Dr. Tori Hudson, N.D.

An estimated 6,000 US women daily and more than 2 million women yearly reach menopause, and that does not include perimenopausal women. The US population aged 65 and over grew nearly five times faster than the total population over the century from 1920 to 2000 according to the 2020 US Census. This group is now 16.8% of the population in the U.S. This dramatic increase in the number of menopausal women is changing the way healthcare providers work with women, and changing medicine itself. At no other time in history have we had so many individuals dealing with the same set of health issues. Now more than ever, clinicians have options for the management of menopause: diet, exercise, stress management, nutrition, nutraceuticals, botanicals, hormones of all sizes/shapes and kinds, and additional pharmaceuticals.

 

One of the most complicated and difficult healthcare decisions that menopausal women face today, is whether to use menopausal hormone therapy (MHT). Women look to their healthcare providers for definitive answers to their questions. Practitioners are faced with an even greater challenge, evaluating the benefits and risks of MHT for an individual patient. Too many women are receiving misinformation from their providers…whether it’s their gynecologist, PCP, functional medicine practitioner, integrative medicine doctor, or naturopathic physician. This short article will hope to provide essential information on MHT and breast cancer risk, so that well informed decisions can be made.

 

History Shows Estrogen and Estrogen Replacement Therapy Do Not Increase Breast Cancer Risk

Let’s do a quick history to help lay the groundwork. A good overview with more details of this history comes from the book, Estrogen Matters (by Avrum Bluming MD and Carol Tavris PhD).

• Late 1800s:

A few physicians suggested a causal relationship between a likely product in the ovaries, estrogen, could lead to the development and progression of breast cancer. They site a few observations in their practice including a perimenopausal woman whose breast cancer regressed 6 months after cessation of menses; one physician hypothesized and another performed bilateral oophorectomy in a woman with breast cancer and her tumor regressed completely, and another removed both ovaries in a woman with metastatic breast cancer and she survived for 12 more years.

• About 50 years later, in 1942, large quantities of estrogen could be extracted from the urine of pregnant mares and Ayerst Laboratories produced the first estrogen tablets, “Premarin”
• 1950s: Ayerst began to market Premarin as a treatment for menopausal symptoms.
• 1980s and 1990s: little evidence to warrant concerns
• 1986: a National Cancer Institute (NCI) study found no statistically significant increase in breast cancer in women on Premarin for users even among women with >20 years of use.[1]
• 1988: Meta-analysis of twenty-two studies found no statistical association between estrogen replacement therapy (ERT) and breast cancer.[2]
• 1989: Women with benign breast biopsies had a median duration of follow-up of 17 years. Women who were given estrogen following the biopsy, even if they had a family history of breast cancer, did not subsequently have an increased risk of breast cancer.[3]
• 1991: Study found no increased risk of breast cancer among Premarin users even after fifteen years of use.[4]
• 1991: Analysis of twenty-eight studies found no association between ERT and breast cancer.[5]
• 1992: First randomized, double-blind, placebo-controlled trial was published. After more than 20 years, 11.5% of the women taking placebo had developed breast cancer but NONE of the women on hormone replacement therapy (HRT) had.[6]
• 1995: The first wave of results from the Nurses Health Study showed that after being followed for 15 years, those nurses who had used HRT at any point, even if more than 10 years, had no increased risk of breast cancer compared to women who never took HRT.[7]
• 1996: A prospective study with the American Cancer Society found that those who had ever taken estrogen therapy had a small but significantly decreased risk of dying of breast cancer.[8]

 

Why Did Everyone Become So Fearful of Estrogen?

