zegarra et al., J Endocr Soc 2024).
About “letrozole is the strongest AI, so it works best.” Letrozole does suppress aromatase slightly more than anastrozole. But in the only large head-to-head trial (FACE), that did not improve breast cancer outcomes, and in boys it gave no more height gain than anastrozole. In men, stronger suppression mainly means a greater fall in estradiol, with the bone and lipid effects described on this page. No controlled trial has studied letrozole for estrogen control or gynecomastia in men using anabolic steroids.
Side effects and risks
The Femara label has no boxed warning. Its warnings cover bone loss, cholesterol, liver impairment, fatigue and dizziness, and harm to a fetus.
Bone loss and fractures
Lowering estrogen speeds bone loss. From the FDA label:
| Setting | Letrozole | Comparator |
|---|---|---|
| Lumbar spine bone density over 24 months (adjuvant bone study) | −4.1% (median) | +0.3% (tamoxifen) |
| Fractures, BIG 1-98 (median follow-up 96 months) | 14.7% | 11.4% (tamoxifen) |
| Osteoporosis, BIG 1-98 | 5.1% | 2.7% (tamoxifen) |
| Fractures, MA.17 (median follow-up 62 months) | 13.3% | 7.8% (placebo) |
| New osteoporosis, MA.17 | 14.5% | 7.8% (placebo) |
The label advises considering bone density monitoring. In boys, letrozole has been linked to vertebral deformities (see above).
Cholesterol
In BIG 1-98, hypercholesterolemia was reported in 52.3% of women on letrozole vs 28.6% on tamoxifen, and lipid-lowering drugs were needed by 29% vs 20%. The label advises considering cholesterol monitoring.
Common side effects
Rates over a median of 60 months of treatment in BIG 1-98 (2,448 women on letrozole vs 2,447 on tamoxifen) (FDA label):
| Side effect | Letrozole | Tamoxifen |
|---|---|---|
| Hot flashes | 33.5% | 38.0% |
| Joint pain or arthritis | 25.4% | 20.6% |
| Night sweats | 14.5% | 17.4% |
| Weight gain | 12.9% | 15.4% |
| Fatigue | 9.6% | 10.2% |
| Muscle pain (myalgia) | 9.0% | 8.7% |
| Vaginal bleeding | 5.3% | 13.1% |
| Thromboembolic events (any time) | 3.2% | 4.6% |
| Endometrial hyperplasia or cancer (any time) | 0.4% | 2.9% |
| Myocardial infarction (any time) | 1.7% | 1.1% |
The pattern mirrors the other aromatase inhibitors: more joint, bone and cholesterol problems, but fewer blood clots and uterine problems than tamoxifen. Fatigue, dizziness and sleepiness are listed as warnings because they can affect driving. Postmarketing reports include hepatitis and raised liver enzymes, tendon problems (tendonitis, trigger finger, tendon rupture), carpal tunnel syndrome, blurred vision, and rare severe skin and allergic reactions.
Pregnancy and fertility
Letrozole is contraindicated in pregnancy. Postmarketing reports describe miscarriages and birth defects, and in rats and rabbits it caused fetal loss and malformations at doses far below the human dose. The label advises a pregnancy test before starting and effective contraception during treatment and for at least 3 weeks after the last dose, and no breastfeeding during treatment and for 3 weeks after. Based on animal studies, it may impair fertility in both females and males.
Interactions
- Tamoxifen: lowered letrozole levels by 38% on average when given together.
- Cimetidine and warfarin: no clinically significant interaction in label studies.
- CYP enzymes: in liver microsomes letrozole inhibited CYP2A6 and CYP2C19; the clinical significance is unknown.
Who should not use it
The label’s contraindications are pregnancy and known hypersensitivity to letrozole or any tablet ingredient. People with cirrhosis or severe liver impairment have about twice the exposure.
Legal status and use outside medicine
In the US, letrozole is a prescription drug (DailyMed; Drugs@FDA, NDA 020726). It is not listed among the Schedule III anabolic steroids (21 CFR 1308.13).
The 2026 WADA Prohibited List names letrozole under S4.1, aromatase inhibitors. It is prohibited in and out of competition, and S4.1 substances are specified substances (WADA 2026 Prohibited List).
