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by Dr. C.H. Weaver M.D. 2/2022

Hormone replacement therapy (HRT) is often prescribed for women during menopause. Menopause is a natural phase of maturing womanhood, during which the ovaries produce significantly less estrogen, ovulation ceases, and menstruation ends. For many women, menopause has uncomfortable side effects. Hot flashes, sleep disturbances, depression, mood swings and anxiety may affect the menopausal woman. Additionally, menopause may also be accompanied by increased urinary tract infections, incontinence, vaginal discomfort due to a lack of estrogen-based lubrication and decreased bone density. HRT has been effectively used to mitigate these side effects and can be prescribed for women experiencing these unpleasant symptoms of menopause. Results from several clinical studies have demonstrated a correlation between the use of HRT and the development of breast cancer, as well as an increase from death caused by breast cancer.

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There are two main types of HRT:

  • Combination HRT contains the hormones estrogen and progesterone
  • Estrogen-only HRT contains only estrogen

Combination HRT

Combination HRT combines and estrogen and progestin and increases breast cancer risk by about 75%.1 Combination HRT also increases the likelihood that the cancer may be found at a more advanced stage, as well as increasing the risk that a woman diagnosed with breast cancer will die from the disease. Breast cancer risk increases the most during the first 2 to 3 years of taking combination HRT. Higher-dose combination HRT increases breast cancer risk more than lower-dose combination HRT. Breast cancer risk goes back down to average about 2 years after you stop taking combination HRT.2 HRT use with estrogen alone or estrogen plus progesterone has also been evaluated among black women and found to increase the risk of breast cancer.5

Estrogen-only HRT

Hormone replacement therapy consisting of estrogen alone increases the risk of breast cancer, but only when used for more than 10 years. However, the risk of stroke with the use of estrogen-only HRT is significantly increased and the Women’s Health Initiative Steering Committee has recommended that HRT should not be used to prevent chronic illness.

Hormone Replacement Therapy in Newly Menopausal Women May Carry More Benefit

Hormone replacement therapy for newly menopausal women may not be as risky as once believed.3 In fact, the researchers concluded that combination HRT in newly menopausal women relieves symptoms and improves mood, bone density, and several markers of cardiovascular risk.

The Kronos Early Estrogen Prevention Study (KEEPS) trial was a multi-center, randomized study that included 727 healthy women ages 42 to 58, all within three years of onset of menopause at baseline. The study differs from many previous studies on HRT, including the WHI, because the participants were younger—the mean age was 52, compared to 60s for the other trials.15

Women in the KEEPS trial were randomly assigned to one of three groups: placebo, progesterone plus oral estrogen, progesterone plus an estrogen patch. Both intervention groups experienced a reduction in menopausal symptoms, including hot flashes and night sweats, as well as improved sexual function and improved bone mineral density compared to the placebo group. What’s more—the results indicated that oral estrogen plus progesterone improved lipid levels and the estrogen patch improved insulin sensitivity. Neither combination raised blood pressure or altered the progression of atherosclerosis (hardening of the arteries).

The data is in sharp contrast with the WHI and other studies that raised the alarm flags regarding the use of HRT. The results of one study cannot provide enough information to make an informed decision regarding HRT use; however, they can add to the existing information so that women can make informed decisions.

The Women’s Health Initiative (WHI) study was a large study involving thousands of postmenopausal women to evaluate the effects of HRT. One component of the WHI included women who received estrogen-only HRT. These women were compared to women who received placebo (inactive substitute)- (a second component of the WHI that evaluated estrogen plus progestin HRT was halted in 2002 due to the increase in health risks with HRT compared to placebo). The estrogen-only HRT component of WHI included over 10,000 women who were aged 50 to 79 years who had a prior hysterectomy (surgical removal of the uterus). After nearly 7 years of follow-up, this component was halted due to the increase in the risk of stroke by nearly 40% for patients treated with estrogen-only HRT compared to those who received placebo. However, the risk of coronary heart disease and bone fractures was decreased in the group of women treated with estrogen-only HRT compared to placebo. The incidence of breast cancer was not significantly different in either group of women.

