Letrozole
Brand names: Femara. Also called Femara, aromatase inhibitor, AI.
Aromatase inhibitor (nonsteroidal) 6 graded human studies Last checked
The short answer
From 11 sourcesLetrozole blocks aromatase, the enzyme that makes estrogen from androgens. Its label covers breast cancer after menopause, where it reduced recurrence compared with tamoxifen. Taken for five days early in a cycle, it is also used to trigger ovulation, and in polycystic ovary syndrome it now comes before clomiphene in the international guideline.
Key facts
Which letrozole products are approved, and for what?
Letrozole 2.5 mg tablets (Femara and generics) are FDA-approved prescription drugs for breast cancer in postmenopausal women: adjuvant, extended adjuvant after tamoxifen, and advanced disease. No boxed warning. Use to trigger ovulation is off-label in the United States, as the 2023 PCOS guideline notes it is in many countries.
Status by form
2 forms| Form | Status | Approved for | Boxed warning |
|---|---|---|---|
| Oral tablets 2.5 mgFemara, generics | FDA-approved prescription drug1 | Postmenopausal women with hormone receptor-positive early breast cancer (adjuvant), extended adjuvant treatment after tamoxifen, and advanced breast cancer | None on the current label |
| Ovulation induction (PCOS, unexplained infertility) | Off-label prescribing of the same tablets; not FDA-approved for this use14 | None | Not applicable; the label warns of fetal harm |
What is letrozole and how does it work?
Letrozole binds aromatase and stops it turning androgens into estrogen. After menopause that removes most estrogen, which slows hormone-sensitive breast cancer. Lower estradiol also weakens its brake on the pituitary, so FSH rises. In women who do not ovulate, a five-day course early in the menstrual cycle is used to bring on ovulation.
How it works
Aromatase inhibitor (nonsteroidal)Letrozole is a nonsteroidal inhibitor of aromatase, the enzyme that converts androgens into estrogens, so after menopause most estrogen disappears. Less estradiol weakens its negative feedback on the hypothalamus and pituitary, and FSH rises, as reviews of aromatase inhibitors describe. A five-day course early in the cycle is used to bring on ovulation.1115
What doses are on the label and in studies?
For breast cancer the label dose is 2.5 mg once daily, with or without food, or every other day with cirrhosis or severe liver impairment. In the PPCOS II fertility trial, letrozole started at 2.5 mg daily from cycle day 3 for 5 days and rose to at most 7.5 mg daily in women who did not ovulate.
Label and study amounts, not a dose for you. A prescriber decides whether and how much; these show what the labels print and what trials used.
Doses by use
3 rows| Use | Form | Amount and schedule | Basis |
|---|---|---|---|
| Breast cancer (adjuvant, extended adjuvant, advanced) | Tablets | 2.5 mg once daily, with or without food; adjuvant treatment ran a median 5 years1 | Label |
| Breast cancer with cirrhosis or severe liver impairment | Tablets | 2.5 mg every other day1 | Label |
| Ovulation induction in women with PCOS | Tablets | 2.5 mg daily from cycle day 3 for 5 days, raised in later cycles to a maximum of 7.5 mg daily if ovulation did not occur, for up to five cycles5 | Study |
What is letrozole combined with?
In breast cancer letrozole follows tamoxifen or replaces it: tamoxifen lowered letrozole levels by 38% when taken together. For ovulation it is used with timed intercourse or insemination, and the 2023 PCOS guideline places it before clomiphene and before gonadotropin injections, which carry far more multiple pregnancies.
Letrozole and tamoxifen
Both are breast cancer endocrine treatments.
Taken together, tamoxifen lowered letrozole levels by 38%, while letrozole given straight after tamoxifen kept its effect. In MA.17, five years of letrozole after five years of tamoxifen improved four-year disease-free survival to 93% from 87% on placebo.13
Letrozole or clomiphene, for ovulation
Both are five-day oral courses that trigger ovulation.
The 2023 international PCOS guideline recommends letrozole as the first-line drug and over clomiphene. A 2022 Cochrane review of 41 trials found higher live birth with letrozole (OR 1.72), similar hyperstimulation (0.5% in both) and similar multiple pregnancy (1.6% vs 2.2%).46
Letrozole and gonadotropins, in unexplained infertility
Injections are the stronger option when pills fail.
In AMIGOS, live birth per cycle was 18.7% with letrozole, 23.3% with clomiphene and 32.2% with gonadotropins; multiple gestations were 13% (all twins) with letrozole and 32% with gonadotropins, including triplets.7
How does letrozole relate to fertility and pregnancy?
In polycystic ovary syndrome letrozole gave more live births than clomiphene (27.5% vs 19.1%), and a Cochrane review of 41 trials found similar twin and hyperstimulation rates. In 911 newborns, malformation rates did not differ from clomiphene. Its breast cancer label warns of fetal harm, so pregnancy is excluded before each course.