There were a few contradictory studies but by the year 2000, the consensus among major research institutions, medical journals including the British Medical Journal and the New England Journal of Medicine, and leading oncologists was that estrogen did not increase the risk of breast cancer. However, there were two big studies that made a case for the dangers of MHT:

• A 1989 study in NEJM reported a 440% increased risk of breast cancer among women who had been on HRT. However, they found NO increased risk among women taking estrogen alone. And, in an unspecified smaller number of the 638 patients who were taking estrogen and progestin, they had calculated that 2.2 breast cancers would be expected. Instead, breast cancer developed in 10 women – that’s where the 440% increase in risk number came from. It is thought by others that with numbers that small, the increase could have been a statistical fluke and as it turns out, the researchers admitted that their result was not statistically significant.[9]
• The second big study cited by those who think that HRT is unsafe is a 1997 study published in the Lancet. It was a survey of fifty-one epidemiological studies from twenty-one countries involving over 52,000 women with breast cancer and over 108,000 women without breast cancer. The researchers reported NO increase in breast cancer among women who had taken HRT in the past, regardless of duration. Instead of this being their final conclusion, they reanalyzed their large amount of data to see if they could find any subgroup of women who showed an increased risk of breast cancer associated with HRT. They did so by extracting the women who were still on HRT at the time of the interview, who had been on it for five or more years.[10] Even in this sample, the increased number of breast cancers in one hundred women taking estrogen for ten or more years was 0.6, less than one additional case.[11]
• In 2002, the Women’s Health Initiative took center stage; the largest prospective study in which
  women were randomized to take either hormones or a placebo and then followed over time.[12] The part of the study that involved women on estrogen (conjugated equine estrogens=CEE, aka Premarin) and progestin, medroxyprogesterone acetate (MPA, aka Provera) was stopped because of increased risks of breast cancer, coronary heart disease, stroke and pulmonary embolism. The story was like a bomb and panic and confusion ensued for several years after.

 

The details of the hormones and breast cancer risk from this initial study were actually the following:

• Women who had been on estrogen only, because they had no uterus and did not need to take the progestin, had NO increased risk of breast cancer.
• The women on estrogen and progestin had a small increased risk of breast cancer (1.26) compared to women on placebo. What that number means, 1.26 is a 26% increase in risk, and in terms of the study “almost reached nominal statistical significance”. Even more importantly, this daily dose of continuous combined CEE + MPA after 4 years resulted in an increased risk of breast cancer, with nine additional breast cancer cases per 10,000 person-years of therapy which is not quite 1 woman out of 1,000 women per year.
• Continuation of estrogen therapy-only women in the WHI: Women who received CEE alone in the WHI showed a non-significant REDUCTION in breast cancer risk after an average of 7.2 years of randomization, with seven FEWER cases of invasive breast cancer per 10,000 person-years of CEE.[13] A significant reduction in breast cancer became evident in the post-intervention phase, with a median of 20 years cumulative follow-up.[14]

 

Where We’ve Come Since Then

As of this time, no large randomized clinical trials (RCTs) have assessed the effect of long durations of MHT. Both the estrogen-progestin therapy (EPT) group from the WHI or the estrogen therapy (ET) only group reported fairly short-term data (7.2 years for the ET and 5.6 for EPT). Both were terminated early because of predefined safety considerations.

They provided long term follow-up at 13 and 20 years about continued use for 5-7 years, but there is no longer-term data available. The recent pooled analysis of observational data in the Collaborative Group Study included data on durations of hormone therapy use in women who started taking hormones when they were 45-54 years of age.[15] The risk of breast cancer increased with duration of use in each age category:

• ET for 1-4 years: 1.23
• ET for 5-9 years: 1.29
• ET for 10-14 years: 1.44
• ET for 15 years or more: 1.61

 

• EPT for 1-4 years: 1.66
• EPT 5-9 years: 1.96
• EPT for 10-14 years: 2.31
• EPT for 15 years or more: 2.68

It’s important to remember that the attributable risk of breast cancer in women with a mean age of 63 from the WHI was randomized to CEE plus MPA, and the results were less than one additional case of breast cancer diagnosed per 1,000 years annually. That was the 1.26 hazard ratio in the original 2002 publication. This risk is only slightly greater than the risk associated with having one glass of wine, it’s lower than the risk of having two glasses of wine, and  similar to the risk reported with obesity and low physical activity.[16]^{, [17]}  Even if a woman falls into one of these categories, there appears to be no additive effect of hormone therapy on personal breast cancer risk or incidence. In other words, she may have an increased risk of breast cancer already.