Researchers from Harvard University evaluated the possible associations between long-term use of estrogen-only HRT among postmenopausal women involved in the Nurses’ Health Study. The research included 28,835 postmenopausal women who had a hysterectomy (surgical removal of the uterus); they reported their use of HRT. Overall, women who had taken estrogen alone for long-term use had an increased risk of developing breast cancer.

  • Women who had taken estrogen alone for 10 years or less did not have an increased risk of breast cancer.
  • Women taking estrogen for 15-20 years had an 18% increased risk of developing breast cancer.
  • Women taking estrogen for 20 or more years had a 42% increased risk of developing breast cancer.

The researchers concluded that long-term use of estrogen only increases the risk of developing breast cancer in women. Individuals taking estrogen to minimize menopausal symptoms or for osteoporosis should discuss their individual risks and benefits of this treatment with their physician.6

The higher breast cancer risk from using HRT is the same for so-called "bioidentical" and "natural" hormones as it is for synthetic hormones. "Bioidentical" means the hormones in the product are identical to the hormones your body produces. Bioidentical hormones are said to be "natural" — derived from plants. Synthetic hormones are made in a lab and are also chemically identical to the hormones in your body. It's important to know that many herbal and bioidentical HRT products fall outside the jurisdiction of the United States Food and Drug Administration and so aren't subject to the same regulations and testing that medications are.

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HRT in Women With Breast Cancer

Women diagnosed with breast cancer or have tested positive for an abnormal breast cancer gene (BRCA1 or BRCA2) shouldn't use HRT. The hormones in HRT can cause hormone-receptor-positive breast cancers to develop and grow.3 HRT however may not increase the risk of developing a cancer recurrence in postmenopausal patients with hormone-receptor negative early stage breast cancer. Patients with hormone-receptor negative, early-stage breast cancer with postmenopausal symptoms may wish to discuss the risks and benefits of HRT with their physician.4

Postmenopausal Hormone Use Linked with Specific Types of Breast Cancer

According to the results of a study published in the journal Lancet Oncology, use of postmenopausal hormones increases the risk of lobular and tubular breast cancers more than other types of breast cancer.13

A question that has remained uncertain is whether the link between postmenopausal hormones and breast cancer varies by type of breast cancer. To explore this question, researchers evaluated information from the U.K. Million Women Study.9 The study enrolled over one million women between the ages of 50 and 64.

During follow-up, roughly 14,000 of the women were diagnosed with breast cancer. Close to 12,000 of these diagnoses were invasive breast cancer (ductal, lobular, mixed ductal-lobular, tubular, medullarly, and mucinous) and the remainder was in situ breast cancer (either ductal or lobular).

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  • Compared to women who had never used postmenopausal hormone therapy, women who were current users had a roughly 60% increased risk of invasive ductal or invasive mucinous cancers, and a more than two-fold increased risk of invasive lobular or invasive tubular cancers. Postmenopausal hormone use was not linked with risk of invasive medullary cancers.
  • Current use of postmenopausal hormone therapy increased the risk of lobular carcinoma in situ (LCIS) to a greater extent than ductal carcinoma in situ (DCIS).
  • Risk of breast cancer was greater in current users of postmenopausal hormone therapy than in past users.
  • For each type of breast cancer, use of combined estrogen plus progestin carried a greater risk of breast cancer than use of estrogen alone.
  • The link between postmenopausal hormone use and breast cancer was weaker among women with a high body mass index (BMI).

The results of this study suggest that postmenopausal hormone therapy increases the risk of lobular and tubular breast cancers to a greater extent than other types of breast cancer. Risk of breast cancer appeared to be higher among current users of postmenopausal hormones than among past users, and was also higher among users of combined estrogen plus progestin than among users of estrogen alone. The link between postmenopausal hormones and breast cancer was weaker among women with a high body mass index.

HRT and Ovarian Cancer

Hormone-replacement therapy is also linked to an increased risk of developing ovarian cancer.9-12

Researchers from England evaluated data from the Million Women Study, a study that involved nearly 950,000 postmenopausal women. The participants had not had previous cancers and had not had their ovaries surgically removed. Use of HRT, incidence of ovarian cancer, and potential variables that may have contributed to ovarian cancer were evaluated.