Fertility, pregnancy and breastfeeding
- Pregnancy
- Letrozole can cause fetal harm; the label asks for a pregnancy test and effective contraception, and the PCOS guideline excludes any chance of existing pregnancy before a course.14
- Birth defects after ovulation induction
- In 911 newborns, overall malformation rates were 2.4% after letrozole and 4.8% after clomiphene, with no significant difference; heart anomalies were less frequent after letrozole.8
What gets checked during treatment?
The breast cancer label suggests monitoring bone density and cholesterol and asks for a pregnancy test in women who could become pregnant. In fertility trials ovulation was checked by mid-luteal progesterone, and the dose was increased in the next cycle when it was low. The PCOS guideline excludes any possibility of existing pregnancy first.
Monitoring
4 checks| Check | When | Why |
|---|---|---|
| Bone density | During breast cancer treatment (the label suggests considering it)1 | Lumbar spine density fell a median 4.1% at 24 months vs a rise on tamoxifen |
| Cholesterol | During breast cancer treatment1 | Total cholesterol can rise |
| Pregnancy test | Before treatment in women who could become pregnant14 | Fetal harm on the label |
| Mid-luteal progesterone | Each fertility cycle in PPCOS II5 | To confirm ovulation and raise the dose next cycle if it did not occur |
What does the research show?
In BIG 1-98 (8,010 women) letrozole improved five-year disease-free survival over tamoxifen, and in MA.17 it cut recurrences after five years of tamoxifen. For fertility, PPCOS II and a 41-trial Cochrane review found more live births than with clomiphene; in unexplained infertility, AMIGOS found no advantage.
Every graded row
6 rows from 6 studiesShowing 6 of 6 outcomes. Human trials only.
AGrade ADisease-free survival vs tamoxifen (early breast cancer)Breast cancerImprovedRCT
n 8,010 · 2005
Five-year disease-free survival 84.0% vs 81.4% on tamoxifen (HR 0.81); distant recurrence HR 0.73.
- Design
- RCT, n = 8,010, 2005
- Population
- Postmenopausal women with hormone receptor-positive early breast cancer
- Form
- Tablets
- Dose
- 2.5 mg daily
- Duration
- Median follow-up 25.8 months
- Source
- Reference 2 · PubMed 16382061 (opens PubMed)
AGrade ALive birth vs clomiphene in PCOSFertility (PCOS)ImprovedMeta-analysis · 41 studies
n 6,522 · 2022
Live birth higher than with SERMs (OR 1.72, 95% CI 1.40 to 2.11; high certainty); hyperstimulation 0.5% in both; multiples 1.6% vs 2.2%.
- Design
- Meta-analysis, 41 studies, n = 6,522, 2022
- Population
- Infertile women with PCOS in 41 randomized trials
- Form
- Tablets
- Dose
- Various
- Duration
- Various
- Source
- Reference 6 · PubMed 36165742 (opens PubMed)
AGrade ARecurrence after five years of tamoxifenBreast cancerImprovedRCT
n 5,187 · 2003
Four-year disease-free survival 93% vs 87% on placebo (75 vs 132 recurrences or new cancers).
- Design
- RCT, n = 5,187, 2003
- Population
- Postmenopausal women who had completed five years of tamoxifen
- Form
- Tablets
- Dose
- 2.5 mg daily
- Duration
- Median follow-up 2.4 years
- Source
- Reference 3 · PubMed 14551341 (opens PubMed)
AGrade ALive birth vs clomiphene in PCOSFertility (PCOS)ImprovedRCT
n 750 · 2014
Live birth 27.5% vs 19.1% on clomiphene (rate ratio 1.44); ovulation 61.7% vs 48.3% of cycles.
- Design
- RCT, n = 750, 2014
- Population
- Women 18 to 40 with polycystic ovary syndrome
- Form
- Tablets
- Dose
- 2.5 to 7.5 mg daily, cycle days 3 to 7
- Duration
- Up to 5 cycles
- Source
- Reference 5 · PubMed 25006718 (opens PubMed)
BGrade BLive birth in unexplained infertilityFertility (unexplained)MixedRCT
n 900 · 2015
Live birth per cycle 18.7% on letrozole, not significantly different from clomiphene (23.3%) and lower than gonadotropins (32.2%); multiples 13%, all twins.
- Design
- RCT, n = 900, 2015
- Population
- Ovulatory women 18 to 40 with unexplained infertility
- Form
- Tablets
- Dose
- Up to four stimulation cycles
- Duration
- Up to 4 cycles
- Source
- Reference 7 · PubMed 26398071 (opens PubMed)
CGrade CBirth defects vs clomipheneFertility safetyNo effectObservational
n 911 · 2006
Malformations 2.4% after letrozole vs 4.8% after clomiphene, not significantly different; fewer heart anomalies after letrozole.
- Design
- Observational, n = 911, 2006
- Population
- Newborns conceived after letrozole or clomiphene
- Form
- Tablets
- Dose
- Ovulation induction courses
- Duration
- Birth outcomes
- Source
- Reference 8 · PubMed 16650422 (opens PubMed)
What are the side effects and risks?
