What is Letrozole?
Letrozole is a potent, nonsteroidal aromatase inhibitor that blocks the conversion of androgens to estrogens by competitively binding to the aromatase enzyme, resulting in profound suppression of estrogen biosynthesis in all tissues. 1
Mechanism of Action
Letrozole works by competitively binding to the heme of the cytochrome P450 subunit of the aromatase enzyme, which is responsible for converting adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol in postmenopausal women. 1 This selective inhibition achieves:
- 75% to 95% suppression of plasma estradiol, estrone, and estrone sulfate from baseline, with maximal suppression within 2-3 days of treatment 1
- Over 98% inhibition of peripheral aromatase in clinical tracer studies 2
- Selective action on aromatase without significant effects on adrenal mineralocorticoid, glucocorticoid, aldosterone, or thyroid hormone synthesis 1
Primary Clinical Uses
Breast Cancer Treatment
Letrozole is FDA-approved and guideline-recommended for hormone receptor-positive breast cancer in postmenopausal women across multiple treatment settings:
- Adjuvant therapy: Standard 5-year treatment for early-stage, hormone receptor-positive breast cancer 3
- Extended adjuvant therapy: Additional 5 years (total 10 years) for higher-risk patients, particularly those with node-positive disease 3, 4
- Metastatic disease: First-line treatment at 2.5 mg daily, often combined with CDK 4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) for improved progression-free survival 3
The MA-17 trial demonstrated that extended letrozole therapy after 5 years of tamoxifen significantly improved disease-free survival (HR 0.52) and overall survival (HR 0.61) compared to placebo. 3
Ovulation Induction (Off-Label Use)
Letrozole has emerged as an effective alternative to clomiphene citrate for ovulation induction in women with polycystic ovarian syndrome (PCOS):
- Mechanism: Temporarily reduces estrogen levels, removing negative feedback on the hypothalamic-pituitary axis, leading to increased FSH secretion and follicular development without depleting estrogen receptors 5
- Advantages over clomiphene: No antiestrogenic effects on endometrium or cervical mucus, higher rates of monofollicular development (68.4% vs 44.8%), and better pregnancy rates (42.2% vs 20.0%) 6
- Dosing: Typically 2.5-7.5 mg daily for 5 days early in the menstrual cycle, though doses up to 12.5 mg have been studied 7
Fertility Preservation
Letrozole is used during ovarian stimulation for embryo or oocyte cryopreservation in women with hormone-sensitive cancers, as it enhances ovarian stimulation while keeping estrogen levels near physiologic levels, with no apparent impact on short-term cancer-free survival. 3
Formulation and Dosing
- Standard dose: 2.5 mg oral tablet taken once daily 1
- Inactive ingredients include: Lactose monohydrate, microcrystalline cellulose, magnesium stearate, and various color additives including FD&C Yellow #5 (Tartrazine) 1
Key Toxicities and Monitoring
Bone health: Extended letrozole therapy significantly increases risk of fractures and osteoporosis, requiring regular bone mineral density monitoring. 8, 4
Cardiovascular effects: Trend toward increased cardiovascular events with extended therapy (odds ratio 1.18). 8, 4
Quality of life: Worsening physical role functioning, ongoing menopausal symptoms (hot flashes, fatigue), and potential for vaginal problems during extended therapy. 8, 4
Important Clinical Distinctions
Letrozole differs from tamoxifen and other selective estrogen receptor modulators in that it does not deplete estrogen receptors or cause antiestrogenic effects on the endometrium. 5 Unlike ovariectomy, letrozole treatment does not lead to increased serum FSH, though it does elevate LH. 1 The drug is highly selective for aromatase inhibition without affecting other steroidogenic pathways. 1, 2