Tamoxifen

What tamoxifen is and how it works

Tamoxifen is a selective estrogen receptor modulator, SERM for short, and prescription-only. In Germany it is approved for adjuvant therapy after the initial treatment of breast cancer and for metastatic breast cancer.

The active substance occupies the estrogen receptor and acts differently there depending on the tissue: in breast tissue as an antagonist of estrogen, on the uterine lining and bone partly estrogen-like. This explains both sides of the balance – less breast cancer and fewer bone fractures, but more growths and cancer of the uterine lining. Tamoxifen only becomes active after conversion in the liver, mainly via the enzyme CYP2D6 to endoxifen. With absent CYP2D6 activity, endoxifen is about 75 percent lower according to the prescribing information; strong CYP2D6 inhibitors lower it to the same extent.

In men, tamoxifen additionally blocks the estrogen feedback in the brain: FSH and testosterone rise. In breast gland tissue it inhibits the effect of estrogen, and this is the basis for its use against gynecomastia. Related substances are raloxifene, which does not act estrogen-like on the uterus, and clomiphene, which acts mainly on the feedback in the brain.

What the studies show

EBCTCG 2011: 20 trials, 21,457 women

The Early Breast Cancer Trialists’ Collaborative Group analyzed individual data from all trials that compared about five years of tamoxifen with no tamoxifen treatment. In estrogen receptor-positive breast cancer (10,645 women), the recurrence rate ratio was 0.53 in years 0 to 4 and 0.68 in years 5 to 9; from year 10 onward there was neither additional gain nor loss. Breast cancer mortality was about two thirds in all three five-year periods. Thromboembolism and uterine cancer led to small absolute increases in mortality in women over 55, yet overall mortality still fell markedly. In estrogen receptor-negative breast cancer, tamoxifen had hardly any effect.

NSABP P-1: prevention in 13,388 women

Fisher 1998 randomized women at increased breast cancer risk to tamoxifen or placebo for five years. Invasive breast cancer fell by 49 percent, non-invasive breast cancer by 50 percent. At the same time, cancer of the uterine lining increased 2.53-fold (95 percent confidence interval 1.35 to 4.97), mainly in women aged 50 and over; all of these tumors were detected at stage I. Strokes, pulmonary embolisms and deep vein thromboses were more frequent. The analysis after seven years (Fisher 2005) confirmed the effects and showed 32 percent fewer osteoporotic fractures and more cataracts.

Fradet 2007: gynecomastia on bicalutamide

282 men with prostate cancer received the antiandrogen bicalutamide for twelve months and, double-blind, in addition tamoxifen at five dose levels or placebo. After six months, breast enlargement or breast pain occurred in 96.7 percent on placebo and, depending on the level, in 86.2 to 8.8 percent on tamoxifen. Tumor control, measured by the PSA level, did not suffer. From the middle dose levels upward, hot flashes were more frequent. After tamoxifen was stopped, breast symptoms frequently occurred in all groups.

Viani 2012: meta-analysis of tamoxifen or radiotherapy

Six randomized trials with 777 men on hormone deprivation for prostate cancer, three of them with tamoxifen. Tamoxifen reduced gynecomastia and breast pain more than prophylactic radiotherapy of the breast, but was associated with six times more side effects. The authors recommend radiotherapy especially in cases of cardiovascular risk or a tendency to thrombosis.

Mannu 2018: idiopathic gynecomastia

At a breast clinic, 81 men with gynecomastia without an identifiable cause were treated with tamoxifen over ten years; in 90.1 percent, the breast enlargement resolved completely. There was no control group, so it remains open how many cases would have resolved without treatment.

Where the data stop

• Gynecomastia from anabolic steroids. The randomized data come from prostate cancer therapy with antiandrogens. For breast gland growth caused by anabolic steroids, there is no controlled trial.
• Hormone axis after anabolic steroids. That anti-estrogens such as tamoxifen or clomiphene raise FSH and testosterone in men is shown by a meta-analysis of 11 randomized trials on male infertility (Chua 2013). Whether this restores the body’s own production faster after anabolic steroid use has not been studied in controlled trials.
• Healthy men. The large safety data come from women. How the thrombosis and eye risks behave in young, healthy men has not been specifically studied.
• Origin of the product. The data apply to the tested medicine, not to products from the gray market.

Status, approval and legal

Tamoxifen is approved and prescription-only in Germany, for adjuvant therapy after primary treatment of breast carcinoma and for metastatic breast carcinoma, for example as Tamoxifen AbZ 20 mg (approved on 1998-06-23). According to the prescribing information, the approved dose is between 20 and 40 mg daily, usually 20 mg. Use against gynecomastia is not an approved use in Germany.

The WADA Prohibited List 2026 lists tamoxifen under S4.2, the anti-estrogenic substances, prohibited in and out of competition and for all athletes. In the annex of the German Anti-Doping Act, it is listed among the anti-estrogenic substances. The prescribing information points out that its use can lead to positive results in doping tests.

Safety

The greatest known risk concerns women: cancer of the uterine lining, increased 2.53-fold in P-1 and, according to the prescribing information, rising to 2 to 4 times with the duration of treatment; uterine sarcomas also occur rarely. Thromboses, pulmonary embolisms and strokes were more frequent in P-1, especially from age 50; with concurrent chemotherapy, the frequency of thrombosis rises further.

For the eyes, the prescribing information lists frequent, only partly reversible visual disturbances due to cataracts, corneal opacities and retinal changes; the cataract risk increases with the duration of intake. In men on antiandrogen therapy, hot flashes were added. Tamoxifen inhibits enzymes of the cytochrome P450 system; strong CYP2D6 inhibitors such as paroxetine weaken its effect, and with coumarin-type anticoagulants, blood clotting changes. Because of the genotoxic potential, men should use contraception during treatment and for six months afterwards, according to the prescribing information. Tamoxifen belongs in a physician’s hands.

Sources

• Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Lancet 2011 – meta-analysis of adjuvant tamoxifen, 20 trials, 21,457 women
• Fisher B et al., J Natl Cancer Inst 1998 – NSABP P-1, tamoxifen for breast cancer prevention, 13,388 women
• Fisher B et al., J Natl Cancer Inst 2005 – NSABP P-1 after 7 years: fractures, thromboses, cataracts, uterine cancer
• Fradet Y et al., Eur Urol 2007 – tamoxifen against gynecomastia on bicalutamide, double-blind, 282 men
• Viani GA et al., Int J Radiat Oncol Biol Phys 2012 – meta-analysis of tamoxifen or radiotherapy against gynecomastia during hormone deprivation, 6 trials, 777 men
• Mannu GS et al., Breast J 2018 – tamoxifen in idiopathic gynecomastia, prospective cohort, 81 men
• Chua ME et al., Andrology 2013 – meta-analysis on clomiphene or tamoxifen in unexplained male infertility, 11 randomized trials
• Prescribing information Tamoxifen AbZ 20 mg tablets (as of April 2026)
• WADA Prohibited List 2026, S4.2 anti-estrogenic substances – official publication in the German Federal Law Gazette II 2025 No. 312
• German Anti-Doping Act, annex – III. Hormone and metabolic modulators, 2. Anti-estrogenic substances