In BIG 1-98 the commonest effects were hot flashes, joint pain and arthritis, night sweats and weight gain. Compared with tamoxifen it caused more fractures, osteoporosis and high cholesterol, and less vaginal bleeding. The label also lists fatigue, dizziness and sleepiness, and fetal harm. It is contraindicated in pregnancy and with hypersensitivity.
Regulatory status. Letrozole tablets are FDA-approved prescription drugs for breast cancer in postmenopausal women, with no boxed warning; use to trigger ovulation is off-label.1
Side effects in the BIG 1-98 trial, compared with tamoxifen
From the label; letrozole vs tamoxifenWarnings on the label
- Bone loss
- Lumbar spine density fell a median 4.1% at 24 months on letrozole while it rose on tamoxifen; fractures and osteoporosis were more frequent.1
- Cholesterol
- Total cholesterol can rise; the label suggests monitoring.1
- Fatigue, dizziness and sleepiness
- Reported on the label, with caution advised when operating machinery.1
- Fetal harm
- Letrozole can harm a pregnancy; a pregnancy test and contraception are part of the label.1
Who should not use it (label contraindications)
Pregnancy; hypersensitivity to letrozole or its ingredients.1
What does letrozole interact with?
The label lists tamoxifen, which lowered letrozole levels by 38% when the two were taken together; giving letrozole straight after tamoxifen did not reduce its effect. Interaction studies with cimetidine and warfarin showed no clinically meaningful change. For ovulation it is taken for only five days a cycle, alongside timed intercourse or insemination.
Interactions
1 agent| With | What happens | Evidence |
|---|---|---|
| TamoxifenTamoxifen | Taken together, lowered letrozole levels by 38%; letrozole given after tamoxifen kept its effect.1 | Drug label |
Check your own medicines and supplements in the Interaction map: every edge is sourced, and nothing you enter leaves your browser.
How do the options compare?
Letrozole and clomiphene are both five-day oral courses for ovulation. In polycystic ovary syndrome letrozole gives more ovulation and live births with similar twin rates; in unexplained infertility the two were similar. Anastrozole is the other nonsteroidal aromatase inhibitor; exemestane is a steroidal one, all three labelled for breast cancer.
Letrozole or clomiphene for ovulation
| Letrozole | Clomiphene | |
|---|---|---|
| Live birth in PCOS (PPCOS II) | 27.5% | 19.1% |
| Multiple pregnancy (Cochrane, PCOS) | 1.6% | 2.2% |
| Live birth per cycle, unexplained infertility (AMIGOS) | 18.7% | 23.3% |
| 2023 PCOS guideline | First-line | After letrozole; above metformin alone |
Frequently asked questions
Common questions
5 answersWhy is a breast cancer drug used for fertility?
Is letrozole better than clomiphene?
Does letrozole cause birth defects?
Does letrozole cause twins?
Sources
Sources cited on this page
11 sources- 1Femara (letrozole) tablets: prescribing information (DailyMed, version effective 2026-06-11)Label Novartis, 2026
- 2A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer (BIG 1-98)RCT N Engl J Med, 2005 · PMID 16382061
- 3A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer (MA.17)RCT N Engl J Med, 2003 · PMID 14551341
- 4Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary SyndromeGuideline J Clin Endocrinol Metab, 2023 · PMID 37580314
- 5Letrozole versus clomiphene for infertility in the polycystic ovary syndrome (PPCOS II)RCT N Engl J Med, 2014 · PMID 25006718
- 6Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndromeMeta-analysis Cochrane Database Syst Rev, 2022 · PMID 36165742
- 7Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility (AMIGOS)RCT N Engl J Med, 2015 · PMID 26398071
- 8Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrateObservational Fertil Steril, 2006 · PMID 16650422
- 9Arimidex (anastrozole) tablets: prescribing information (DailyMed, version effective 2026-03-02)Label ANI Pharmaceuticals, 2026
- 10Aromasin (exemestane) tablets: prescribing information (DailyMed, version effective 2025-12-24)Label Pharmacia & Upjohn (Pfizer), 2025
- 11Clinical application of aromatase inhibitors to treat male infertilityReview Hum Reprod Update, 2021 · PMID 34871401
What changed
Change log
2 entries| Date | Change | Who and why |
|---|---|---|
| "Off-label" now appears only in the status box and the safety band; the fertility dose row names the population instead of tagging it. | Writer: Kymata Health EditorialTrigger: Growth review (2026-10-23): status once or twice per page | |
| Page created: label status and dose, off-label ovulation induction, combinations with tamoxifen, clomiphene and gonadotropins, fertility safety, monitoring, six graded rows, BIG 1-98 side-effect rates and a comparison with clomiphene. | Writer: Kymata Health EditorialTrigger: Owner request (2026-10-22): hormone library |
Kymata Health hormone library. Educational information only; it is not medical advice and does not replace a clinician. Doses are shown as labels and studies print them; a prescriber decides whether and how any hormone is used.