HRT Safety, Reframed

The most common concern I hear every day is “but is it safe?”. For most of our mothers, hormone therapy wasn’t an option, or it was taken away. My own mother was 50 when the Women’s Health Initiative (WHI) headlines hit in 2002, and like millions of other women, she was never given the chance to start hormones. That moment changed the trajectory of midlife medicine, but the story was not what it seemed.

Why uterus status matters (a pre-note)

In conventional practice, you’ll often hear this simple rule: if a woman has a uterus, she needs progesterone with estrogen; if she doesn’t, estrogen can be used alone. That’s because estrogen on its own can overstimulate the uterine lining (the endometrium), causing it to thicken, a condition called endometrial hyperplasia, which raises the risk of uterine cancer. Progesterone balances that effect and protects the endometrium.

As I review the evidence, you’ll hear the term “intact uterus.”  This simply means that there’s been no hysterectomy. 

And while the conversation often begins with “uterus intact or not,” I think it’s too limited. For me, progesterone has a role beyond just uterine protection (and we’ll get into that too). 

What happened in the WHI - and why it was overblown

The WHI tested two pills. One was CEE (conjugated equine estrogens). The other combined CEE with MPA (medroxyprogesterone acetate, a synthetic progestin). The combined CEE+MPA trial was stopped in July 2002, and the CEE-alone trial in 2004 (JAMA 2002; JAMA 2004) secondary to researcher and media hysteria about the increased risk of breast cancer in the women receiving hormone treatment. 

Here’s the critical piece: the early risks were presented in relative terms and treated as absolutes. Reporters led with “26% increased risk of breast cancer.” But in absolute terms, that meant 8 additional cases per 10,000 women per year. A relative risk sounds frightening; the absolute numbers show only a negligible increase in risk.

Long-term follow-up makes it clearer. Women on estrogen alone had lower breast cancer incidence and lower breast cancer mortality than placebo (JAMA 2020). And there were benefits no one talks about: women on CEE+MPA had fewer colon cancers while taking therapy (NEJM 2004). This was left out of the headlines. 

We’ll discuss later why the type of HRT was also important, especially the synthetic progestin used. 

Timing matters: what later studies showed

The ELITE trial compared women who started estradiol within six years of menopause to women who started ten or more years after. The results were striking: arteries in the early-start group thickened more slowly, a sign that estrogen slowed vascular aging. In the late-start group, no benefit appeared (NEJM 2016). Same hormone, different outcome, depending on timing.

The DOPS trial followed women who began estradiol soon after menopause, with a progestin added if the uterus was intact. After a decade of treatment and extended follow-up, women on therapy had fewer heart attacks, strokes, and deaths, without an increase in overall cancer risk (BMJ 2012). That’s what prevention can look like when therapy is started early.

Breast cancer safety: name the hormone (“Progestogens” be gone)

This part is simple but crucial. Progesterone is bio-identical, sold commercially as Prometrium. Progestins are synthetic versions, like MPA or norethisterone acetate. They are not the same molecule, and they don’t carry the same risk. “Progestogens” is a blanket term encompassing of both, but the two should always be considered separately. 

In the WHI, MDA (Medroxyprogesterone acetate) is the only hormone medication associated with an increased incidence of breast cancer. Conjugated estrogen alone wasn’t. 

In the French E3N cohort, women who used estradiol plus bio-identical progesterone did not have a higher risk of breast cancer compared with women who never used hormones, and their risk was lower than that of women using estradiol with synthetic progestins (Breast Cancer Research 2005). 

Takeaway: Don’t choose synthetic if you don’t have to. Whenever possible, choose bio-identical progesterone (Prometrium).

Cardiovascular safety: what clot risk really means

Many women are concerned that HRT carries the same risk of clots that birth control does. The answer is that transdermal estradiol absolutely does not. 

Blood clots, or venous thromboembolisms (VTEs), are a known risk with oral estrogen pills because they go through the liver and change clotting proteins. But transdermal estradiol, estrogen delivered through the skin by a patch, gel, or cream, bypasses the liver and does not increase clot risk. That’s why I categorically prefer transdermal estradiol. It’s safer for blood clots, better for triglycerides, and easier on the gallbladder. Oral estrogen is acceptable for some women, but transdermal is my first line (Circulation 2007).

What’s really off the table, and what isn’t

One of the most damaging legacies of the WHI was the black box warning that came to every estrogen product afterward. Those warnings, on blood clots, heart disease, stroke, and breast cancer, made an entire generation of clinicians afraid to prescribe HRT. They also led to an overly rigid view of what counts as a true contraindication.

Here’s the reality: family history of breast cancer is not an absolute contraindication. Neither is a personal history of breast cancer, cardiovascular disease, advancing age, or even a past history of blood clots. These scenarios require thoughtful, individualized risk–benefit assessment, but the evidence does not support automatic exclusion. In fact, many women in these categories may benefit more from the metabolic, bone, and cardiovascular protection that hormones provide. Similarly, a history of non-hormone-driven cancers (like colon cancer) doesn’t mean HRT is off the table forever.. 

So what are the true absolute contraindications? Active breast cancer, active or recent estrogen-sensitive endometrial cancer, active liver disease, and unexplained vaginal bleeding (simply because the vaginal bleeding should be worked up first). Those are the clear lines. Everything else falls into the realm of careful counseling, shared decision-making, and weighing not just the potential risks of therapy, but also the very real risks of not treating hormone loss. Every time we reject HRT reflexively, we have to ask: what benefits are we abandoning? Bone health, brain function, metabolic stability, and quality of life all sit on that list.

Benefits that deserve airtime

Hormones don’t just relieve hot flashes. They support systems.

Bone health. Estrogen and progesterone stimulate osteoblasts (the cells that build bone) and slow down osteoclasts (the cells that break it down). That’s why HRT prevents bone loss and reduces fractures during use (Cochrane 2017).

Metabolism. When hormones are restored, the system works better. Trials and clinical experience show improvements in fasting glucose, insulin sensitivity, and LDL cholesterol (Diabetes Care 2004.

Colon cancer. In WHI, combined CEE+MPA reduced the number of colon cancers diagnosed during therapy (NEJM 2004). That finding deserves airtime.

Earlier is better

“Start near menopause” often gets interpreted as “wait until you’re miserable.” That’s not my approach. I believe in starting earlier, when you stop feeling like yourself. Brain fog, restless sleep, mood shifts, energy loss. Those are signals worth addressing.

I don’t use the lowest effective dose. I use the dose needed to restore physiology, mental clarity, and energy, and to reach serum estradiol levels of at least 80 pg/mL in static regimens, or higher in physiologic cycling protocols. I don’t treat symptoms. I treat the whole system.

In my programs, women are supported intensively for the first six months, with frequent labs in the first year. After that, I reassess every 6–12 months. It’s structured, ongoing care that’s always assessing the whole system and whole person, not just relief of symptoms or a single blood marker. 

Guardrails

I don’t follow a one-size protocol. Every plan is individualized. I take a full personal and family history. I use transdermal estradiol as my preferred route. I choose bio-identical progesterone as the standard. I prescribe the dose that restores physiology, not just masks symptoms. And I reassess regularly with labs and structured follow-up.

Bottom line

It’s time to move beyond headlines from 2002 and to treat women today. Start earlier, when you notice you’re not yourself. Use estradiol. Choose bio-identical progesterone (Prometrium) over synthetic options. Prefer transdermal estradiol, it’s safer and better tolerated for most women, though oral can be right in select cases. Pair hormones with nutrition, sleep, strength, and lifestyle. Hormone replacement isn’t just about relief. It’s about restoring health and quality of life for years to come.