Letrozole

What it is

Letrozole is a small synthetic molecule given as a 2.5 mg film-coated tablet once a day. It is a non-steroidal competitive inhibitor of the aromatase enzyme system, the enzyme that converts adrenal androgens such as androstenedione and testosterone into oestrone and oestradiol. It is absorbed completely from the gut regardless of food, has a terminal half-life of about two days, and is cleared mainly by conversion to an inactive carbinol metabolite whose glucuronide is passed in urine. It is marketed as Femara and is contraindicated in pregnancy.

What the research says

In postmenopausal breast cancer the evidence is strong and quantified. Letrozole cuts recurrence compared with tamoxifen, and the patient-level meta-analysis of 31,920 women put 10-year breast cancer mortality at 12.1% on an aromatase inhibitor against 14.2% on tamoxifen. The cost is bone: fractures at five years 8.2% against 5.5%, offset by fewer endometrial cancers. Extending treatment from five to ten years reduces recurrence further but has never improved overall survival, and a meta-analysis of eight extension trials found no significant survival gain at all. Separately, and entirely off-label, letrozole is one of the most widely used fertility drugs in the world: a Cochrane review of 41 trials rated it high-certainty better than clomiphene for live birth in polycystic ovary syndrome. In unexplained infertility it performed worse than standard therapy.

Evidence grade: Well established.

How it works

Drug class: Non-steroidal aromatase inhibitor (third generation)

After the menopause the ovaries no longer make oestrogen, and nearly all the oestrogen left in the body is made by the enzyme aromatase, which converts androgens from the adrenal glands into oestrone and oestradiol in fat, muscle and tumour tissue. Letrozole competitively blocks that enzyme, so oestrogen levels fall and breast cancers that depend on oestrogen lose their fuel. In a woman whose ovaries still work, the same drop in oestrogen removes the feedback on the pituitary, which releases more follicle-stimulating hormone and prompts a follicle to develop - which is the basis of its off-label use for ovulation induction. (Source 1)

What it is used for

• BIG 1-98 showed five-year disease-free survival of 84.0% on letrozole against 81.4% on tamoxifen, and the patient-level meta-analysis of all the aromatase inhibitor trials showed 10-year breast cancer mortality of 12.1% against 14.2%. The gain is real but modest in absolute terms, and it is bought with more fractures and more raised cholesterol. Evidence: established. (Source 2)
• MA.17 found four-year disease-free survival of 93% on letrozole against 87% on placebo and was stopped early, but deaths were 31 against 42 and overall survival was not significantly different. So the evidence supports fewer recurrences, not longer life. Evidence: established. (Source 3)
• MA.17R raised five-year disease-free survival from 91% to 95% and halved contralateral breast cancers, but five-year overall survival was 93% against 94% - no better. A meta-analysis of eight extension trials found no significant gain in overall or disease-free survival and more arthralgia, myalgia, hot flushes and bone toxicity. Whether the extra five years is worth it is genuinely contested. Evidence: disputed. (Source 4)
• First-line letrozole delayed progression by a median of 41 weeks against 26 weeks for tamoxifen and produced more responses. Survival was not mature in that report, so the demonstrated benefit is on progression and response, not life expectancy. Evidence: established. (Source 5)
• This is probably the most common use of letrozole worldwide and it is off-label everywhere. A Cochrane review of 41 trials in 6,522 women rated the evidence high certainty: letrozole gives more live births than clomiphene, with about ten women treated for one extra live birth, and hyperstimulation, miscarriage and multiple pregnancy rates are no worse. The NICHD PPCOS II trial found live births in 27.5% against 19.1%. Evidence: established. (Source 6)
• Here the evidence goes the other way. In the NICHD AMIGOS trial letrozole gave live birth in 18.7% of cycles against 32.2% with gonadotropin and 23.3% with clomiphene; it was significantly worse than standard therapy. Its only advantage was fewer multiple gestations than gonadotropin. Evidence: not-supported. (Source 7)
• Letrozole is contraindicated in pregnancy. The label records spontaneous abortions and congenital birth defects in post-marketing reports of use during pregnancy, and animal studies showed pregnancy loss and renal and skeletal malformations. This is why ovulation-induction courses are short and timed before conception. Evidence: not-supported. (Source 8)

