Hormone Replacement Therapy
At a Glance
Hormone replacement therapy (HRT) often includes a combination of estrogen and progestin, prescribed to treat menopausal symptoms in women.
HRT is a known carcinogen recognized by the International Agency for Research on Cancer (IARC) that has been associated with an increased risk of breast cancer, heart disease, stroke and blood clots.
The components of BiCs, estradiol and progesterone, have also been determined by IARC to be either known or reasonably anticipated carcinogens and associated with numerous negative health outcomes.
What are traditional hormone replacement therapy (HRT) and Bioidentical compounds (BiCs)?
HRT is generally prescribed for menopausal symptoms. Most standard formulations include both estrogen and progestin components, with both the estrogen and the progestin being in a synthetic form. Conjugated equine estrogen and ethinylestradiol are commonly used estrogens; medroxyprogesterone acetate or norethisterone acetate are common progestins used in these formulations. Estrogen-only HRT can be prescribed, but only for women who have previously undergone surgical hysterectomies.
Because of concerns about potential health effects of using synthetic-hormone based HRT, many women have moved to taking ‘Bioidentical Compounds’ (BiCs), or compounds that contain estradiol (or another natural estrogen) and progesterone, chemicals that are normally produced by the ovary across the normal menstrual cycle, but are actually synthesized from plant estrogens for use in BiCs.
While the components of traditional HRT are described by pharmaceutical companies on packaging in the formulations, BiCs have varying formulations, sometimes being custom-mixed for an individual woman.
Where is hormone replacement therapy found?
Both HRT and BiCs are pharmaceutical compounds and must be prescribed by a physician. While commonly taken in the form of a pill, both forms of hormone treatment may also be offered as creams or patches.
What evidence links hormone replacement therapy to breast cancer?
Several studies have found an increased risk of breast cancer in people using HRT.
- The Women’s Health Initiative (WHI) was a clinical trial and observational study designed to explore the benefits and risks of combined estrogen-progestin HRT in post-menopausal women. In 2002, the project was halted prior to the end of the study, because researchers observed a significant increase in the relative risk of breast cancer. ,
- Analyses of a second arm of the WHI study clarified that the increased risk of breast cancer detected in the study occurred in women taking the combined estrogen-progestin formula, while a decreased risk for breast cancer was found among women taking estrogen-only HRT supplements., It is critical to note that the estrogen-only option can only be offered to women who have previously undergone surgical hysterectomies, because estrogen alone increases the risk of uterine cancer.
- Swedish researchers halted a five-year study in 2003 after only two years because women with a history of breast cancer taking the combined estrogen-progestin HRT had a significant increase in new tumors compared to women who received other treatments for menopausal symptoms.
- In 2003, researchers in the Million Women Study (MWS) in the United Kingdom reported the then-current use of all types of post-menopausal HRT significantly increased the risk of breast cancer., Again, the risk was greatest among users of estrogen-progestin combination therapy.
- Through a California statewide registry and California Health Interview Survey of almost 3 million women, researchers confirmed that combined HRT increases the risk of breast cancer in post-menopausal women, and that stopping use of the combination pill leads to decreased risk of developing breast cancer. Decreased incidence in breast cancer was highest (22.6%) in groups with the greatest decline in using HRT, reducing to 13.9% in moderate HRT use, and smallest (8.8%) with least decline in HRT use.
- A Danish study followed for about 18 years almost 30,000 women aged 50-64 at the beginning of the study. Researchers found that use of HRT at the time of entering the study was associated with a significant increase in later development of breast cancer risk. Alcohol consumption also increased breast cancer risk, and together, alcohol and HRT exerted additive risk.
What evidence links bioidentical compounds to breast cancer?
Studies on bioidentical compounds are more difficult to conduct because the formulations are often personalized, so the dosage may not be standardized. Their use is more recent so there has been less time for extensive follow-up. Nevertheless, there have been a few important studies in the area.
- In a systematic review of published articles on the use of progesterone as part of hormone therapy formulations, the authors concluded that there was no indication of increased risk of breast cancer for women who had taken combined estradiol-progesterone treatments for less than five years. They found ‘limited evidence’ that there was a slightly increased risk for developing breast cancer when the BiCs were taken for more than five years.
- A study found that women taking bioidentical progesterone had a lower risk of developing invasive breast cancer than women taking a synthetic progesterone.
- Researchers found that women who had undergone surgical removal of the uterus and who initiated use of BiC estrogen (estradiol) alone had a decreased risk of developing breast cancer. However, the synthetic estrogens used in traditional HRT decrease breast cancer risk at a greater magnitude than the natural or bioidentical form. Similarly, when paired with synthetic progestins, the bioidentical form of estrogen is less effective than the synthetic forms found in HRT.
What about effects of taking HRT or BiCs by women who have been diagnosed with breast cancer?
- Swedish researchers examined the effects of taking HRT for 2 years following treatment for metastatic breast cancer. As compared to breast cancer survivors who did not take HRT, those taking the compound had an increased risk of a new breast cancer event—either a recurrence of the previously diagnosed cancer or diagnosis of a new, contralateral cancer. At the end of the 5-year follow-up, there was no difference in either the risk of distant metastasis of breast cancer, nor of mortality. 