 

Breast Cancer Risks Associated with HRT and Genetic Factors

Current observational evidence suggests that MHT use does not further increase the relative risk of breast cancer in women with a family history of breast cancer, in women after oophorectomy (removing both ovaries) for BRCA 1 or 2 genetic variants, or in women having undergone a benign breast biopsy.[18], [19], [20], [21], [22],[23], [24] The Two Sister study of 1,419, which sister-matched cases of breast cancer in women younger than 50 years of age, also showed no increased risk of young-onset breast cancer with the use of EPT. Unopposed estrogen use was also associated with a reduction in the diagnosis of breast cancer in these younger women.[25]

 

Some Risks Are Associated with Other Types of Hormones

There is no evidence of any difference in the risk of breast cancer as it relates to estrogen, whether it be bio-identical estradiol or CEE.  This might be surprising to hear.  There are some modest differences in stroke and anxiety between bio-identical estradiol and CEE, but it is minor and with only a small amount of evidence.  However, there is some observational scientific published data that suggests that bio-identical micronized progesterone and dydrogesterone may have a lesser association with breast cancer than do the synthetics such as norethindrone and MPA.[26]  I have concluded that this is a primary reason to use micronized progesterone, aka bio-identical progesterone vs. synthetic progestins in peri and postmenopausal women who have a uterus and are on systemic estrogen.

 

Should Female Patients Take Hormone Therapy After Breast Cancer?

Two randomized clinical trials report conflicting outcomes of the recurrence of breast cancer with MHT. As a result, systemic use of hormone therapy in survivors of breast cancer is generally not recommended. If symptoms of menopause persist and are unresponsive to non-hormone options, whether that be herbal, nutraceutical or pharmaceutical, some patients may choose hormone therapy after being fully informed of the benefits and risks. I would always communicate with her PCP and/or oncologist in such situations. This point does not include the low dose vulvo-vaginal estrogen options for genitourinary syndrome of menopause (GSM). Both the Menopause Society and the American College of Ob/Gyns have published position statements on GSM and the use of low dose vaginal or vulvar estrogen.

 

Key Takeaways from the Research

• The risk of breast cancer related to MHT (estrogen plus progestogens) use is very low, indicating rare occurrence (less than one additional case per 1,000 women per year of hormone therapy use).
• To put things in perspective, women need their providers to inform them that the risk of breast cancer and MHT is less than one daily drink of alcohol, less than being obese, and less than low physical activity. Drinking two glasses of alcohol per day is a higher risk.
• The effect of hormone therapy on breast cancer risk may depend on the type, with bio-identical micronized progesterone in conjunction with systemic estrogen presenting lower to no risk.
• Bio-identical estradiol has no difference in safety than CEE in terms of breast cancer risk.
• Most of the data show no additive effect of underlying breast cancer risk with hormone therapy use on breast cancer incidence. These underlying risks include age, family history of breast cancer, family member with genetic risk of breast cancer, benign breast disease, and personal breast cancer risk factors.
• Observational data suggests that hormone therapy use does not further increase the risk of breast cancer in women at high risk due to a family history of breast cancer or after bilateral salpingo-oopohrectomy (BSO) for BRCA 1 or 2 genetic variants.
• Do not use systemic MHT for breast cancer survivors, although a judgment call can be made, by the patient, if symptoms are unresponsive to other non-hormonal efforts.
• If breast cancer survivor with GSM, one can safely use low dose vaginal estrogen or DHEA if the symptoms are bothersome or persist after attempts at moisturizers three times weekly.
• Regular breast cancer screening is recommended for all postmenopausal women, whether on MHT or not.

 

I highly recommend the 2022 hormone therapy position statement of The North American Menopause Society (NAMS )in Menopause 2022; 29(7): 767-794. This will provide the citations for this topic from important papers, along with a full concise discussion of the benefits and risks of MHT for those readers who want more in depth information. They, unfortunately, take a contrarian view on compounding hormones, although they do have some good points, but I do not agree with all of their conclusions. Practitioners of an alternative and integrative model recognize that individualized dosing that is not available from big pharmaceutical companies can be a meaningful option if not a game changer. NAMS and the FDA do recognize that patients can have allergies and sensitivities to some ingredients in those hormones, and they acknowledge that compounding of medications may be necessary for these patients. I recommend the book Estrogen Matters as an excellent, reliable, and science-based summary of the debates, decisions, and cases for the safety and benefits of MHT. Wise use of MHT also involves knowing for whom MHT is contra-indicated, and for whom it will increase select risks such as cardiovascular disease, stroke, clots, dementia, and more. Key safety issues along with a concise understanding of the benefits and risks of MHT are also well articulated in the NAMS position statement.

