Letrozole and mood: what you should know
Letrozole is an effective medicine, but it lowers oestrogen everywhere – including in the brain. Our editorial team explains why low mood, poor sleep and fatigue can occur, who is most affected and what can help.
What letrozole does
Letrozole is a non-steroidal aromatase inhibitor. Aromatase is the enzyme that converts androgens such as testosterone and androstenedione into oestrogens. By blocking it, letrozole sharply reduces oestrogen production in tissues throughout the body, including fat, muscle, bone and the brain.
In the UK letrozole is a prescription-only medicine licensed mainly for hormone receptor-positive breast cancer in postmenopausal women, both after surgery (adjuvant therapy) and in advanced disease. Large trials such as BIG 1-98, reported by Thürlimann and colleagues in 2005, established it as a standard option. The licensed dose in breast cancer is 2.5 mg once daily.
Letrozole is also widely used off-label in fertility care to induce ovulation, especially in polycystic ovary syndrome, where the 2023 international guideline recommends it as first-line therapy. Here it is given for only a few days per cycle under specialist supervision.
Because oestrogen influences brain chemistry, lowering it can affect mood, sleep, energy and cognition. These effects are well described in breast cancer patients and are also relevant to anyone considering the drug for other reasons.
Oestrogen and the brain
Oestrogen receptors are present in brain regions involved in emotion and memory, including the hippocampus, amygdala and prefrontal cortex. Oestradiol modulates serotonin, dopamine and noradrenaline signalling, influences neuroplasticity and contributes to temperature regulation.
When oestrogen falls rapidly, as after surgical menopause or with aromatase inhibitors, many people notice hot flushes, disrupted sleep, irritability and low mood. Sleep disturbance in particular can amplify emotional symptoms: poor sleep lowers stress tolerance and concentration, which in turn worsens mood.
In men, oestradiol made from testosterone also plays a role in libido, mood and bone health. Finkelstein and colleagues showed in 2013 that oestrogen deficiency contributed to increased fat mass and reduced sexual function in men, independent of testosterone. A review by de Ronde and de Jong outlined the consequences of aromatase inhibition in men, including effects on bone and lipids.
What patients actually report
In breast cancer trials, the most common adverse effects of letrozole include hot flushes, joint and muscle pain, fatigue and night sweats. Depression and anxiety are listed in the product information as common side effects, although it is difficult to separate drug effects from the psychological burden of a cancer diagnosis and treatment.
- Hot flushes and night sweats – disrupt sleep and can indirectly worsen mood.
- Fatigue – may combine with joint pain to reduce physical activity.
- Low mood and anxiety – reported in a meaningful minority of patients.
- Cognitive complaints – "brain fog" is described by some, with mixed objective evidence.
Joint pain, known as aromatase inhibitor-associated arthralgia, deserves mention because it affects mood indirectly. Pain limits exercise, worsens sleep and is one of the most common reasons patients stop treatment early. Exercise programmes have been studied as a way to reduce it.
In fertility treatment, short courses of letrozole generally cause fewer mood problems than clomifene, although headaches, fatigue and hot flushes are still reported. The Legro trial found lower rates of hot flushes with letrozole than with clomifene.
Use outside medical care
Aromatase inhibitors are sometimes used without prescription by men using anabolic steroids, with the intention of controlling oestrogen-related effects. This use is unsupervised and carries specific risks. Driving oestradiol too low can cause low mood, anxiety, loss of libido, joint pain and adverse changes in lipids and bone density.
| Context | Mood-related concerns | Supervision |
|---|---|---|
| Breast cancer therapy | Low mood, sleep problems, fatigue | Oncology team, GP |
| Ovulation induction | Usually mild and short-lived | Fertility specialist |
| Non-medical use by men | Very low oestradiol – mood, libido, joints | None – not recommended |
Aromatase inhibitors are prohibited at all times for athletes under section S4 of the WADA list. Products sold online without prescription may also be mislabelled or of uncertain quality.
Managing mood during prescribed treatment
Anyone prescribed letrozole who notices persistent low mood, anxiety, loss of interest or sleep problems should tell their doctor rather than stopping the medicine on their own. Options may include treating hot flushes, addressing sleep, psychological support or, in some cases, switching to another endocrine therapy.
Regular physical activity is one of the best-supported self-help measures. It improves mood, sleep and fatigue in people with cancer and may lessen joint pain. Resistance training also helps protect bone density, which aromatase inhibitors reduce.
Some antidepressants interact with other breast cancer treatments; in particular, certain SSRIs inhibit the enzyme that activates tamoxifen. Letrozole does not share this problem to the same extent, but medication choices should always be made with the oncology team.
Editorial team's conclusions
Letrozole lowers oestrogen throughout the body, including in the brain, so effects on mood, sleep and energy are biologically plausible and are reported in clinical practice.
In breast cancer, these effects must be weighed against substantial benefits; support, symptom management and exercise can help. In fertility care, short courses are generally well tolerated.
Use without medical supervision risks excessive oestrogen suppression with consequences for mood, libido, joints and bone.
Related topics on our site include anastrozole versus letrozole, oestradiol in men, and exercise during cancer treatment.
References
- Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):2747–2757.
- 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.
- Teede HJ, Tay CT, Laven JJE, 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.
- Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011–1022.
- de Ronde W, de Jong FH. Aromatase inhibitors in men: effects and therapeutic options. Reprod Biol Endocrinol. 2011;9:93.
- Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