  • Women who were currently taking HRT and had taken HRT for at least five years had an approximate 23% increased risk of death from ovarian cancer compared with women who had never used HRT.
  • The risk of ovarian cancer returned to normal among women who had stopped taking HRT.
  • The researchers stated that the risks of three cancers-breast cancer, endometrial cancer, and ovarian cancer-was increased 63% among current users of HRT compared with women who had never used HRT.
  • Overall, an increased risk of ovarian cancer translates to one extra death among approximately 3,300 users of HRT, or 1,300 additional cases of ovarian cancer and 1,000 deaths from ovarian cancer since 1991 in England alone.
  • The type of HRT formulation did not affect risk of ovarian cancer.

Ovarian Cancer Rates Appeared to Drop Along with a Drop of Hormone Therapy

Ovarian cancer rates began to decline faster in 2002, which is about the same time many older women stopped using hormone replacement therapy, according to the results of a study published in the Journal of Clinical Oncology.

Although HRT had been widely prescribed for menopausal women, it came under scrutiny as a result of the Women’s Health Initiative (WHI) Study in 2002, which indicated that it could be linked to increased incidence of certain types of cancer and other health problems—most notably, breast cancer, stroke, and heart attack. After the WHI report, many women stopped using menopausal HRT in the United States—and the precipitous decline was linked to a decline in breast cancer rates. Because HRT has also been associated with an increased risk in ovarian cancer, researchers conducted a study to determine whether ovarian cancer rates also declined after 2002.

The researchers used the North American Association of Central Cancer Registries database to compare changes in ovarian cancer incidence rates from 1995 to 2002 (before the WHI report) and from 2003 to 2008 (after the WHI report). They found a significant change in the incidence rate for women over 50, but not younger women. Among this population, ovarian cancer rates fell by about 0.8 percent per year prior to 2002 and then by 2.4 percent per year after 2002. Analysis models confirmed an accelerated decline in ovarian cancer rates after 2002. The researchers note that this does not mean there is a cause-effect relationship between ovarian cancer and HRT—but there may be an association and it is important to understand how exposures affect incidence rates.

HRT appears to increase the risk of developing ovarian cancer among postmenopausal women. However, women who have not used HRT for at least five years and those who have stopped using HRT appear to have a risk similar to that of the general population. Postmenopausal women who are experiencing menopausal symptoms should discuss their individual risks and benefits of HRT with their healthcare provider.

HRT and Lung Cancer

Researchers identified a potentially increased risk of dying from lung cancer in women taking HRT.14 To explore the relationship between HRT and lung cancer specifically, researchers evaluated information from the Vitamins and Lifestyle [VITAL] Study. This study enrolled 36,588 women from Washington State who were aged 50 to 76. Among study participants, 344 cases of lung cancer were identified.

  • Use of combined HRT for one to nine years was associated with a 27% increased risk of lung cancer.
  • Use of combined HRT for 10 or more years was associated with a 48% increased risk of lung cancer.
  • HRT with estrogen only was not associated with an increased risk of lung cancer.
  • Longer duration of combined HRT use was associated with diagnosis of lung cancer at a more-advanced stage.

The researchers concluded that risk of lung cancer increased among women with increasing duration of use of combined HRT. As well, women using combined HRT for longer periods had more-advanced stage lung cancer at diagnosis.

Other Risks of HRT

Use of hormone-replacement therapy is linked to an increased risk of developing ovarian cancer. Researchers from England evaluated data from the Million Women Study, a study that involved nearly 950,000 postmenopausal women. The participants had not had previous cancers and had not had their ovaries surgically removed. Use of HRT, incidence of ovarian cancer, and potential variables that may have contributed to ovarian cancer were evaluated.

