Study Bolsters Evidence Linking Menopausal Hormone Therapy to Breast Cancer

Menopause, the permanent cessation of a woman’s menstrual cycle, is associated with a natural decrease in the levels of the female sex hormones known as estrogen and progesterone. U.S. women reach menopause at a median age of 51 and are expected to live an average of approximately 30 years afterwards.[1]

As a result of declining hormones, some women experience postmenopausal symptoms, including hot flashes, night sweats and sleeping difficulty, as well as vaginal or vulvar atrophy and thinning bones (osteoporosis). Some women may find these symptoms uncomfortable and seek treatment for them.

The Food and Drug Administration (FDA) has approved synthetic hormone medications — known as menopausal hormone therapy (referred to hereafter as “hormone therapy”) — to treat moderate-to-severe postmenopausal symptoms, to treat vaginal or vulvar atrophy, and to prevent (but not treat) menopausal osteoporosis.[2] Not all hormone therapy products are approved for all three of these uses. Approved hormone therapy medications include estrogen-only medications (such as estradiol [VAGIFEM and others] and esterified estrogens [MENEST]), progestin-only medications (such as medroxyprogesterone [PROVERA]) and combination estrogen and progestin medications (such as conjugated estrogens and medroxyprogesterone [PREMPHASE, PREMPRO]).[3]

The FDA-approved labeling of all of these products indicates that they should be used at the lowest effective dose and for the shortest duration because they are associated with several serious risks.[4] One of these risks is breast cancer.

Although previous research has found that hormone therapy increases breast cancer risk, there was little evidence on whether this risk differs based on the type of hormone therapy and how this risk may vary over time.

A recent large study that addressed these questions showed that the longer the use of all types of hormone therapy (except vaginal estrogen, such as estradiol vaginal cream [ESTRACE]), the higher the risk of invasive breast cancer (breast cancer that spreads into surrounding breast tissue). It also found that combination hormone therapy is associated with a higher breast cancer risk than estrogen-only therapy. The study was led by U.K. researchers and was published in the Sept. 28, 2019, issue of the Lancet.

The Lancet study[5]

The researchers of the new study pooled data from 58 previous studies that were conducted in developed countries and published between 1992 and 2018. Collectively, the new study included long-term data on nearly 110,000 average-weight women who developed invasive breast cancer at an average age of 65 years. Half of those women had used menopausal hormone therapy. The researchers examined all types of hormone therapy (including oral, transdermal and vaginal). The average age at which women started using hormone therapy in these studies was 50 years.

The researchers found that all types of hormone therapy, except vaginal estrogen creams, were associated with an increased risk of developing invasive breast cancer when they compared similar users and nonusers of this therapy (similarity was based on participation in the same study as well as similar weight, age information, alcohol consumption and family history of breast cancer). Notably, breast cancer risk was greater for estrogen and progestin combination drugs than for estrogen-only drugs, particularly if the progestin was taken daily rather than intermittently.

Although the researchers found little risk of breast cancer following less than one year of hormone therapy, there was a definite increased risk within one to four years of using hormone therapy and progressively greater risks with longer use.

The researchers compared average-weight users of hormone therapy with similar average-weight nonusers of hormone therapy and estimated the number of women who would develop invasive breast cancer within 20 years as a result of hormone therapy (starting at age 50). They projected that after five-year use of hormone therapy, there would be one additional case of invasive breast cancer for every 50 women who used estrogen and daily progestin, one additional case for every 70 women who used estrogen and intermittent progestin and one additional case for every 200 women who used estrogenonly hormone therapy.

The researchers also estimated that the risk of breast cancer associated with 10-year use of hormone therapy (starting at age 50) in average-weight women is about twice as great as the risk for five-year use of hormone therapy. Overall, about one million of the 20 million cases of breast cancer diagnosed in western countries since 1990 was associated with hormone therapy, according to the researchers.

Other risks of hormone therapy

All types of hormone therapy can cause severe allergic reactions, blood clots (in the legs, lungs or eyes), high blood pressure, stroke, gallbladder disease or high triglyceride levels in the blood that could lead to pancreatitis (inflammation of the pancreas), dementia in women aged 65 or older, and liver problems.[6] Progestin-containing drugs also increase the risk of heart attacks.

Estrogen-only medications increase the risk of endometrial (lining of the uterus) cancer for women who still have a uterus. Therefore, women with a uterus who use these drugs need to take a progestin as well to prevent this cancer. Hormone therapy should not be used in women with unusual vaginal bleeding; those who have or had breast or uterine cancer; and those with a history of blood clots, bleeding disorders, heart attack, liver problems or stroke.

What You Can Do

If you are a woman who is considering hormone therapy to treat bothersome postmenopausal symptoms, discuss the benefits and risks of these medications with your doctor. If you decide to use hormone therapy, take the lowest effective dose of the FDA-approved form of the drug for the shortest time possible. Do not take compounded hormone therapy products (including those containing estriol) to treat menopausal symptoms because they are neither reviewed nor approved by the FDA.[7]

If your primary postmenopausal symptoms are related to vaginal or vulvar atrophy, you may want to try vaginal estrogens for these symptoms because they do not increase the risk of breast cancer.

Do not use ospemifene (OSPHENA) to treat moderate-to-severe pain with sexual activity due to vaginal changes that occur with menopause because this drug can trigger or increase hot flashes and may increase the risk of uterine cancer.[8]

Do not take paroxetine (BRISDELLE) to treat hot flashes because there is not sufficient evidence that it provides significant benefits (see the article for details).[9]

Maintain a healthy lifestyle after menopause, including maintaining a healthy weight and exercising, to optimize your health.
 

References

[1] U.S. Preventive Services Task Force. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force recommendation statement. JAMA. 2017;318(22):2224-2233.

[2] Pfizer Inc. Label: conjugated estrogens and medroxyprogesterone (PREMPRO). August 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=3aff3442-641c-4639-8273-cf0347d8e4c8&type=display. Accessed January 3, 2020.

[3] Food and Drug Administration. Menopause: Medicines to help you. August 22, 2019. https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you. Accessed January 3, 2020.

[4] Pfizer Inc. Label: conjugated estrogens and medroxyprogesterone (PREMPRO). August 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=3aff3442-641c-4639-8273-cf0347d8e4c8&type=display. Accessed January 3, 2020.

[5] Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: Individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394(10204):1159-1168.

[6] Food and Drug Administration. Menopause: Medicines to help you. August 22, 2019. https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you. Accessed January 3, 2020.

[7] Food and Drug Administration. Menopause and hormones common questions. December 5, 2019. https://www.fda.gov/consumers/free-publications-women/menopause-hormones-common-questions. Accessed January 3, 2020.

[8] Risks of ospemifene for menopause-related pain during intercourse. Worst Pills, Best Pills News. June 2014. /newsletters/view/903. Accessed January 3, 2020.

[9] Carome MA, Almashat S, Wolfe S., Public Citizen's Health Research Group. Testimony before the FDA's Advisory Committee on Reproductive Health Drugs on new drug application (NDA) 204-516, paroxetine mesylate capsules for treatment of vasomotor symptoms associated with menopause. https://www.citizen.org/wp-content/uploads/migration/2100.pdf. Accessed January 3, 2020.