New Nature Medicine Study Shows Hormone Therapy Rewrites the Body’s Protein Profile in Six Months

Several days after I published “Two New Studies Undermine the Entire Basis for Trans Athlete Bans,” a reader sent me a third study. This one was published in Nature Medicine last October and I’d missed it. It belongs in the same conversation.

Researchers at the Murdoch Children’s Research Institute and the University of Melbourne measured 5,279 blood proteins in 40 transgender women before and after six months of feminizing hormone therapy. They found that hundreds of those proteins shifted toward levels typical of cisgender women. Proteins tied to male reproductive function dropped. Proteins associated with lipid metabolism, breast tissue development, immune regulation, and cardiovascular health rose. The team benchmarked these changes against a UK Biobank reference set of more than 55,000 people and confirmed the direction: feminizing hormone therapy moved the plasma proteome—the full set of proteins circulating in the blood—toward a female-typical profile.

That makes three studies in three months, from three different research teams, measuring three different systems—brain structure, athletic performance, blood chemistry—and finding the same thing: hormone therapy does what it says it does. It changes the body.

The study

The Nguyen et al. study compared two standard feminizing regimens: estradiol combined with either cyproterone acetate or spironolactone—the two most commonly prescribed antiandrogens. Testosterone levels dropped sharply in the cyproterone group and less dramatically in the spironolactone group, which is consistent with what clinicians already observe in practice. Among the 5,279 proteins measured, 245 changed significantly in the cyproterone group and 91 in the spironolactone group. More than 95% of the changes were decreases—the body was, in effect, turning down the volume on male-associated protein expression.

The finding that matters most for the ongoing policy debate is this: 43% of the proteins altered by feminizing hormone therapy overlapped with proteins that change in cisgender women taking hormone replacement therapy for menopause. Same proteins. Same direction. One treatment is a routine part of women’s healthcare that nobody is trying to ban. The other is the subject of executive orders.

The study also documented a shift in disease-risk biomarkers. The proteomic profile moved toward patterns associated with autoimmune conditions—which are more prevalent in women—and away from patterns associated with atherosclerosis, which is more common in men. Trans women on hormone therapy are developing female-pattern disease risk profiles at the molecular level. That’s not what you’d expect if sex were as fixed as the people writing the bans keep saying it is.

Boris Novakovic, the study’s corresponding author, described the results: the therapy reduced protein biomarkers related to male reproduction and fertility and increased those associated with body fat distribution, breast development, immune function, and cardiovascular health. Ada Cheung, who heads the Trans Health Research Group at the University of Melbourne, said proteomic monitoring could allow clinicians to calibrate hormone dosages and identify side effects earlier.

Why this matters now

The BJSM meta-analysis I wrote about last week measured what trans women’s bodies can do—strength, aerobic capacity—and found no significant performance gap after one to three years of hormone therapy. The Hüpen brain study measured how the brain reorganizes in response to hormones. This proteomics study measures what’s happening at the molecular level—the protein infrastructure underneath both of those findings.

It also neutralizes a specific line of criticism. Alun Williams of Manchester Metropolitan University, whose critique I included in the last piece, argued that the sports data was limited by the fact that strength measurements depend on voluntary effort—you can’t know how hard someone was trying. Blood protein levels don’t have that problem. Nobody is sandbagging their plasma proteome. The molecular data doesn’t depend on effort, self-reporting, or sample size at a gym. It’s what the body is doing on its own, measured by mass spectrometry.

The study has limitations. Forty participants is meaningful for proteomics research but not definitive. Only feminizing hormone therapy was examined—there’s no equivalent data yet for trans men. Six months captures the initial trajectory but not the full arc of change. And protein levels are not the same as athletic performance; the study tells you what the body is doing biochemically, not whether that translates to a competitive advantage or disadvantage on a playing field.

But the direction is consistent. Brain, body, blood. Three measurement systems. Three research groups. One direction.

The gap

The proteomics study was published on October 20, 2025—four months before the BJSM meta-analysis. It was available when the NCAA’s blanket ban turned one year old. It was available when USA Hockey adopted its Participant Eligibility Policy. It was available when state legislatures passed their bans. None of them cited it.

The blanket bans rest on the claim that prior testosterone exposure confers permanent physical advantages that hormone therapy cannot erase. Three peer-reviewed or major-journal studies now challenge that claim at the level of brain structure, functional performance, and circulating proteins. The policy response has been to keep banning.

On April 1, USA Hockey’s new policy takes effect. Harrison Browne—the first openly transgender professional hockey player, who competed in the NWHL for three seasons—will be ineligible for both women’s and men’s recreational leagues. The proteomics study sat in Nature Medicine’s archive the entire time the policy was being drafted.

The question was never whether the science would catch up. The question was whether anyone writing the bans would read it.