Interactions

• Tamoxifen (pharmacokinetic study): Taking tamoxifen at the same time lowers letrozole blood levels by around 38% on average. The label notes that giving letrozole straight after a course of tamoxifen does not seem to blunt its effect, but the two are not meant to be taken together. (Source 8)
• Food and meals (pharmacokinetic study): Food does not matter for absorption. Letrozole is completely absorbed from the gut whether or not it is taken with a meal, and the label says the tablet can be taken without regard to meals. (Source 9)
• St John's wort (Hypericum perforatum) (theoretical): Letrozole is broken down in part by the liver enzyme CYP3A4. St John's wort is the best-documented herbal inducer of that enzyme. A 2026 review restates a study in 11 healthy volunteers in which St John's wort raised the clearance of a CYP3A probe drug roughly two- to five-fold depending on dose. Those figures are the review's account of someone else's trial, not a measurement the review made, and the primary trial was not read. Nobody has measured letrozole levels alongside St John's wort, so the concern that it could lower letrozole exposure is mechanistic rather than demonstrated. (Source 10)
• Cimetidine (pharmacokinetic study): A dedicated interaction study found cimetidine had no clinically significant effect on letrozole handling. (Source 8)
• Warfarin (pharmacokinetic study): An interaction study found letrozole had no clinically significant effect on warfarin handling - relevant because the same question comes up for anyone also taking fish oil or vitamin K-rich foods for their anticoagulation. (Source 8)
• Alcohol and anything else that adds to fatigue or dizziness (label): Letrozole itself causes fatigue, dizziness and somnolence often enough that the label warns about operating machinery. No study has measured alcohol plus letrozole; the concern is that the two effects add up. (Source 11)
• Other anticancer drugs (label): The label states there is no clinical experience of letrozole combined with other anticancer agents, so combinations rest on trial data for the specific combination rather than on the label. (Source 8)

Stopping it

• There is no withdrawal syndrome and no taper. The label says the best duration in the adjuvant setting is simply not known, that the median in both adjuvant studies was five years, and that treatment should be stopped at relapse. (Source 12)
• Whether to stop at five years or keep going is the real question, and the trials disagree. MA.17R found more disease-free survival but identical overall survival when letrozole was continued to ten years, and a meta-analysis of eight extension trials found no significant survival or disease-free survival gain at all, with more joint and bone problems. (Source 13)
• A lot of stopping is unplanned. In a multicentre Italian study of 903 women on adjuvant aromatase inhibitor therapy, 26.9% said they did not keep to the intake times, 87% had side effects and musculoskeletal symptoms affected 86.2% - though side effects were the stated reason for non-adherence in only 19.6%. (Source 14)

What goes wrong

In the same trial letrozole caused more skeletal and cardiac events and more raised cholesterol, while tamoxifen caused more clots, endometrial cancer and vaginal bleeding. (Source 2)

• Randomized trial, High certainty.
• Size: 8,010 women.
• Who: postmenopausal women with hormone-receptor-positive early breast cancer.
• How long: median follow-up 25.8 months at this analysis.
• Result: direction of harm reported without rates in this first publication; the label's later 96-month safety table gives bone fractures 14.7% versus 11.4% and hypercholesterolaemia 52.3% versus 28.6%.
• Funding: not stated in the abstract we read.

Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia.

The same patient-level meta-analysis quantified the trade-off: aromatase inhibitors caused fewer endometrial cancers than tamoxifen but about 2.7 percentage points more bone fractures over five years. (Source 15)

• Meta-analysis, High certainty.
• Size: 31,920 postmenopausal women.
• Who: postmenopausal women with oestrogen-receptor-positive early breast cancer.
• How long: 5 years of treatment; fracture risk measured at 5 years, endometrial cancer at 10 years.
• Result: bone fractures 5-year risk 8.2% versus 5.5% (RR 1.42, 95% CI 1.28-1.57); endometrial cancer 10-year incidence 0.4% versus 1.2% (RR 0.33, 0.21-0.51); non-breast-cancer mortality similar.
• Funding: Cancer Research UK and the Medical Research Council, as stated in the abstract.

There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar.

In that extended-therapy trial the typical complaints on letrozole were hot flushes and joint and muscle symptoms, with slightly more new osteoporosis diagnoses but no difference in fractures at that early point. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 5,187 women.
• Who: postmenopausal women after five years of tamoxifen.
• How long: median 2.4 years.
• Result: new osteoporosis in 5.8% on letrozole versus 4.5% on placebo (P=0.07); fracture rates similar; vaginal bleeding less frequent on letrozole.
• Funding: not stated in the abstract we read.

