Letrozole in women: medical indications

Letrozole was created for women, and it is precisely in women's medicine that it has the largest evidence base. However, the indications for it are very different: from many years of breast cancer therapy to a few tablets at the start of the menstrual cycle to stimulate ovulation. The editors explain where the official indications end, where off-label practice begins and why self-administration is unacceptable.

Why letrozole acts differently depending on age

Letrozole is a non-steroidal inhibitor of aromatase, the enzyme that converts androgens into estrogens. However, the effect of this blockade in a woman is determined by where the main part of the estrogens in her body comes from. And that depends on reproductive status.

In premenopausal women the main source of estradiol is the ovaries, whose function is controlled by the pituitary. If estrogens are lowered, the hypothalamus and pituitary "notice" the deficit and increase production of follicle-stimulating hormone (FSH). As a result the ovaries receive a stronger stimulus. It is on this mechanism that the use of letrozole for ovulation induction is based.

In postmenopausal women the ovaries hardly synthesize estrogens, and there is effectively no feedback that could "override" the blockade. Estrogens are formed in peripheral tissues from adrenal androgens, and letrozole suppresses this pathway deeply and steadily. Therefore in postmenopause the drug effectively lowers estrogens, while in premenopause, without accompanying ovarian suppression, it does not.

This difference explains why the Femara prescribing information limits its oncological indications to postmenopausal women, while in younger patients with breast cancer aromatase inhibitors are combined only with medical or surgical shutdown of ovarian function.

Breast cancer: the main indication

The official indications for letrozole, set out in the prescribing information of the FDA and European regulators, concern hormone receptor-positive breast cancer in postmenopausal women. About two-thirds of such tumors have estrogen receptors, and for them lowering estrogens is one of the main methods of treatment.

The drug is used in several scenarios: as adjuvant therapy after surgery, as extended adjuvant therapy after several years of tamoxifen, and also in advanced or metastatic disease. In clinical trials and in the prescribing information a dose of 2.5 mg per day is used, and the duration of treatment is determined by the oncologist, usually amounting to years.

The BIG 1-98 trial showed that letrozole as initial adjuvant therapy reduces the risk of recurrence compared with tamoxifen. The EBCTCG meta-analysis (2015) confirmed the advantage of aromatase inhibitors as a class in postmenopause. The ASCO guideline (Burstein et al., 2019) regards aromatase inhibitors as a standard component of hormonal therapy for this group of patients.

Chemoprophylaxis in women at high risk of breast cancer is considered separately. For this purpose other aromatase inhibitors — exemestane and anastrozole — are best studied, whereas letrozole has less data in prevention.

Ovulation induction and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common causes of anovulatory infertility. For decades the standard of ovulation stimulation was clomiphene, but it blocks estrogen receptors in the endometrium and cervical mucus as well, which can worsen the conditions for implantation.

Letrozole acts differently: it briefly lowers estrogen levels without blocking receptors, and after the drug is stopped the estrogenic effect on the endometrium is restored. The drug has a short half-life — about two days — so a course at the start of the cycle leaves no lasting "trace" by the time of implantation.

In the randomized trial by Legro et al. (2014), published in the New England Journal of Medicine, among 750 women with PCOS the rate of live births was higher in the letrozole group than in the clomiphene group. The international evidence-based guideline on PCOS (Teede et al., 2023) recommends letrozole as a first-line drug for ovulation induction in this group of patients.

Despite this, in many countries the manufacturer's prescribing information does not contain this indication, so use takes place off-label, on the basis of clinical guidelines and with informed consent. Treatment is carried out by a reproductive specialist with ultrasound monitoring of follicles, since there is a risk of multiple pregnancy, although it is lower than with gonadotropins.

Fertility preservation and other areas of use

Women with estrogen-dependent breast cancer who want to freeze embryos or eggs before starting treatment need ovarian stimulation. Standard protocols sharply raise estradiol levels, which is theoretically undesirable in a hormone-sensitive tumor.

Oktay et al. (2005) proposed combining gonadotropins with letrozole: this allows eggs to be obtained while keeping estradiol at a considerably lower level. Such protocols are used today in many oncofertility centers, but the decision is always made jointly by the oncologist and the reproductive specialist.

The use of letrozole in endometriosis has been studied, especially in postmenopausal women or those with resistance to standard therapy. The data here are limited, and such regimens are not part of routine practice. It has also been studied in some gynecological tumors with estrogen receptors.

• Oncofertility — in combination with gonadotropins to lower estradiol.
• Endometriosis — individual studies, mainly as reserve therapy.
• Estrogen-dependent tumors of the endometrium and ovaries — the decision of the gynecologic oncologist.

All these scenarios share one thing: letrozole is a tool within a complex treatment plan under the supervision of a specialist, not a stand-alone means for "tuning hormones".

Contraindications, side effects and monitoring

According to the prescribing information, letrozole is contraindicated during pregnancy: in animals it caused embryotoxicity and developmental defects. Before prescribing it to women of reproductive age, the doctor must make sure there is no pregnancy. The drug is also not used during breastfeeding.

The most common side effects of long-term therapy are related to estrogen deficiency: hot flashes, joint and muscle pain, fatigue, dryness of the mucous membranes, decreased libido. In the BIG 1-98 trial, fractures and increased cholesterol were observed more often on letrozole than on tamoxifen.

Long-term treatment requires monitoring of bone mineral density. The ASCO guideline on osteoporosis in cancer patients (Shapiro et al., 2019) recommends assessing fracture risk and, if necessary, prescribing antiresorptive therapy. The lipid profile and, when indicated, liver tests are also monitored.

Short courses for ovulation induction are tolerated much more easily: headache, hot flashes and fatigue are possible. However, even in this case ultrasound monitoring and medical supervision are important to avoid hyperstimulation and multiple pregnancy.

Editorial conclusions

In women letrozole has two fundamentally different medical uses. In postmenopause it is a long-term therapy for hormone-sensitive breast cancer with a powerful evidence base. In reproductive age it is short courses for stimulating ovulation, best studied in PCOS.

Both directions are based on the same mechanism but give opposite hormonal results: steady suppression of estrogens or increased stimulation of the ovaries via FSH.

The benefit of the drug is accompanied by risks for the bones, joints and lipid metabolism, and pregnancy is an absolute contraindication. Therefore treatment must always take place under the supervision of an oncologist or a reproductive specialist.

The editors also recommend familiarizing yourself with our materials "The history of letrozole's creation", "Tests during the use of letrozole" and "Exemestane in women: medical indications".

References

1. Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):2747–2757.
2. 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.
3. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2019;37(5):423–438.
4. 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.
5. Teede HJ, Tay CT, Laven J, et al. Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023;108(10):2447–2469.
6. Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol. 2005;23(19):4347–4353.
7. Shapiro CL, Van Poznak C, Lacchetti C, et al. Management of osteoporosis in survivors of adult cancers with nonmetastatic disease: ASCO clinical practice guideline. J Clin Oncol. 2019;37(31):2916–2946.
8. Novartis. Femara (letrozole) tablets: prescribing information. U.S. Food and Drug Administration.