Side Effects of Tamoxifen

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Tamoxifen has been used for several years to treat hormone receptor-positive types of breast cancer. This is due to its ability to competitively block estrogen binding to estrogen receptors, which stimulates breast cancer cell growth. As a selective estrogen receptor modulator (SERM); however, tamoxifen not only antagonizes the actions of estrogen at its receptor by blocking its binding but also mimics other actions through its own binding to the estrogen receptor.

This is common to most SERMs, including raloxifene and toremifene, all of which act as estrogen antagonists in some organs or tissues, such as the breast, as well as partial estrogen agonists in other target tissues like the uterus and bone. Tamoxifen thus promotes uterine endometrial hyperplasia, as well as bone growth, but restricts the growth of breast tissue.

Understanding Risks & Benefits of Tamoxifen

Side effects due to the estrogen antagonistic activity of tamoxifen

The binding of tamoxifen to estrogen receptors has a profound effect on normal feedback processes. It induces the hypothalamus to sense a falsely high estrogen level, resulting in the cessation of ovarian stimulation. In short, tamoxifen induces artificial menopause.

Tamoxifen-induced estrogen deprivation causes side effects such as hot flashes in 35% of patients. Other related hypoestrogenic symptoms include night sweats, dryness or excessive discharge from the vagina, memory lapses, depressive symptoms, and reduced libido. Moreover, 17% of women on tamoxifen report insomnia, while 14% have weight gain. Bone loss and cataracts are other commonly reported side effects.

Such side-effects are more likely when women also take other medications that inhibit cytochrome P450 2D6, which metabolizes natural estrogen. However, such women also have lower recurrence rates of breast cancer as compared to women who have no side effects.

Side effects due to the estrogen agonist activity of tamoxifen

Tamoxifen also causes side effects due to its modest estrogen-like activity. These include endometrial proliferation, endometrial hyperplasia, endometrial polyp formation, invasive endometrial cancer, uterine sarcoma, venous thromboembolism, and its complications, such as stroke.

Endometrial cell hyperplasia

Endometrial cell hyperplasia can result in troublesome vaginal bleeding and discharge. The incidence of endometrial hyperplasia in women taking tamoxifen was almost 12% in women with prior endometrial lesions, as compared to 0.7% in women without endometrial lesions at the time of initiation of tamoxifen.

There is a chance that endometrial cell hyperplasia can progress to invasive cancer of the endometrium. Tamoxifen raises the risk of endometrial cancer in post-menopausal women who have not had a hysterectomy, but not in premenopausal women.

Endometrial polyps

Endometrial polyps show an 18-fold increase in risk, which is sharply demarcated by the presence of initial lesions in the endometrium. Thus 17.6% of women with endometrial lesions developed polyps, which is comparable to almost 13% of those with a normal endometrium at the start of therapy.

Endometrial cancer

Research shows that women taking tamoxifen develop endometrial cancer at a rate of 1.26 per 1,000 patient-years, versus 0.58 in women on placebo. However, the rate of 5-year survival in women with breast cancer who are treated with tamoxifen is 38% greater than in breast cancer patients not on tamoxifen.

There is a 2-3% risk of endometrial cancer over the 15 years after the start of tamoxifen therapy in older women, as calculated for 5 years of tamoxifen adjuvant therapy. The risk is increased by approximately 2% at year 15 if tamoxifen is continued for 10 years. The risk ratio is thus about 2.5 for endometrial cancer. However, the death rate from endometrial cancer in this group is roughly 10% of the calculated incidence.

Uterine sarcomas

Uterine sarcomas are a rare form of cancer that accounts for only 8% of uterine cancers. However, they occur at a rate of 17 per 100,000 patients in women who are taking tamoxifen, whereas there were no cases in the placebo group and 1-2 per 100,000 patients in the general population.

Despite the low mortality rate from endometrial cancer in women taking tamoxifen, and the improvement in the 5-year survival of women with breast cancer who are on tamoxifen adjuvant therapy, there remains a statistically significant rise in the number of endometrial cancers and deaths from this cause after approximately 5 years on tamoxifen, as compared to placebo.

Venous thromboembolism (VTE)

VTE and post-surgical thromboembolism are also significantly more common in women on tamoxifen.

Tamoxifen in men has been known to cause headaches, nausea, vomiting, skin rashes, impotence, and loss of libido.

Cost-benefit ratio with prolonged therapy

The risks of endometrial cancer and of VTE are increased with the duration of tamoxifen therapy. This fact, along with the development of both new and acquired drug resistance, accounts for the recommendation to stop tamoxifen after 5 years.

Lately, however, the period has been increased to 10 years, in the face of evidence of continuing benefit from tamoxifen in the shape of lowered breast cancer recurrence and mortality rates in these patients.

Favorable side effects of tamoxifen

The partial estrogen agonist action of tamoxifen also leads to beneficial effects such as:

  • Reduced serum cholesterol levels
  • Reduced bone loss
  • Protection against atherosclerosis and cardiovascular disease in older women


Further Reading

Last Updated: Aug 16, 2023

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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