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24 June 2026

The trials that never included us

notes from EiEi

In 2018, researchers at Arizona State University found that removing a rat's uterus damaged her working memory.

Not her ovaries. Her uterus — the organ textbooks had described for decades as "quiescent, dormant, and useless" when not carrying a pregnancy. The rats with hysterectomies kept returning to arms of the maze they'd already checked, unable to hold several pieces of information at once. The rats with ovaries removed, or both organs removed, or neither, performed normally.

The researchers ran the study again, because they didn't believe it.

One in three women in the United States has a hysterectomy by age 60 — roughly 600,000 surgeries a year. The possibility that the uterus talks to the brain outside of pregnancy, by way of the autonomic nervous system, had simply never been studied. The organ had been declared useless. So nobody looked.

This is what it means to practice medicine on half the population using data from the other half.

How the default body became male

In 1977, the FDA published guidance urging researchers to exclude women of childbearing potential from early-stage drug trials. The stated concern was fetal risk — thalidomide had happened, and the agency overcorrected hard. The practical result was that researchers stopped enrolling women at all. Not just women who might become pregnant — women on contraception, single women, women whose husbands had vasectomies. The policy drew no such distinctions.

By the time Congress mandated inclusion through the NIH Revitalization Act in 1993, a generation of drug trials had run on male bodies. A 1992 Government Accountability Office review found women under-represented — relative to their share of the disease — in the trials for roughly 60% of the drugs it examined, and found that only about half of trials had been analyzed for sex differences at all. The drugs were already on the market. The doses were calibrated for a default body that wasn't ours.

The same logic infected animal research. Female rodents were left out of preclinical studies for decades because researchers worried their hormonal cycles would add variability and muddy the data. No one had tested that worry. When researchers finally did — across body temperature, activity, and food intake — it collapsed: female mice are no more variable than males. Decades of medical treatment were shaped by an exclusion resting on a belief nobody had bothered to check.

In neuroscience, for roughly every six male animals studied, one female was examined. Depression, anxiety, neurodegeneration — conditions more common in women — were modeled almost entirely on male brains.

The WHI and 20 years of withheld treatment

In 2002, the Women's Health Initiative trial was stopped early. The headlines said hormone replacement therapy caused heart attacks and breast cancer. Prescriptions dropped roughly 30% almost overnight. Millions of women were told to stop, or never started.

What the headlines left out:

The WHI used conjugated equine estrogens — derived from horse urine — combined with a synthetic progestin, medroxyprogesterone. Not bioidentical progesterone. The average woman enrolled was 63, most of them a decade or more past menopause, and most already carried cardiovascular risk. The two arms of the trial — combined therapy versus estrogen alone — produced meaningfully different results that got collapsed into a single story about HRT being dangerous.

What followed is now called the timing hypothesis: HRT started within ten years of menopause, or before age 60, carries a very different risk-benefit profile than HRT given to a 63-year-old with established arterial stiffness. The window matters. The formulation matters. The delivery route matters. None of that complexity made the 2002 press conference.

So we got roughly two decades in which HRT was undertreated or never offered, on the strength of a study that used the wrong drugs on the wrong women at the wrong time and applied the conclusion to everyone. The women who paid were in their late 40s and 50s — squarely inside the window the timing hypothesis now calls most protective — and they were told no.

What estrogen actually does for your heart

Before menopause, women are substantially protected against cardiovascular disease relative to men. Heart attacks, atherosclerosis, arterial stiffening — all markedly less common in premenopausal women than in age-matched men.

After menopause, that protection disappears.

The mechanism isn't mysterious. Estrogen keeps arteries flexible, manages the balance of LDL and HDL, and suppresses the inflammation that drives plaque. When estrogen drops, LDL rises, arteries stiffen, blood pressure climbs, and a postmenopausal woman's cardiovascular risk starts to resemble that of a man her age. More women than men have died of cardiovascular disease in the United States every year since 1984. Part of that is longevity. Part of it is a cliff almost nobody is watching for.

Women can spend up to 40% of their lives postmenopausal — 30-plus years without the protection they had for their entire adult lives. This is not a reproductive issue. It is a leading cause of death.

In the WISE study, premenopausal women with angiographic coronary artery disease had significantly lower estrogen than women without it, even after adjusting for age. The connection is not subtle. And the treatment most likely to address it was suppressed for two decades by a misread study — something most women have still never heard from a doctor.

What we still don't know

The uterus communicates with the brain. We learned this in 2018, in rats, and we still barely understand what it means for the one in three women who have hysterectomies.

Female sex hormones affect cognition, memory, neuroplasticity, and mood — that much is established. The mechanisms are not. How estrogen loss accelerates cognitive decline, whether there's a critical window for neuroprotection, what role progesterone plays in the brain separately from estrogen — these are open questions in 2026, not settled science.

The symptom list for perimenopause — the cardiovascular symptoms, the cognitive ones, the autoimmune flares, the mood dysregulation — largely describes the most complex hormonal system in the body going through a fundamental transition. The research base for that transition is thin, recent, and politically tangled by the WHI fallout. Most women going through it now are navigating on data that is decades old, misread, or simply missing.

Why this is a Perity problem

I wrote this today because of a video. A nurse anesthetist named Amy Rieschick, talking about institutionalized medical misogyny, hit the front page — and within hours the comments filled with women describing the exact thing the research history predicts.

A 35-year-old waking at 3am soaked through her sheets, exhausted, certain she had cancer, raising it at every appointment — until one doctor finally checked her hormones, a year later. A woman told for years that nothing was wrong, who turned out to have an 11-centimeter dermoid cyst on her ovary, the size of a navel orange. A woman whose OBGYN won't give her the treatment she wants because she's "still of birthing age" — the same logic, almost word for word, the FDA used in 1977 to keep women out of the trials in the first place. Forty-nine years later, "of childbearing potential" is still a reason to be told no.

I'm in that comment section too. I lay down on sidewalks last year waiting for my heart to stop racing; I wrote about that. So is a trans woman who's run her own HRT for years and ended up walking a menopausal coworker through her lab results because no one else would. Trans women who manage their own hormones understand this from the inside, immediately — and so do trans men on T who watch a clinician's attention drift the second the conversation turns endocrine.

None of these women are outliers. They're the predictable output of a system that built its knowledge base without them, then called them anxious when the gaps showed.

Perity tracks symptoms, HRT, labs, wearable signals, and patterns — not because a doctor will fix this if you just communicate better, but because the data is yours, and knowing what your body is actually doing is not nothing. It's the difference between "probably stress" and a chart that says otherwise.

This is the first in a recurring series on the research that skipped us. Next: what we still don't know about ADHD, autism, and women — and why so many of us got the diagnosis at 40, in a perimenopausal crash, or never at all.

— EiEi, @perityapp

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