Hormone Therapy for Perimenopause: Is It Safe?

I can’t tell you how many times a patient has sat across from me and said some version of, “I’ve been afraid to even bring this up.” She’ll describe the night sweats, the sleep that never feels restorative, the brain fog that makes her question her own sharpness, and then, almost apologetically, ask: “Is hormone therapy actually safe? My mother’s generation was terrified of it.”

That fear didn’t come from nowhere. For over two decades, hormone therapy has lived under the shadow of the 2002 Women’s Health Initiative (WHI) study, which reported increased risks of breast cancer, heart disease, and stroke in women using combination estrogen-progestin therapy. That study understandably changed clinical practice overnight, and it scared an entire generation of women away from a therapy that, for many, could have meaningfully improved not just how they felt, but how they aged.

Here’s what I tell my patients now: the research has moved on, even if the fear hasn’t caught up yet. And the story it’s telling is far more nuanced than most women realize. It all comes down to one key idea: timing.

The Timing Hypothesis

Think of your blood vessels in your 40s as still being flexible, like a garden hose that bends easily. By your 60s, after years without estrogen’s effects, those same vessels can behave more like an old hose left out in the sun, stiffer and less forgiving. That distinction turns out to matter.

A retrospective analysis of more than 120 million patient records, presented as a poster at the 2025 Annual Meeting of The Menopause Society, is worth noting up front for what it is: an early, preliminary finding that has not yet completed peer review, based on observational (not randomized) data. With that context in mind, the researchers found that women who began estrogen therapy during perimenopause, and continued it for at least a decade, had roughly 60% lower odds of developing breast cancer, heart disease, or stroke compared to women who started later or never used hormone therapy at all. Women who waited until after menopause to begin estrogen therapy saw only minimal protective benefit, and a small increase in risk for one of the three outcomes measured compared to non-users. The researchers themselves describe the findings as preliminary, and note that further prospective research is needed, though it adds to a growing body of evidence.

This lines up with earlier vascular research, including a randomized trial published in the New England Journal of Medicine, showing that estradiol started early in menopause (within six years of a woman’s final period) was associated with less progression of arterial plaque than estradiol started later. Researchers now call this the “timing hypothesis” of hormone therapy, and it’s reshaping how thoughtful physicians approach this conversation.

Why would timing matter this much? The current thinking is that estrogen may help support blood vessels that are still healthy and flexible, but may not reverse damage in vessels that have already begun to stiffen and accumulate plaque over years of estrogen deficiency. In other words: the same hormone that may support a 45-year-old’s arteries doesn’t appear to have the same association in a 65-year-old’s.

Beyond Hot Flashes: What Estrogen May Support

It’s easy to think of hormone therapy as symptom relief, something to quiet the hot flashes and night sweats so you can finally sleep through the night. And it does that. But research suggests its reach may extend further, into several systems relevant to how women age:

• Bone health. Women can lose up to 10% of their bone density in the five years following menopause. Estrogen therapy has been shown to slow this loss, which is relevant to long-term fracture risk and frailty.

• Cardiovascular health. Estrogen is associated with maintaining blood vessel flexibility and healthier cholesterol patterns, though, as above, this appears to depend heavily on when therapy starts.

• Brain health. Estrogen is involved in neuroplasticity and in the balance of serotonin and dopamine, the chemistry behind mood, focus, and motivation. Observational research suggests hormone therapy started near menopause is associated with a lower risk of Alzheimer’s disease later in life, though this is not a proven causal or preventive effect.

• Cellular aging. As I discuss in The Golden Gate, hormonal balance intersects with several of the recognized hallmarks of cellular aging, including telomere maintenance. This is an active area of research, and while it’s too early to call hormone therapy an anti-aging intervention, it does suggest hormone health is relevant to more than day-to-day symptoms.

Understanding why timing matters and what estrogen may support is only half the story, though. The other half is deeply personal: no two women, and no two hormone therapy plans, should look the same. In the next blog, I’ll walk through why hormone therapy is never one-size-fits-all, how fasting and nutrition fit into the picture, who may not be a good candidate, and answer the questions I hear most often in my office.

This blog is for educational and informational purposes only and is not intended to provide medical advice, diagnosis, or treatment. Hormone therapy is available by prescription and requires individualized medical evaluation. Please seek the advice of your personal physician before starting any new therapy.

References

• Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368. https://doi.org/10.1001/jama.2013.278040

• Rossouw JE, Anderson GL, Prentice RL, 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):321–333. https://doi.org/10.1001/jama.288.3.321

• Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. New England Journal of Medicine. 2016;374(13):1221–1231. https://doi.org/10.1056/NEJMoa1505241

• Shufelt CL, Manson JE. Menopausal hormone therapy and cardiovascular disease: the role of formulation, dose, and route of delivery. Journal of Clinical Endocrinology & Metabolism. 2021;106(5):1245–1254. https://doi.org/10.1210/clinem/dgab042

• Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using QResearch and CPRD databases. BMJ. 2020;371:m3873. https://doi.org/10.1136/bmj.m3873

• Rekkas PV, Wilson AA, Lee VW, et al. Greater monoamine oxidase A binding in perimenopausal age as measured with carbon 11-labeled harmine positron emission tomography. JAMA Psychiatry. 2014;71(8):873–879. https://doi.org/10.1001/jamapsychiatry.2014.250

• Darvish NK. The Golden Gate: Unleash Your Feminine Powers to Graceful Aging. The Boss Books.