- A qualitative summary of the safety of HRT use following diagnosis with breast cancer reported that many of the studies were poorly designed and sometimes contradictory. The researchers concluded that, “There are currently no reassuring data indicating the absence of a harmful effect of” HRT in women who have been treated for breast cancer.
Who is most likely to be exposed to hormone replacement therapy?
Women who are experiencing menopausal symptoms and have been prescribed HRT by their physician.
Who is most vulnerable to health effects of hormone replacement therapy?
A study examining the possible interactions between use of HRT and race, weight and breast density found that HRT use increased risk for breast cancer in White, Asian and Hispanic women, but not Black women. It is important to note there was no interaction between HRT use and either body mass index or breast density.
Similar data for different ethnicities have not been conducted for BiCs. The American College of Clinical Endocrinologists and the American College of Endocrinologists, along with the U.S. Preventive Task Force, all recommend against the use of BiCs because of potential adverse health effects, including increased risk of developing breast cancer.
What are the top tips to avoid exposure?
Limit use. The IARC advises that, if possible, you should avoid or limit the use of hormone replacement therapy. If HRT is started, the treatment should be taken for the shortest time and at the lowest dose possible to control the symptoms of menopause. The precise therapy should be discussed with the physician before starting treatment.
 Writing Group for the Women’s Health Initiative Investigators (2002). Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. J Am Med Assoc, 288(3):321-333. doi:10.1001/jama.288.3.321.
 Rossouw, J., Anderson, G., Prentice, R., LaCroix, A., Kooperberg, C., Stefanick, M., … Ockene, J. (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women. J Am Med Assoc, 288, 321–333.
 Anderson, G., Limacher, M., Assaf, A., Bassford, T., Beresford, S., Black, H., … Wasserthell-Smoller, S. (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled study. J Am Med Assoc, 291, 1701–1712.
 Anderson, G.L., Chlebowski, R. T., Aragaki, A.K., Kuller, L.H., Manson, J.E., Gass, M., … Wactawski-Wende, J. (2012). Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol, 13(5), 476–486.
 Holmberg, L., & Anderson, H. (2004). HABITS (hormonal replacement therapy after breast cancer—is it safe?) trial stopped. Lancet, 363, 453–455.
 Beral, V. (2003). Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 362(9382), 419–427.
 Anderson, G.L., Chlebowski, R.T., Aragaki, A.K., Kuller, L.H., Manson, J.E., Gass, M., … Wactawski-Wende, J. (2012). Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol, 13(5), 476–486.
 Robbins, A., & Clarke, C. (2007). Regional changes in hormone therapy use and breast cancer incidence in California from 2001 to 2004. J Clin Oncol, 25, 3437–3439.
 Holm M, Olsen A, Kyrø C, Overvad K, Kroman N, Tjønneland A. The Influence of Menopausal Hormone Therapy and Potential Lifestyle Interactions in Female Cancer Development—a Population-Based Prospective Study. Hormones and Cancer. 2018;9(4):254–64.
 Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018;21(2):111–22.
 Davis, R., Batur, P., & Thacker, H. L. Risks and effectiveness of compounded bioidentical hormone therapy: A case series. J Wom Health. 2014; 23(8): 642-648.
 Zeng Z, Jiang X, Li X, Wells A, Luo Y, Neapolitan R. Conjugated equine estrogen and medroxyprogesterone acetate are associated with decreased risk of breast cancer relative to bioidentical hormone therapy and controls. PLoS ONE. 2018;13(5).
 Holmberg L, Iversen O-E, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Nat Cancer Inst. 2008;100(7):475–82.
 Antoine C., Liebens, F., Carly, B., Pastijin, A., Neusy, S. & Rozenberg, S. Safety of hormone therapy after breast cancer: a qualitative systematic review. Human Reprod. 2007; 22(2): 616-622.
 Files, J. A., Ko, M. G., & Pruthi, S. Bioidentical hormone therapy. Mayo Clinic proceedings. Mayo Clin. 2012; 86(7): 673–680.
 Hou, N. (2013). Hormone Replacement Therapy and Breast Cancer: Hererogeneous Risks by Race, Weight, and Breast Density. Oxford Journals, 105 (18).
 Cobin RH, Goodman NF. American association of clinical endocrinologists and American college of endocrinology position statement on menopause – 2017 update. Endocrine Practice. 2017;23(7):869–80.
 Gartlehner G, Patel SV, Feltner C, Weber RP, Long R, Mullican K, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women evidence report and systematic review for the US preventive services task force. JAMA – Journal of the American Medical Association. 2017;318(22):2234–49.
 IARC: International Agency for Research on Cancer (2016). European Code Against Cancer: 12 Ways to Reduce Your Cancer Risk. http://cancer-code-europe.iarc.fr/index.php/en/ecac-12-ways/pharmaceutical-drugs/questions/68-hormone-replacement-therapy. (Retrieved August 31, 2016.