Letrozole

What letrozole is

Letrozole is a non-steroidal aromatase inhibitor and prescription-only. It is approved for postmenopausal women with hormone-dependent breast cancer: as adjuvant treatment after surgery, as extended treatment after five years of tamoxifen, in the advanced stage and in certain cases before surgery. The European Medicines Agency harmonized the indications EU-wide in 2012.

What is rated is the state of knowledge. For the approved use it is very good. In men there are two randomized studies – one on low testosterone in severe overweight, one on infertility – and a few small studies without a control group. On use alongside anabolic steroids there are no controlled data.

How it works

The enzyme aromatase converts androgens such as testosterone and androstenedione into estrogens. Letrozole inhibits it highly specifically. In postmenopausal women, estradiol, estrone and estrone sulfate fall by 75 to 95 percent according to the US prescribing information; the greatest reduction is reached after two to three days. Cortisol, aldosterone and other adrenal hormones do not change to a clinically relevant degree.

In men, less estradiol loosens the feedback on the pituitary gland. In the placebo-controlled study in severely overweight men, estradiol fell from 119 to 59 pmol/l, LH rose from 3.3 to 8.8 U/l and testosterone from 8.6 to 21.5 nmol/l. The leverage is large in overweight because fat tissue converts a lot of testosterone into estradiol.

What the studies show

BIG 1-98: letrozole versus tamoxifen

The BIG 1-98 study (NEJM 2005) compared letrozole and tamoxifen double-blind as adjuvant treatment in 8,010 postmenopausal women with hormone receptor-positive breast cancer. After a median of 25.8 months there were 351 versus 428 events, hazard ratio 0.81 (0.70 to 0.93; p = 0.003), for distant metastases 0.73 (0.60 to 0.88; p = 0.001). Thromboses, uterine cancer and vaginal bleeding were more frequent under tamoxifen; under letrozole there were more bone and cardiac events and more frequently elevated cholesterol.

Loves 2013: six months in severely overweight men

Loves 2013 (Eur J Endocrinol) treated 42 men with a BMI above 35 and testosterone below 10 nmol/l for six months, double-blind, with low-dose letrozole or placebo; 39 completed the study per protocol. Estradiol fell from 119 to 59 pmol/l, LH rose from 3.3 to 8.8 U/l, testosterone from 8.6 to 21.5 nmol/l. This had no significant effect on the predefined endpoints – psychological well-being, body composition, exercise capacity, glucose, lipid and bone metabolism. The authors conclude: despite a marked rise in testosterone, no physical or psychological effects.

The pilot studies without a control group

Two smaller studies by the same research group ran without placebo. In 10 severely overweight men, testosterone rose from 7.5 to 23.8 nmol/l after 6 weeks; at the highest dose tested, LH overshot (de Boer 2005). The authors noted that the clinical significance would first have to be shown in controlled long-term studies. In 12 men over 6 months, testosterone reached the normal range in all of them, but free testosterone was above it in 7 of 12 (Loves 2008).

Sun 2026: severe male infertility

Sun 2026 (JAMA Netw Open) randomized 296 men with severe infertility at 10 centers in China, three quarters of them without sperm in the ejaculate, to three months of letrozole plus vitamins C and E or the vitamins alone. The study was open-label, the assessment blinded. A better WHO category of sperm concentration was reached by 14.3 versus 5.4 percent (risk difference 9.2 percentage points; 2.5 to 15.8; p = 0.01). There were no significant differences in the individual semen parameters. Reduced libido was reported by 12.2 versus 5.4 percent. Pregnancies were not an endpoint.

Where the data stop

• Alongside anabolic steroids. No controlled studies on lowering estradiol during anabolic steroid use were found in the research.
• Benefit in low testosterone. The rise is a surrogate marker. In the only placebo-controlled study it was not followed by any measurable effect on body, mind or metabolism over six months.
• Fertility. What is established is a jump to a better category of sperm concentration in a minority. Whether this leads to more pregnancies was not measured; the study was open-label and ran for three months.
• Long-term consequences in men. The longest studies in men lasted six months. Fractures and cardiovascular events have not been studied in men on letrozole.

Status, approval and legal

Letrozole is approved as Femara in all EU states via national procedures. Following a harmonization procedure by the European Medicines Agency, uniform indications in postmenopausal women have applied since the European Commission decision of May 22, 2012: adjuvant treatment of hormone receptor-positive early breast cancer, extended adjuvant treatment after five years of tamoxifen, first-line treatment of advanced hormone-dependent breast cancer, advanced breast cancer after antiestrogens, and treatment before surgery when chemotherapy is not an option. The approved dose is 2.5 mg once daily.

In Germany, letrozole is prescription-only (Annex 1 of the German Ordinance on Prescription-Only Medicines). Use in men is not approved.

In sport, letrozole is on the World Anti-Doping Agency’s Prohibited List 2026 under S4.1 aromatase inhibitors and is prohibited at all times, in and out of competition. In Germany it is listed in the annex of the Anti-Doping Act under hormone and metabolic modulators; this means acquisition and possession in non-small quantities for the purpose of doping in sport are also prohibited.

Safety

In women, the bone risk is well measured. After 24 months, lumbar spine bone density fell by a median of 4.1 percent; under tamoxifen it rose by 0.3 percent. In BIG 1-98, after a median of 96 months, fractures occurred in 14.7 versus 11.4 percent, osteoporosis in 5.1 versus 2.7 percent. The US prescribing information recommends monitoring bone density and checking cholesterol. If you are prescribed letrozole, both points belong in the conversation.

In BIG 1-98, cardiac events and elevated cholesterol occurred more frequently under letrozole than under tamoxifen. Fatigue, dizziness and drowsiness are possible; the prescribing information advises caution when operating machinery.

In men, two findings stand out. In one pilot study, free testosterone rose above the normal range in 7 of 12 men, and at the highest dose tested LH overshot. In the fertility study, 12.2 percent on letrozole reported reduced libido, 5.4 percent without letrozole. For bones and heart there are no data in men covering more than six months.

Sources

• BIG 1-98 Collaborative Group (Thürlimann B et al.), N Engl J Med 2005 – letrozole versus tamoxifen after breast cancer, 8,010 women
• Loves S et al., Eur J Endocrinol 2013 – letrozole in obese men with low testosterone, RCT with 42 men, 6 months
• Loves S et al., Eur J Endocrinol 2008 – letrozole in obese men, open-label pilot study with 12 men, 6 months
• de Boer H et al., Diabetes Obes Metab 2005 – letrozole in 10 severely overweight men, 6 weeks, without control group
• Sun Y et al., JAMA Netw Open 2026 – letrozole in severe male infertility, RCT with 296 men, 3 months
• EMA, Femara – harmonization procedure, decision of May 22, 2012: indications
• US prescribing information Femara (DailyMed) – dose, effect on estrogens, bone density, fractures, cholesterol
• German Ordinance on Prescription-Only Medicines (AMVV), Annex 1 – prescription requirement
• WADA Prohibited List 2026, informational German translation by NADA – S4.1 aromatase inhibitors, prohibited at all times
• German Anti-Doping Act, annex – III. hormone and metabolic modulators, 1. aromatase inhibitors