Key takeaways
- A breast cancer drug. Letrozole 2.5 mg once daily is approved only for hormone receptor-positive breast cancer in postmenopausal women.
- The strongest aromatase blocker, but not better in practice. It blocked over 99% of aromatization vs 97% for anastrozole, yet the FACE trial found no difference in survival or side effects.
- Widely used for fertility in women, off-label. In PCOS it produced more live births than clomiphene (27.5% vs 19.1%), and a Cochrane review rated this evidence high certainty.
- Raises testosterone sharply in men. Testosterone rose 99–146% in 28 days in healthy men, and overshoot above the normal range was common. No trial has measured muscle, bone or heart outcomes in men.
- Bone, joints and cholesterol are the main risks. Fractures, osteoporosis and high cholesterol were all more frequent than with tamoxifen or placebo, and some boys treated for short stature developed vertebral deformities.
- Contraindicated in pregnancy and banned in sport. WADA prohibits it at all times under S4.1.
Sources
- Novartis Pharmaceuticals. Femara (letrozole) tablets, prescribing information. DailyMed; Drugs@FDA, NDA 020726.
- ANI Pharmaceuticals. Arimidex (anastrozole) tablets, prescribing information. DailyMed.
- Pfizer. Aromasin (exemestane) tablets, prescribing information. DailyMed.
- National Center for Biotechnology Information. Letrozole, PubChem CID 3902. PubChem.
- Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE. 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. PubMed.
- Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21(11):2101–2109. PubMed.
- 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. PubMed.
- Ruhstaller T, Giobbie-Hurder A, Colleoni M, et al. Adjuvant letrozole and tamoxifen alone or sequentially for postmenopausal women with hormone receptor-positive breast cancer: long-term follow-up of the BIG 1-98 trial. J Clin Oncol. 2019;37(2):105–114. PubMed.
- Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):1793–1802. PubMed.
- Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016;375(3):209–219. PubMed.
- 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. PubMed.
- 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. PubMed.
- Franik S, Le QK, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2022;9(9):CD010287. PubMed.
- Tulandi T, Martin J, Al-Fadhli R, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril. 2006;85(6):1761–1765. PubMed.
- T’Sjoen GG, Giagulli VA, Delva H, et al. Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. J Clin Endocrinol Metab. 2005;90(10):5717–5722. PubMed.
- Lapauw B, T’Sjoen G, Mahmoud A, Kaufman JM, Ruige JB. Short-term aromatase inhibition: effects on glucose metabolism and serum leptin levels in young and elderly men. Eur J Endocrinol. 2009;160(3):397–402. PubMed.
- de Boer H, Verschoor L, Ruinemans-Koerts J, Jansen M. Letrozole normalizes serum testosterone in severely obese men with hypogonadotropic hypogonadism. Diabetes Obes Metab. 2005;7(3):211–215. PubMed.
- Loves S, Ruinemans-Koerts J, de Boer H. Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism. Eur J Endocrinol. 2008;158(5):741–747. PubMed.
- Sun Y, Yao C, Liu G, et al. Letrozole and infertility among males with spermatogenic failure: a randomized clinical trial. JAMA Netw Open. 2026;9(6):e2618422. PubMed.
- Guo B, Li JJ, Ma YL, Zhao YT, Liu JG. Efficacy and safety of letrozole or anastrozole in the treatment of male infertility with low testosterone-estradiol ratio: a meta-analysis and systematic review. Andrology. 2022;10(5):894–909. PubMed.
- Hero M, Wickman S, Dunkel L. Treatment with the aromatase inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of puberty. Clin Endocrinol (Oxf). 2006;64(5):510–513. PubMed.
- Hero M, Toiviainen-Salo S, Wickman S, Mäkitie O, Dunkel L. Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty. J Bone Miner Res. 2010;25(7):1536–1543. PubMed.
- Zegarra W, Ranadive S, Toulan D, Neely EK. Anastrozole vs letrozole to augment height in pubertal males with idiopathic short stature: a 3-year randomized trial. J Endocr Soc. 2024;8(10):bvae141. PubMed.
- US Code of Federal Regulations. 21 CFR 1308.13, Schedule III. eCFR.
- World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. WADA.