Estrogen: No Black Box Warning—Now What?

Allison Sayre, MSN, WHNP

For more than twenty years, the phrase “black box warning” has cast a long shadow over estrogen therapy. Many women spent this time believing estrogen therapies carried dangerous, poorly understood risks, particularly for breast cancer and heart disease, while many clinicians felt pressured to avoid hormone replacement therapy (HRT) altogether. In 2025, that cloud began to lift when the Federal Drug Administration (FDA) removed the black box warning from estrogen-only therapies.

This is a major update, as it signals a shift toward nuance and scientific accuracy, but it does not mean hormone therapy is risk-free, or appropriate for everyone. Instead, it opens a clearer pathway for conversations that are individualized, evidence-informed, and rooted in shared decision-making.

How the WHI Study Shaped a Generation of Fear

To understand the significance of the FDA’s recent label change, it helps to revisit how hormone replacement therapy became a cultural and clinical lightning rod. In the early 2000s, the Women’s Health Initiative (WHI) released results that seemed to show increased risks with HRT. "Seemed" is the operative word, because the fuller story was far more nuanced than the headlines suggested.

The WHI used oral, synthetic hormones in the form of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), which are not the bioidentical estradiol and micronized progesterone commonly used today. [1] Oral hormones also behave differently than transdermal forms, as they undergo first-pass liver metabolism, which can raise clotting factors and inflammatory markers. [2] These differences alone would have shifted how we interpreted the results if they had been properly described.

When the preliminary data was published in 2002, the reported increases in breast cancer, stroke, and cardiovascular events were alarming. The trial was halted early, and media coverage amplified the fear by not clarifying that these findings applied to oral, synthetic formulations of hormones, used in women who were, on average, 63 years old and often more than a decade past menopause.

This lack of context allowed the WHI results to be interpreted as universal truths. The result was two decades of confusion, avoidance, and fear surrounding HRT, with much of it rooted not in the data itself, but in how the data was communicated.

The Missing Context: Understanding Relative vs. Absolute Risk

One of the most misunderstood parts of the WHI was the way risk was communicated. Early reports focused on relative risk, which can sound significant, even when the actual numerical change is very small. The combined estrogen–progestin arm was said to show a 26% increase in breast cancer risk, which understandably alarmed people. But that percentage came from a difference of 30 cases per 10,000 women per year in the placebo group versus 38 per 10,000 in the hormone group.

When you compare 30 to 38, you get a 26% relative increase, but the absolute risk increase was less than one-tenth of one percent. That difference was not statistically significant, meaning the study couldn’t confidently determine whether the increase was real, or simply due to chance. Even more importantly, the estrogen-only arm did not show an increased breast cancer risk. Later analyses even found a lower risk of breast cancer in women taking estrogen alone compared to the placebo. [3]

When reporting on findings from this study, the WSI should have more clearly communicated differences such as relative and absolute risk, estrogen-only vs. combined therapy, younger vs. older women, oral vs. transdermal hormones, and  bioidentical vs. synthetic is essential. Unfortunately, the original WHI messaging didn’t include this nuance, and the resulting black box warning reflected the early, incomplete interpretation of the data rather than the full picture we have today.

Why the Black Box Warning Was There, and Why It’s Changing

When the FDA added the black box warning on estrogen therapies in the early 2000s, it did so in a climate of understandable caution. At the time, researchers did not yet have detailed sub-analyses by age, route of administration, timing of initiation, or prior health history. The findings seemed universally applicable, and the precautionary principle prevailed. Decades of follow-up data, plus an improved understanding of estrogen physiology, have provided a far more refined picture. We now know:

• Women who start HRT within 10 years of menopause experience more benefit (improved bone, brain and heart health to name a few!) and fewer risks. This is not to say that you can’t start HRT later on. It just may not reap the same benefits as starting sooner. [4]
• Bioidentical estrogen and progesterone therapy does not increase breast cancer risk, with many studies showing a reduced risk. [3]
• The cardiovascular risks highlighted in the early WHI publications were significantly influenced by the age and baseline health of participants, as well as the form (synthetic) and route (oral) of administration used in the study. [4]
• The form (synthetic vs bioidentical) and route (oral vs. topical) of HRT matter far more than originally understood.

With this expanded evidence base, the FDA acknowledged that the black box warning overstated generalized risk, and no longer reflected the best available science. Its removal is an attempt to replace alarm with accuracy.

What the Label Change Means, and What It Doesn’t

The new label doesn’t mean estrogen therapy is free of risk. It simply reflects a more accurate understanding of what the research has shown over the past two decades. Estrogen can be safe and highly effective for many women, but it still requires thoughtful, individualized care.

It is important to note that any woman with an intact uterus must take progesterone, ideally the bioidentical form, along with estrogen. Bioidentical progesterone is different from the synthetic progestins used in the WHI study and offers its own benefits. Most importantly, it protects the uterine lining from estrogen-driven overgrowth. [5] This is a core safety requirement in hormone therapy, not an optional step.

Additionally, factors such as family history, cardiovascular profile, lifestyle, genetics, symptom burden, and personal goals should also guide decision-making. Fear alone should not make the choice. 

Moving Forward with Clarity Instead of Fear

Fear has kept too many women from therapies that could improve sleep, emotional resilience, cognitive clarity, bone density, metabolic health, and overall quality of life. This doesn’t mean estrogen is the right choice for everyone. It means we can finally have the conversation without a warning label doing the talking for us. Healing happens when we understand the history, embrace the nuance, and make decisions rooted in evidence rather than anxiety.

Whether you are a patient exploring HRT, or a practitioner guiding someone through the process, the goal is the same: Clear information, aligned values, and a path that feels grounded and empowering. HRT is not simply a medical intervention, but it is a partnership. The label has changed. The science is clearer. And your decisions (made in partnership, not panic) can now be guided by knowledge, trust, and a renewed sense of possibility.

Disclaimer:

The information provided is for educational purposes only. Consult your physician or healthcare practitioner if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.

Allison Sayre is a board-certified women’s health nurse practitioner with advanced expertise in hormonal health, integrative gynecology, and patient-centered care across the lifespan. She holds a Master of Science in Nursing and has served as both a clinical provider and educator in functional and conventional women’s health settings.

Allison has led clinical programming, practitioner training, and content development for leading health brands and organizations. Her work bridges the clinical and commercial worlds, helping translate scientific evidence into practical tools for healthcare practitioners. At ARG, Allison contributes to medical education, clinical protocol development, and strategic content that supports the evolving needs of women's healthcare practitioners.