The American College of Obstetricians and Gynecologists (ACOG) is a professional organization that establishes evidence-based clinical guidelines for women’s healthcare providers. Comprised of about 58,000 doctors, ACOG has existed since 1951 and has been influential in women’s health. Until recently, ACOG’s position on peri-menopausal and post-menopausal hormone therapy has been conservatively influenced by the findings of the Women’s Health Initiative trial (WHI) which was discontinued early due to a perceived increase of adverse events in the treatment group taking conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA, a synthetic progestin). This perception of harm associated with menopausal hormone replacement therapy (HT) was extrapolated to all forms of hormone replacement, all menopausal women, and all delivery methods. As a result, over the past 20 years many women have suffered needlessly. In March of 2024, ACOG published a review of WHI data and other large studies leading to an updated take on hormone therapy for postmenopausal women, “A Contemporary View of Menopausal Hormone Therapy” by Barbara Levy MD and James A Simon MD. Let’s break down some of their recent findings as they relate to breast cancer risk.
The WHI
The WHI was a randomized controlled trial (RCT) that took place from 1993 – 1998, which intended to analyze whether postmenopausal women should be offered hormonal therapy to reduce the incidence of cardiovascular disease (CV). Because of the relatively low incidence of CV in the younger population, 160,000 women over age 65 were recruited. In 2002 the NIH announced preliminary findings of harms associated with the CEE plus medroxyprogesterone acetate treatment arm. The benefits of reduced osteoporosis, osteoporotic fractures, and colon cancer were not reported. As a result, hormone replacement therapy plummeted by 79%, symptomatic patients were taken off hormone therapy, and health care professionals and patients alike adopted a fear of all hormone use which persisted for twenty years. It’s important to note the demographics of the women enrolled in the study as well as the formulations of hormones that were used: postmenopausal women over the age of 65, which is generally ten years past when most women go through menopause, using oral conjugated equine estrogen and medroxyprogesterone acetate, formulations that are no longer the most commonly prescribed hormones. Fortunately, we’ve learned a lot about hormones since 2002 and can begin to draw some conclusions about the safety of hormone therapy for our patients.
CEE vs Estradiol
Conjugated equine estrogens are derived from horse’s urine and contain many metabolites of which some are similar and many dissimilar to endogenously produced human estrogens. While estradiol binds to alpha and beta estrogen receptors, CEE binds primarily to beta receptors leading to more potent effects including an increase in inflammatory markers such as C-reactive protein, and inducing matrix metalloproteinase 9, an enzyme that breaks down collagen. Early WHI cardiovascular events are attributed to resulting plaque destabilization and rupture.
Conversely, estradiol in tablet, patch and gel forms has been shown to improve clinical outcomes such as vasomotor symptoms, vulvovaginal symptoms and preserving bone mineral density.
Medroxyprogesterone Acetate (MPA) vs Micronized Progesterone
Like CEE, synthetic progestins have problematic receptor binding actions, including to progesterone receptors, androgens, and glucocorticoid receptors. It’s been shown to contribute to an increase in insulin-like growth factor 1 (IGF-1) and insulin resistance; and when added to estrogen therapy, medroxyprogesterone acetate has been shown to enhance thrombotic risk. It’s implicated in increased breast cancer risk and adverse metabolic effects. Conversely, bioidentical micronized progesterone has neither been associated with thrombosis nor has it contributed to increased breast cancer incidence.
Risk of Breast Cancer: CEE plus MPA
In the WHI Estrogen Plus Progestin Trial, 16,608 postmenopausal women with a uterus were randomized to a combination of daily CEE 0.625mg/d and MPA 2.5mg/d or placebo. Due to a perceived increase of breast cancer incidence in the treatment arm, the CEE + MPA trial was stopped early.
In 2018 these results were reviewed by Hodis and Sarrel who concluded the treatment of .0625mg CEE plus 2.5mg MPA actually had a null effect on breast cancer in the typical postmenopausal population: women who had never used HT. They stated, “For women who were HT naïve when randomized to WHI (treatment), the breast cancer incidence rate was not affected by CEE+MPA therapy relative to placebo for up to 11 years of follow-up.”
Then what made the initial trial so controversial that it was stopped early? Hodis and Sarrel noted that there was an unusually low occurrence of breast cancer incidence in the placebo group relative to the treatment arm, specifically in the 25% with a history of previous HT use. Placebo participants were considered “washed out” or no longer under the influence of hormones and eligible to be randomized to the control group, if it had been 3 months since their last use of HT. So, it’s important to recognize that the placebo group was not a group of naïve hormone users – it consisted of never users and “washed out” recent users. This detail is what contributed to the controversial breast cancer data leading to the cessation of the WHI – the treatment arm having a higher breast cancer rate than controls - because previous users were combined with never users. Imagine if they had stated it differently: the placebo arm had a lower rate of cancer than the treatment arm – and then investigated why. Notably, the HT treatment group’s breast cancer incidence was no different from hormone naïve controls. And “washed out” previous users of HT in the control group were found to have the lowest rates of breast cancer. They went on to conclude that breast cancer risk of CEE plus MPA was similar in magnitude or lower than breast cancer risk from other factors such as lipid-lowering and anti-hypertensive medications, obesity, low physical activity, and drinking two glasses of wine daily.
Risk of Breast Cancer: Conjugated Estrogen alone (CEE)
In the WHI Conjugated Estrogen-Alone Trial, which randomized 10,739 postmenopausal women with a prior hysterectomy to either daily CEE .0625mg vs placebo, CEE was associated with a 45% statistically significant reduction in breast cancer mortality after 18 years of follow up.
Risk of Breast Cancer: Estradiol (E2) alone
The Nationwide Finnish Comparative Study, an observational trial of 489,105 women, analyzed data on breast cancer mortality risk in women using estradiol-only, compared to those using estradiol plus progestogen therapy, and those using no hormones. Study members used either oral delivery in 1 and 2 mg dosages, transdermal patches in .025 - .1mg dosages, or gels .5-1.5 mg. Researchers concluded that mortality risk was reduced in all HT users, with exposure up to 5 years, 5-10 years, and 10 plus years, concluding that E2 when used more than 10 years is safe for the breast. Even when combined with a progestin there was a 50% breast cancer mortality risk reduction compared to placebo, which remained more than 10 years across all age groups. Note: Delivery system and dose was not differentiated due to the authors’ claim that previous data indicated there was no difference between these factors and cancer risk.
In summary, there is no conclusive evidence showing that HT causes breast cancer, and if anything, HT has been shown to have a null or protective effect. Ironically, the controversial interpretation of WHI results in 2002 that led to twenty years of fearing estrogen, was erroneously attributed to HT, when instead the perceived increased rate of breast cancer was due to a decreased incidence in women randomized to placebo who had used HT at least three months prior to randomization. What a difference a new perspective can make! It’s interesting to note that all therapies reported in the ACOG paper with a null or reduced rate of breast cancer contained a form of estrogen, (including conjugated equine estrogens, even when paired with synthetic medroxyprogesterone acetate). While research will be ongoing in these areas and conclusions updated, this long-awaited audit will enable providers to have more nuanced conversations with patients regarding informed consent as it pertains to breast cancer risk, the most encountered fear for patients and providers alike when considering hormone replacement.