There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar.

The extra five years of letrozole came at a clear cost to bone. (Source 4)

• Randomized trial, High certainty.
• Size: 1,918 women.
• Who: postmenopausal women continuing an aromatase inhibitor beyond five years.
• How long: median follow-up 6.3 years.
• Result: higher incidence of bone pain, bone fractures and new-onset osteoporosis with letrozole; most quality-of-life subscales unchanged.
• Funding: Canadian Cancer Society and others, as stated in the abstract.

Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis.

In the same trial letrozole caused more fatigue and dizziness than clomiphene, and the congenital anomaly numbers were too small to be reassuring or alarming. (Source 16)

• Randomized trial, Moderate certainty.
• Size: 750 women.
• Who: women with polycystic ovary syndrome.
• How long: up to five cycles plus pregnancy follow-up.
• Result: four major congenital anomalies with letrozole versus one with clomiphene (P=0.65); pregnancy loss 31.8% versus 29.1%; twin pregnancy 3.4% versus 7.4%.
• Funding: NICHD and others, as stated in the abstract.

Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness.

The label quantifies the bone harm over nearly eight years: more fractures and more osteoporosis on letrozole than on tamoxifen, and a measured fall in spine bone density. (Source 17)

• Official position, Certainty not rated.
• Size: BIG 1-98 safety population of 2,448 on letrozole and 2,447 on tamoxifen; a separate bone density substudy.
• Who: postmenopausal women on adjuvant endocrine therapy.
• How long: median treatment 60 months, median safety follow-up 96 months.
• Result: bone fractures 14.7% letrozole versus 11.4% tamoxifen; osteoporosis 5.1% versus 2.7%; lumbar spine bone mineral density median fall of 4.1% on letrozole against a median rise of 0.3% on tamoxifen at 24 months (difference 4.4%, P < 0.0001)
• Funding: manufacturer's own label (Novartis)

In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for letrozole and 11.4% for tamoxifen at a median follow-up of 96 months. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen

Raised cholesterol is the commonest laboratory abnormality on letrozole, affecting about half of users. (Source 17)

• Official position, Certainty not rated.
• Size: 2,448 on letrozole, 2,447 on tamoxifen.
• Who: postmenopausal women on adjuvant endocrine therapy.
• How long: median treatment 60 months.
• Result: hypercholesterolaemia in 52.3% on letrozole versus 28.6% on tamoxifen; grade 3-4 in 0.4% versus 0.1%.
• Funding: manufacturer's own label (Novartis)

Limit of this finding: The label contradicts itself on the severe form of this: Section 5.2, quoted here, puts Grade 3-4 hypercholesterolaemia at 0.4% on letrozole and 0.1% on tamoxifen, while Table 1 of the same label gives 11 (0.4%) and 6 (0.2%). The 0.1% against 0.2% mismatch is in the FDA label itself. Either way the severe form is uncommon in both arms; it is the ordinary raised cholesterol, at about half of letrozole users, that the difference is really about.

In the adjuvant trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. Grade 3-4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients.

Joint pain is the symptom people notice most, and the label puts it at about a quarter of users against a fifth on tamoxifen. (Source 18)

• Official position, Certainty not rated.
• Size: 2,448 on letrozole, 2,447 on tamoxifen.
• Who: postmenopausal women on adjuvant endocrine therapy.
• How long: median treatment 60 months, median follow-up 96 months.
• Result: arthralgia or arthritis in 621 (25.4%) on letrozole versus 504 (20.6%) on tamoxifen, Grade 3-4 in 84 (3.4%) versus 50 (2.0%); hot flashes 819 (33.5%) versus 929 (38.0%); hypercholesterolemia 1280 (52.3%) versus 700 (28.6%); any adverse reaction 2309 (94.3%) versus 2212 (90.4%). The four numeric columns are, in order, letrozole Grades 1-4, tamoxifen Grades 1-4, letrozole Grades 3-4, tamoxifen Grades 3-4. The same table reports bone fractures on two separate clocks, which is why the fracture figures are not quoted from it here: 361 (14.7%) versus 280 (11.4%) is the table's footnote 1, counting any fracture at any time after randomisation over a median follow-up of 96 months, while 249 (10.2%) versus 175 (7.2%) is footnote 2, counting only fractures during the median 60 months of treatment plus the 30 days after it stopped. The 96-month figures are the ones quoted, with their period named, under femara-label-warnings.
• Funding: manufacturer's own label (Novartis)