 

References

[1] Brinton L, Hoover R, Fraumeni J. Menopausal oestrogens and breast cancer risk: An expanded case-control study. Br J Cancer. 1986;54:825-32.

[2] Armstrong B. Estrogen therapy after the menopause: Boom or bane? Med J Aust. 1988; 148: 213-14.

[3] Dupont W, Page D, Rogers L, et al. Influence of exogenous estrogens, proliferative breast disease, and other variables on breast cancer risk. Cancer. 1989;63:948-57

[4] Palmer J, Rosenberg L, Clark E, et al. Breast cancer risk after estrogen replacement therapy: Results from the Toronto breast cancer study. Am J Epidemiol. 1991;134:1386-95.

[5] Dupont W, Page D. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med. 1991;151:67-72.

[6] Nachtigall M, Smilen S, Nachtigal R, et al. Incidence of progestin replacement therapy. Obstet Gynecol. 1992;80:827-30.

[7][7] Colditz G, Hankinson S, Hunter D, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women.  NEJM 1995; 332:1589-93.

[8] Willis D, Calle E, Miracle-McMahill H, et al. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the U.S. Cancer xauses Control. 1996;7:449-57.

[9] Bergkvist L, Adami H, Persson I, et al. The risk of breast cancer after estrogen-progestin replacement. NEJM. 1989; 321:393-397.

[10] Collaborative group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350:1047-59.

[11] Shapiro S, Farmer R, Seaman H, et a. Does hormone replacement therapy cause breast cancer? An application of causal prinsicples to three studies. Part 1. The Collaborative Reanalysis. J Fam Plann Reprod Health Care. 2011;37;103-109.

[12] Rossouw J, Anderson G, Prentice R, LaCroix A, Kooperberg C, Stefanick M, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–33

[13][13] Manson J, Chlebowski R, Stefanick M, et al. Menopausal hormone therapy and health outcomes during the intervention and estended posstopping phases of the WHI randomized trias. JAMA 2013;310:1353-1368.

[14] Chlebowski R, Anderson G, Aragaki A, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA 2020;324:369-380.

[15] 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; 394:1159-1168.

[16] Li C, Daling J, Tang M, Haugen K, Porter P, Malone IK. Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern Med 2013;173:1629-1637.

[17] Singletary, S. Rating the risk factors for breast cancer. Ann Surg 2003;237:474­482.

[18] Fournier A, Mesrine S, Dossus L, Boutron-Rualt M, Clavel-Chapelon F, Chabbert-Buffet N. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat 2014;145:535-543.

[19] Dupont W, Page D. Menopausal estrogen replacement therapy and breast cancer. AArch Intern Med 1991; 151:67-72.

[20] Colditz G, Egan K, Stampfer M. Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol 1993;168:1473-1480.

[21] Lecuru F, Laforest H, Darles C, Taurelle R. Does hormone replacement therapy incrsae the risk of breast cancer? Eur J Obstet Gynecol Reprod Biol 1995;62:159-166.

[22] Rebbeck T, Friebel T, Wagner T, et al. PROSE Study Group. Effect of short-term hormone therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2005;23:7804-7810.

[23] Eisen A, Lubinski J, Gronwald J, et al. Hereditary Breast Cancer Clinical Study Group. Hormone therapy and the risk of breast cancer in BRCA 1 mutation carriers. J Natl Cancer Inst 2008;100:1361-1367.

[24] Kotsopoulos J, Gronwald J, Karlan B, et a. Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA 1 mutation carriers. JAMA Oncol 2018; 4:1059

[25] O’Brien K, Fei C, Sandler D, Nichols H, DeRoo L, Weinberg C. Hormone therapy and young-onset breast cancer. Am J Epidemiol 2015;181;799-807.

[26] Fournier A, Berrino F, Clvel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103-111.