  • Women who were currently taking HRT and had taken HRT for at least five years had an approximate 23% increased risk of death from ovarian cancer compared with women who had never used HRT.
  • The risk of ovarian cancer returned to normal among women who had stopped taking HRT.
  • The researchers stated that the risks of three cancers-breast cancer, endometrial cancer, and ovarian cancer-was increased 63% among current users of HRT compared with women who had never used HRT.
  • Overall, an increased risk of ovarian cancer translates to one extra death among approximately 3,300 users of HRT, or 1,300 additional cases of ovarian cancer and 1,000 deaths from ovarian cancer since 1991 in England alone.
  • The type of HRT formulation did not affect risk of ovarian cancer.

The researchers concluded that HRT appears to increase the risk of developing ovarian cancer among postmenopausal women. However, women who have not used HRT for at least five years and those who have stopped using HRT appear to have a risk similar to that of the general population. Postmenopausal women who are experiencing menopausal symptoms should discuss their individual risks and benefits of HRT with their healthcare provider.8

Steps you can take

Menopausal side effects can dramatically reduce quality of life for some women. These women have to weigh the benefits of HRT against the risks. If you're having severe hot flashes or other menopausal side effects and are considering HRT, talk to your doctor about ALL of your options. Ask how you can minimize your breast cancer risk AND relieve your symptoms. Be sure to discuss the pros and cons of different types of HRT. Research strongly suggests that estrogen-only HRT appears to increase breast cancer risk less than combination HRT. If you do decide to take HRT, ask if you can take a lower-dose formula and talk to your doctor about taking it for the shortest time possible.

References

  1. Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684-1692. doi:10.1001/jama.2010.1500.
  2. Olsson HL, Ingvar C, Bladstrom A, Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer. 2003; 97: 1387-1392.
  3. Holmberg L, Anderson H, for the HABITS Steering and Data Monitoring Committees, HABITS (Hormonal Replacement Therapy After Breast Cancer-is it Safe?), A Randomized Comparison:Trial Stopped. The Lancet, Published Online February 3, 2004.
  4. Vassilopoulou-Sellinn R, Cohen DS, Hortobagyi GN, et al. Estrogen replacement therapy for menopausal women with a history of breast carcinoma. Results of a 5-year, prospective study.
  5. Rosenberg L, Palmer J, Wise L, Adams-Campbell L. A Prospective Study of Female Hormone Use and Breast Cancer Among Black Women. Archives of Internal Medicine. 2006;166:760-765.
  6. Chen W, Manson J, Hankinson S, et al. Unopposed Estrogen Therapy and the Risk of Invasive Breast Cancer. Archives of Internal Medicine. 2006; 166:1027-1032.
  7. The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative Randomized Controlled Trial. Journal of the American Medical Association. 2004;291:1701-1712.
  8. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet [early online publication].2007. April 19, 2007. doi:10.1016/S0140-6737(07) 60534-0.
  9. Beral V, et al. Ovarian cancer and hormone replacement therapy in the Million Women Study.Lancet [early online publication].2007. April 19, 2007. doi:10.1016/S0140-6737(07) 60534-0.
  10. Riman T, Dickman P, Nilsson S, et al. Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. Journal of the National Cancer Institute. 2002:94;497-504)
  11. Journal of the American Medical Association. 2002;288:334-341.
  12. Yang HP, Anderson WF, Rosenberg PS, et al. Ovarian cancer incidence trends in relation to changing patterns of menopausal hormone therapy use in the United States. Journal of Clinical Oncology. Published early online May 6, 2013. doi: 10.1200/JCO.2012.45.5758.
  13. Reeves GK, Beral V, Green J, Gathani T, Bull D for the Million Women Study Collaborators. Hormonal Therapy for Menopause and Breast Cancer Risk by Histological Type: a Cohort Study and Meta-analysis. Lancet Oncology. 2006;7:910-18.
  14. Chlebowski RT, Schwartz AG, Wakelee H, et al. Estrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): A post-hoc analysis of a randomized controlled trial. The Lancet [early online publication]. September 20, 2009. DOI: 10.1016/S0140-6737(09)61526-9.
  15. Manson JE, et al. New findings from the Kronos early estrogen prevention study (KEEPS) Randomized trial. Presented at the 23rd Annual Meeting of the