Grades 1-4 Grades 3-4 Femara Tamoxifen Femara Tamoxifen Adverse Reactions N = 2448 N = 2447 N = 2448 N = 2447 n (%) n (%) n (%) n (%) Patients with any adverse reaction 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8) Hypercholesterolemia* 1280 (52.3) 700 (28.6) 11 (0.4) 6 (0.2) Hot flashes* 819 (33.5) 929 (38.0) - - - - Arthralgia/arthritis* 621 (25.4) 504 (20.6) 84 (3.4) 50 (2.0)

In real-world practice almost nine in ten women on an aromatase inhibitor report side effects, most often musculoskeletal, and a quarter do not take it as scheduled. (Source 14)

• Survey study, Low certainty.
• Size: 903 women, median age 63.
• Who: women on adjuvant aromatase inhibitor therapy for at least 12 months at Italian centres.
• How long: at least 12 months of therapy.
• Result: 26.9% said they did not respect intake times; 87% had one or more adverse events; musculoskeletal symptoms in 86.2%; hot flushes 74.5%; tiredness 74.4%; adverse events drove non-adherence in only 19.6%.
• Funding: not stated in the abstract we read.

Most patients (87%) suffered from one or more AEs. The most frequent are musculoskeletal symptoms, which occurred in 86.2% of the patients.

What the evidence supports

As the first five years of adjuvant endocrine therapy, letrozole reduced recurrence compared with tamoxifen, with a 2.6 percentage point higher five-year disease-free survival. (Source 2)

• Randomized trial, High certainty.
• Size: 8,010 women (4,003 letrozole, 4,007 tamoxifen)
• Who: postmenopausal women with hormone-receptor-positive early breast cancer.
• How long: 5 years of planned treatment; median follow-up 25.8 months at this analysis.
• Result: five-year disease-free survival 84.0% versus 81.4% (an absolute difference of 2.6 percentage points); hazard ratio 0.81 (95% CI 0.70 to 0.93; P=0.003); distant recurrence hazard ratio 0.73 (95% CI 0.60 to 0.88; P=0.001)
• Funding: not stated in the abstract we read; BIG 1-98 was run with the manufacturer's support.

After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group and 428 events in the tamoxifen group, with five-year disease-free survival estimates of 84.0 percent and 81.4 percent, respectively.

Pooling all the individual patient data, five years of an aromatase inhibitor instead of five years of tamoxifen lowered 10-year breast cancer mortality by about two percentage points in absolute terms. (Source 15)

• Meta-analysis, High certainty.
• Size: 31,920 postmenopausal women across the randomised trials.
• Who: postmenopausal women with oestrogen-receptor-positive early breast cancer.
• How long: 5 years of treatment with follow-up to 10 years.
• Result: in the comparison of 5 years of an aromatase inhibitor versus 5 years of tamoxifen: 10-year breast cancer mortality 12.1% versus 14.2% (RR 0.85, 95% CI 0.75-0.96; 2p=0.009); recurrence RR 0.64 (95% CI 0.52-0.78) during years 0-1 and 0.80 (0.68-0.93) during years 2-4, and non-significant thereafter.
• Funding: Cancer Research UK and the Medical Research Council, as stated in the abstract.

In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009).

Giving letrozole for five more years after a full course of tamoxifen cut recurrences, with a 6 percentage point higher four-year disease-free survival, but did not improve survival. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 5,187 women.
• Who: postmenopausal women with breast cancer who had completed five years of tamoxifen.
• How long: median follow-up 2.4 years when the trial was stopped early at the first interim analysis.
• Result: four-year disease-free survival 93% versus 87% (an absolute difference of about 6 percentage points; P at most 0.001); 75 versus 132 recurrences or new contralateral cancers; deaths 31 versus 42 (P=0.25 for overall survival)
• Funding: not stated in the abstract we read.

A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival).

In advanced breast cancer, first-line letrozole delayed progression longer than tamoxifen and produced more responses, but survival was not reported. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 907 patients (453 letrozole, 454 tamoxifen)
• Who: postmenopausal women with locally advanced or metastatic breast cancer, receptor positive or unknown.
• How long: to progression.
• Result: median time to progression 41 versus 26 weeks (hazard ratio 0.70, 95% CI 0.60 to 0.82, P=.0001); objective response 30% versus 20% (P=.0006); clinical benefit 49% versus 38% (P=.001)
• Funding: not stated in the abstract we read; conducted by the International Letrozole Breast Cancer Group.

