Letrozole is a medication that lowers estrogen levels in the body. It is primarily prescribed to treat hormone receptor-positive breast cancer in postmenopausal women, and it is also widely used off-label to help induce ovulation in women struggling with infertility. Sold under the brand name Femara, letrozole belongs to a class of drugs called aromatase inhibitors.
How Letrozole Works
Your body produces estrogen through an enzyme called aromatase, which is found in fat, muscle, liver, and breast tissue. Aromatase converts other hormones (androgens) into estrogen. Letrozole blocks this enzyme, reducing estrogen production by more than 99%.
This matters for two very different reasons depending on the condition being treated. In breast cancer, many tumors rely on estrogen to grow. Starving the tumor of estrogen slows or stops its progression. In fertility treatment, temporarily suppressing estrogen tricks the brain into ramping up the hormones that trigger ovulation, helping the ovaries release eggs.
Breast Cancer Treatment
Letrozole is approved for several breast cancer scenarios in postmenopausal women whose tumors are hormone receptor-positive, meaning the cancer cells have receptors that use estrogen to fuel growth. These scenarios include:
- Adjuvant therapy: Treatment given after surgery to reduce the risk of cancer returning. The standard course is 5 years of daily use.
- Extended adjuvant therapy: An additional course of letrozole for women who have already completed 5 years of another hormonal therapy called tamoxifen. Research from the NCIC CTG MA-17 trial showed that this sequential approach further reduces recurrence risk.
- Advanced or metastatic breast cancer: Letrozole can be used as a first-line treatment when breast cancer has spread or returned.
For early-stage breast cancer, current guidelines recommend at least 5 years of hormonal therapy. Some women benefit from extending treatment to 7 or 8 years, which has been shown to reduce recurrences compared to 5 years alone. For lower-risk cases, extending beyond 8 years to a full 10 does not appear to add further benefit. Your oncologist will weigh recurrence risk against side effects when recommending a duration.
Letrozole is only used in postmenopausal women for breast cancer. In premenopausal women, the ovaries are still actively producing large amounts of estrogen, and blocking aromatase alone isn’t enough to suppress it. Premenopausal women with hormone-sensitive breast cancer are typically treated with tamoxifen or a combination approach that also suppresses ovarian function.
Fertility and Ovulation Induction
Letrozole has become a go-to treatment for women with polycystic ovary syndrome (PCOS) who are trying to conceive. PCOS is one of the most common causes of infertility, largely because it disrupts regular ovulation. By temporarily lowering estrogen early in the menstrual cycle, letrozole prompts the pituitary gland to release more of the hormones that stimulate the ovaries to develop and release an egg.
For fertility purposes, letrozole is taken for a short window during each menstrual cycle, typically for 5 to 10 days starting around day 3 or day 5 of the cycle. Common doses range from 2.5 mg to 5 mg daily. Research suggests that starting at 5 mg or using a longer 10-day course improves ovulation rates compared to the more traditional 2.5 mg for 5 days. Cumulative conception rates in studies have ranged from roughly 65% to 76% over multiple cycles, depending on timing and protocol.
Letrozole produces higher live birth rates than clomiphene citrate, the older fertility drug it has largely replaced for PCOS. One comparative trial found live birth rates of 36.5% with letrozole versus 22.4% with clomiphene. Letrozole also carries a lower risk of twins or higher-order multiples, because it is less likely to cause the ovaries to release several eggs at once.
It is important to note that while letrozole is used briefly to trigger ovulation, it is contraindicated during pregnancy itself. It can cause fetal harm, and postmarket reports have linked its use during pregnancy to miscarriage and birth defects. Women using letrozole for fertility stop taking it well before ovulation and conception occur in each cycle.
Common Side Effects
Side effects depend heavily on how long you take letrozole. Women using it for a few days per cycle during fertility treatment experience far fewer issues than those taking it daily for years as breast cancer therapy. The side effects below reflect what’s seen in long-term breast cancer use.
The most frequently reported effects mirror what you’d expect from drastically lowering estrogen. In a large adjuvant trial with a median treatment duration of 5 years, hot flashes affected about 34% of patients, joint pain or arthritis occurred in 25%, and night sweats in roughly 15%. Weight gain was reported by about 13% of women, and nausea by around 12%. Fatigue, muscle pain, and general weakness are also common, affecting roughly 9 to 10% of long-term users. Some women notice dizziness or sleepiness, which can affect driving or operating machinery.
Bone Health and Cholesterol
Two side effects deserve special attention because they develop quietly over time. Estrogen plays a key role in maintaining bone density, so suppressing it for years accelerates bone loss. In the large BIG 1-98 trial, 14.7% of women on letrozole experienced bone fractures over a median follow-up of 8 years, compared to 11.4% on tamoxifen. Osteoporosis developed in about 5% of letrozole users.
Because of this risk, women starting letrozole for breast cancer should have their bone density measured and monitored every 1 to 2 years. Calcium and vitamin D supplements are recommended for all patients on aromatase inhibitor therapy. Women with a bone density T-score below -2.0, or those with multiple risk factors like age over 65, low body weight, a family history of hip fracture, or smoking, may need additional bone-protective medication.
Cholesterol is the other concern. More than half of women in the adjuvant trial (52.3%) developed elevated cholesterol levels while on letrozole, compared to about 29% on tamoxifen. While severely elevated cholesterol was rare (under 1%), this is something that should be monitored with routine blood work throughout treatment.
Who Should Not Take Letrozole
Letrozole is contraindicated during pregnancy due to the risk of fetal harm. It is also not appropriate for premenopausal women being treated for breast cancer, since their ovaries would compensate for the blocked aromatase by producing even more estrogen. Anyone with a known allergy to letrozole or its inactive ingredients should avoid it. Liver function does not formally restrict its use, but since letrozole is processed by the liver, women with severe liver impairment may require closer monitoring.