Survival data are currently immature and not reported here.

For ovulation induction in polycystic ovary syndrome - an off-label use - letrozole produced more live births than clomiphene, with ten women needing treatment for one extra live birth, on high-certainty evidence. (Source 6)

• Systematic review, High certainty.
• Size: 41 randomised controlled trials, 6,522 women (11 trials and 2,060 participants for the live birth comparison)
• Who: infertile women with anovulatory polycystic ovary syndrome.
• How long: treatment cycles followed by timed intercourse or insemination.
• Result: live birth OR 1.72 (95% CI 1.40 to 2.11; NNTB = 10); from a 20% live birth rate on a SERM, 27% to 35% on letrozole; clinical pregnancy OR 1.69 (1.45 to 1.98; NNTB = 10)
• Funding: not stated on the page we read.

Live birth rates were higher with letrozole (with or without adjuncts) compared to SERMs followed by timed intercourse (OR 1.72, 95% CI 1.40 to 2.11; I 2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; 11 trials, 2060 participants; high-certainty evidence).

In the same review, ovarian hyperstimulation syndrome was equally rare with letrozole and clomiphene, and miscarriage and multiple pregnancy rates did not differ. (Source 6)

• Systematic review, High certainty.
• Size: 10 trials, 1,848 participants for hyperstimulation; 15 trials for miscarriage; 14 trials, 2,247 participants for multiple pregnancy.
• Who: infertile women with anovulatory polycystic ovary syndrome.
• How long: treatment cycles.
• Result: ovarian hyperstimulation syndrome 0.5% in both arms (risk difference -0.00, 95% CI -0.01 to 0.01); miscarriage per pregnancy 25% versus 24% (OR 0.94, 0.66 to 1.32); multiple pregnancy 2.2% versus 1.6% (OR 0.74, 0.42 to 1.32)
• Funding: not stated on the page we read.

There is high-certainty evidence that OHSS rates are similar with letrozole or SERMs (0.5% in both arms: risk difference (RD) −0.00, 95% CI −0.01 to 0.01; I 2 = 0%; 10 trials, 1848 participants; high-certainty evidence).

The NICHD PPCOS II trial is the single largest randomised comparison: letrozole gave a higher cumulative live birth rate than clomiphene in polycystic ovary syndrome, 27.5% against 19.1%. (Source 16)

• Randomized trial, High certainty.
• Size: 750 women (374 letrozole, 376 clomiphene)
• Who: women aged 18 to 40 with polycystic ovary syndrome by modified Rotterdam criteria, patent tube, partner sperm concentration at least 14 million/mL.
• How long: up to five treatment cycles.
• Result: cumulative live birth 103/374 (27.5%) versus 72/376 (19.1%), P=0.007, rate ratio 1.44 (95% CI 1.10 to 1.87) - an absolute difference of 8.4 percentage points; cumulative ovulation 61.7% versus 48.3% of cycles (P<0.001)
• Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development and others, as stated in the abstract.

Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65).

What the evidence does not support

A meta-analysis of eight randomised trials of extending aromatase inhibitor therapy found no statistically significant gain in overall or disease-free survival, and more side effects. (Source 13)

• Meta-analysis, Low certainty.
• Size: 8 randomised controlled trials, 17,190 participants.
• Who: postmenopausal women who had already completed about five years of endocrine therapy.
• How long: extension beyond 5 years.
• Result: overall survival OR 1.033 (95% CI 0.925-1.154, P=0.56); disease-free survival OR 1.049 (0.930-1.185, P=0.435); recurrence-free survival OR 1.063 (0.952-1.187, P=0.276); contralateral breast cancer OR 1.094 (0.920-1.301, P=0.311)
• Funding: not stated in the abstract we read.

Limit of this finding: The four results this finding rests on all have confidence intervals that cross 1, so the meta-analysis found no significant difference either way - yet the paper's own conclusion recommends extended aromatase inhibitor use in selected high-risk women. That recommendation is the authors' judgement, not something these numbers show. The published abstract also never states which arm the odds ratios favour and its whole stated method is one sentence, naming no databases, search dates or inclusion criteria, so the direction and the quality of the pooling cannot be checked from it.

Extending the duration of AI did not show any statistically significant advantage in OS with OR of 1.033 (95% CI: 0.925-1.154, P=0.56), DFS OR of 1.049 (95% CI: 0.930-1.185, P=0.435), recurrence-free survival (RFS) OR of 1.063 (95% CI: 0.952-1.187, P=0.276), and contralateral breast cancer (CBC) OR of 1.094 (95% CI: 0.920-1.301, P=0.311).

Where the evidence is mixed

Extending letrozole from five to ten years raised five-year disease-free survival from 91% to 95% but left overall survival unchanged. (Source 4)

• Randomized trial, High certainty.
• Size: 1,918 women.
• Who: postmenopausal women with hormone-receptor-positive breast cancer who had already had about five years of an aromatase inhibitor.
• How long: median follow-up 6.3 years.
• Result: 5-year disease-free survival 95% (95% CI 93-96) versus 91% (89-93), hazard ratio 0.66, P=0.01; 5-year overall survival 93% versus 94%, hazard ratio 0.97, P=0.83; annual contralateral breast cancer 0.21% versus 0.49%.
• Funding: Canadian Cancer Society and others, as stated in the abstract.

The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83).

For unexplained infertility - a different off-label use - letrozole met its primary aim of fewer multiple pregnancies than gonadotropin, but it also produced fewer live births than standard therapy and showed no advantage over clomiphene on either outcome. (Source 7)

• Randomized trial, High certainty.
• Size: 900 women (301 gonadotropin, 300 clomiphene, 299 letrozole)
• Who: ovulatory women aged 18 to 40 with unexplained infertility and at least one patent tube.
• How long: up to four cycles of ovarian stimulation.
• Result: primary outcome, multiple gestation among ongoing pregnancies: 13% (9 of 67) with letrozole versus 32% (34 of 107) with gonadotropin alone (P=0.006), versus 9% (8 of 85) with clomiphene alone (P=0.44); live birth per cycle 32.2% gonadotropin, 23.3% clomiphene, 18.7% letrozole; letrozole pregnancy rates significantly lower than standard therapy (P=0.003) and than gonadotropin alone (P<0.001) but not clomiphene alone (P=0.10); all multiple gestations on clomiphene and letrozole were twins, while gonadotropin produced 24 twin and 10 triplet gestations.
• Funding: National Institutes of Health and others, as stated in the abstract.

After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006).

Where the research disagrees

Whether adjuvant aromatase inhibitor therapy should be extended beyond five years

• MA.17R investigators (Goss and colleagues, 2016), double-blind placebo-controlled randomised trial, 1,918 women, median follow-up 6.3 years: The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Source 4)
• Authors of the meta-analysis of extension trials (2018), meta-analysis of 8 randomised controlled trials, 17,190 participants; the published abstract's entire method is one sentence naming no databases, search dates or inclusion criteria, and it never defines which arm the odds ratios favour: Extending the duration of AI did not show any statistically significant advantage in OS with OR of 1.033 (95% CI: 0.925-1.154, P=0.56), DFS OR of 1.049 (95% CI: 0.930-1.185, P=0.435), recurrence-free survival (RFS) OR of 1.063 (95% CI: 0.952-1.187, P=0.276), and contralateral breast cancer (CBC) OR of 1.094 (95% CI: 0.920-1.301, P=0.311). Higher rates of side-effects of arthralgia, myalgia, hot flushes and bone toxicity was seen among the extended AI group. (Source 13)

How much

• Reference intake: There is no reference intake for a drug; the dose is set by the prescriber. The US label (revised 12/2024) states the recommended dose is one 2.5 mg tablet once daily, taken without regard to meals, and 2.5 mg every other day in cirrhosis or severe hepatic impairment. That is the label's position. (Source 11)
• Upper limit: The label gives no higher dose than 2.5 mg daily; 2.5 mg is both the only strength marketed and the recommended dose, reduced to every other day in cirrhosis or severe hepatic impairment. That is the label's position as of 12/2024. (Source 11)
• Studied: In the first-line advanced breast cancer trial, 453 patients were randomly assigned letrozole 2.5 mg once daily and 454 tamoxifen 20 mg once daily. (Source 5)
• Studied: In BIG 1-98, 8,010 postmenopausal women were randomised to five years of adjuvant endocrine therapy in four arms: letrozole, letrozole then tamoxifen, tamoxifen, or tamoxifen then letrozole. (Source 2)
• Studied: In MA.17, letrozole was given for a planned five years to women who had already completed five years of tamoxifen; 5,187 women were enrolled. (Source 3)
• Studied: In the NICHD PPCOS II fertility trial, 750 women were randomised to letrozole or clomiphene for up to five treatment cycles with visits to determine ovulation and pregnancy. (Source 16)

A common belief, and what the research shows

The belief: That because letrozole beats tamoxifen, more of it for longer must be better - so ten years beats five.

What the research shows: Longer treatment reduces recurrence but has not been shown to make anyone live longer. MA.17R raised five-year disease-free survival from 91% to 95%, and yet "The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83)." Pooling eight extension trials, there was no significant advantage in overall or disease-free survival, and "Higher rates of side-effects of arthralgia, myalgia, hot flushes and bone toxicity was seen among the extended AI group."

Questions and answers

What is it?

Letrozole is a small synthetic tablet-form drug, not a hormone and not a natural substance. It is a non-steroidal aromatase inhibitor: it blocks the enzyme aromatase, which is how the body makes oestrogen after the menopause. It is sold as Femara in a single 2.5 mg strength and is taken once a day. It is also used, off-label, as a fertility tablet. (Source 1)

What does it do in the body?

After the menopause the ovaries have stopped making oestrogen, and almost all the oestrogen left in the body comes from aromatase converting adrenal androgens into oestrone and oestradiol in fat, muscle and the tumour itself. Letrozole blocks that enzyme, so oestrogen levels fall sharply. Breast cancers that need oestrogen to grow are starved. In a premenopausal woman with working ovaries the same oestrogen drop makes the pituitary release more follicle-stimulating hormone, which is why it triggers ovulation. (Source 1)

Is it good or bad for you?

It depends entirely on the setting. In postmenopausal early breast cancer the patient-level meta-analysis of all the trials showed 10-year breast cancer death at 12.1% on an aromatase inhibitor against 14.2% on tamoxifen - a real gain of about two lives per hundred women. The same analysis showed 8.2% against 5.5% bone fractures over five years. For ovulation induction in polycystic ovary syndrome it is better than clomiphene on high-certainty evidence. For unexplained infertility it was worse than gonadotropin. And in pregnancy it is contraindicated. (Source 15)

How do you get more of it?

Letrozole is prescription-only and there is no way to get more of it from food or supplements. Its dose is fixed rather than titrated: the label gives one 2.5 mg tablet once daily, with or without food, halved to every other day in cirrhosis or severe liver impairment. In the breast cancer trials the planned duration was five years. In ovulation induction it is given in short courses timed to the cycle. (Source 11)

If it is harmful, what reduces it?

There is no antidote and nothing speeds its removal; letrozole has a half-life of about two days and is cleared by the liver to an inactive metabolite excreted in urine. Because the drug has to be stopped rather than reversed, the practical questions are about managing its effects: bone density monitoring for the bone loss, cholesterol monitoring for the lipid rise, and management of joint pain. In an Italian cohort, combination management of musculoskeletal symptoms kept more women on treatment than single-measure management. (Source 9)

Why might someone be low in it or missing it?

This question does not apply in the usual sense - nobody is deficient in letrozole. What does happen is that people stop taking a prescribed course. In a multicentre study of 903 women on adjuvant aromatase inhibitor therapy, 26.9% said they did not keep to the intake times, and 87% reported side effects, mostly musculoskeletal. Women also stop because of the bone, joint and vaginal effects documented in the trials. (Source 14)

Which whole foods contain it or feed it?

No food contains letrozole. Food does not change how it is absorbed either: it is rapidly and completely absorbed from the gut whether or not it is taken with a meal. The interaction worth knowing about is in the opposite direction - St John's wort strongly induces the CYP3A4 enzyme that helps clear letrozole, and that is the one supplement with a documented mechanism for lowering drug exposure, although it has never been measured with letrozole. (Source 9)

What happens if you do not have it?

Not taking letrozole when it is indicated means losing the benefit it is prescribed for. In early breast cancer that benefit is quantified: without it, the trials put 10-year breast cancer mortality 2.1 percentage points higher than with it, and five-year disease-free survival 2.6 percentage points lower than with it in the head-to-head trial against tamoxifen. In extended therapy after tamoxifen, going without letrozole meant four-year disease-free survival of 87% instead of 93%, though overall survival was the same. (Source 2)

How can you test for it?

There is no routine blood test for letrozole itself. What is monitored instead is its effects and its risks: the label asks for consideration of bone mineral density monitoring and serum cholesterol monitoring, and a pregnancy test in women of reproductive potential before starting. In fertility use, ovulation and pregnancy are tracked cycle by cycle. In breast cancer, the drug is only prescribed once the tumour has been tested and found hormone-receptor positive. (Source 11)

References

1. DailyMed / Novartis Pharmaceuticals Corporation (US prescribing information, revised 12/2024). FEMARA (letrozole) tablet, film coated - FDA prescribing information (Section 12.1 Mechanism of Action). 2024. Read the source
2. The New England journal of medicine. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.. 2005. PMID 16382061, DOI 10.1056/nejmoa052258. Read the source
3. The New England journal of medicine. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.. 2003. PMID 14551341, DOI 10.1056/nejmoa032312. Read the source
4. The New England journal of medicine. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years.. 2016. PMID 27264120, DOI 10.1056/nejmoa1604700. Read the source
5. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.. 2001. PMID 11352951, DOI 10.1200/jco.2001.19.10.2596. Read the source
6. Cochrane Database of Systematic Reviews. Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome. 2022. DOI 10.1002/14651858.CD010287.pub4. Read the source
7. The New England journal of medicine. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility.. 2015. PMID 26398071, DOI 10.1056/nejmoa1414827. Read the source
8. DailyMed / Novartis Pharmaceuticals Corporation (US prescribing information, revised 12/2024). FEMARA (letrozole) tablet, film coated - FDA prescribing information (Section 7 Drug Interactions). 2024. Read the source
9. DailyMed / Novartis Pharmaceuticals Corporation (US prescribing information, revised 12/2024). FEMARA (letrozole) tablet, film coated - FDA prescribing information (Section 12.3 Pharmacokinetics - absorption and metabolism). 2024. Read the source
10. Current Medicinal Chemistry. Herbal Medicines and Drugs Interactions: Cytochrome P450 Responsibility (full text). 2026. PMID 41764614, DOI 10.2174/0109298673428595251209114801. Read the source
11. DailyMed / Novartis Pharmaceuticals Corporation (US prescribing information, revised 12/2024). FEMARA (letrozole) tablet, film coated - FDA prescribing information (Highlights: Indications, Dosage, Contraindications, Warnings and Precautions). 2024. Read the source
12. DailyMed / Novartis Pharmaceuticals Corporation (US prescribing information, revised 12/2024). FEMARA (letrozole) tablets, US prescribing information - Section 2 DOSAGE AND ADMINISTRATION (2.1 Recommended Dose through 2.3 Use in Extended Adjuvant Treatment). 2024. Read the source
13. Gland surgery. Extended duration of adjuvant aromatase inhibitor in breast cancer: a meta-analysis of randomized controlled trials.. 2018. PMID 30505766, DOI 10.21037/gs.2018.08.03. Read the source
14. The breast journal. Adherence to Aromatase Inhibitor Therapy in Breast Cancer: Insights From a Multicenter Italian Study.. 2025. PMID 41438121, DOI 10.1155/tbj/8976679. Read the source
15. Lancet (London, England). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.. 2015. PMID 26211827, DOI 10.1016/s0140-6736(15)61074-1. Read the source
16. The New England journal of medicine. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.. 2014. PMID 25006718, DOI 10.1056/nejmoa1313517. Read the source
17. DailyMed / Novartis Pharmaceuticals Corporation (US prescribing information, revised 12/2024). FEMARA (letrozole) tablet, film coated - FDA prescribing information (Sections 5.1-5.2 Bone Effects and Cholesterol). 2024. Read the source
18. DailyMed / Novartis Pharmaceuticals Corporation (US prescribing information, revised 12/2024). FEMARA (letrozole) tablet, film coated - FDA prescribing information (Section 6.1 Table 1, adjuvant study monotherapy arms, median follow-up 96 months and median treatment 60 months). The excerpt is deliberately restricted to the column headers and the first four data rows, because the table's superscript markers flatten to bare characters when the page is captured as text and the later rows cannot then be read correctly: the table reports bone fractures twice on two different clocks (footnote 1 "At median follow-up of 96 months (i.e., any time after randomization)" giving 361 (14.7) versus 280 (11.4), and footnote 2 "At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment)" giving 249 (10.2) versus 175 (7.2)), and in the flattened text those two rows are indistinguishable. In the full table "*" marks "Target events pre-specified for analysis" and "**" marks "Events pre-printed on CRF"; footnote 3 is "Excluding women who had undergone hysterectomy before study entry." The 96-month fracture figures are quoted with their follow-up period named under femara-label-warnings.. 2024. Read the source