Nature Medicine Publishes First Study on how Gender-Affirming Hormones Reshape the Body’s Biology
- Trans Health Research team
- Nov 6
- 6 min read
By Lachie Angus, Boris Novakovic, Julian Grace, Sav Zwickl, and Ada Cheung.
Key takeaways
This is the first trans health research paper published in Nature Medicine, which is a major milestone.
Oestrogen-based gender-affirming hormone therapy (GAHT) doesn’t just change hormone levels, it reshapes thousands of proteins in the body, helping align biology with gender identity.
After six months of oestrogen-based GAHT, protein patterns in trans and gender diverse people on estradiol and anti-androgens began to resemble those of cisgender women.
These findings show that human biology is adaptable, even in adulthood.
Read the paper here: https://doi.org/10.1038/s41591-025-04023-9.
We’re proud to share that our latest study, a collaboration between the University of Melbourne, Austin Health, and the Murdoch Children’s Research Institute, has just been published in Nature Medicine, one of the most prestigious medical journals in the world.
This is the first-ever original research paper on trans health published in Nature Medicine, a huge milestone for our community and for trans health science globally.
What was this study about?
We wanted to understand how GAHT affects the body beyond the visible changes we can see or feel, like skin, fat, or breast development. Specifically, we looked at proteins in the blood, which tell us a lot about how our bodies function on the inside.
Sex characteristics have a big effect on our health, particularly when it comes to the prevalence of certain conditions. For example, autoimmune conditions such as rheumatoid arthritis and hypothyroidism are more common in people recorded female at birth, while heart disease occurs more often in people recorded male at birth.
These patterns are influenced in part by sex hormones like oestrogen and testosterone, which affect far more than reproductive organs. They help regulate body composition, immune function, and metabolism, impacting many systems throughout the body.
When it comes to GAHT, most attention so far has focused on shifts in hormone levels and visible changes (such as skin texture, breast growth or facial appearance). However, far less is understood about how GAHT influences the underlying biology or the cellular and biochemical processes that shape long-term health.
Why this is a world-first?
Most past studies have focused only on hormone levels, this is the first to look downstream, at what those hormones actually do inside the body. By examining proteins, we can see the biological effects in finer detail, setting a new standard for future research on hormones and health.
This breakthrough doesn’t just advance trans and gender diverse medicine, it changes how science understands hormones, health, and human diversity.
What is “proteomics”?
Proteins are the ‘molecular workhorses’ of the body. They carry out nearly every function that keeps us alive, from building tissues to regulating metabolism and immune responses. Unlike DNA or chromosomes, which are fixed blueprints that tell the body what it can do, proteins show what the body is actually doing right now.
While hormone levels tell us how much of a certain hormone (like oestrogen or testosterone) is circulating, proteins reveal the effects of those hormones on cells and organs.
In other words, DNA and genes provide the instructions, hormones act as the signals, and proteins are the real-time results of those signals in action. Studying proteins gives us a more dynamic picture of how the body responds to GAHT, moving beyond static measures of sex or hormone levels to understand biology as something fluid and adaptable.
Using a technique called high-throughput proteomic analysis, we studied over 5,000 proteins in the blood of 40 trans people starting oestrogen-based GAHT (oestrogen and anti-androgens). We looked at their protein profiles before starting hormones and again after six months, and compared these with data from 55,000 people in a UK biobank.
What did we find?
After just six months of GAHT:
In trans people taking oestrogen-based GAHT, the sex-specific proteins began to resemble those of cisgender women. Participants who reached lower testosterone levels (regardless of anti-androgen used) showed the largest shifts.
Proteins linked to sperm production and testicular function (SPINT3 and INSL3) decreased.
Proteins linked to breast development and body fat (prolactin and leptin) increased.
Proteins related to immune function (proteins involved in allergic asthma, allergic rhinitis and autoimmune disease) increased.
Proteins related to atherosclerosis or heart disease decreased in people using estradiol and cyproterone acetate, suggesting a protective effect.
These protein changes suggest that long-term health risks for trans people using oestrogen and anti-androgens may begin to align with those of cisgender women, with a greater tendency toward autoimmune conditions but a lower risk of cardiovascular disease.
In short, the body’s molecular “fingerprint” shifted in line with gender identity, showing just how adaptable human biology is, even in adulthood.
Why is this important?
These results confirm that hormone therapy doesn’t just change hormone levels, it changes how the body works at a much deeper level. This helps explain why some health risks and benefits may shift after starting GAHT.
For example:
Some immune-related proteins increased, which might relate to slightly higher rates of autoimmune conditions seen in people recorded female at birth.
Heart-related proteins shifted towards a pattern linked to better heart health, potentially reducing risks more common in people recorded male at birth.
Higher amounts of the proteins leptin and prolactin was associated with greater breast growth.
This means that as we continue to learn how to use proteomic data, healthcare can become more personalised, helping clinicians better monitor long-term effects and tailor treatment for each person.
What does this mean for trans and gender diverse people?
This study gives scientific weight to something many trans people already know; that gender-affirming hormones have real, powerful biological effects that help the body align with gender identity.
It also shows that our biology is not fixed. Hormones can reshape the body at a molecular level, proving that sex-related traits are part of a continuum, not a rigid binary.
Should we aim to increase prolactin levels for better breast growth?
Our research used two different ways to look at hormones. Routine blood tests for prolactin (the same kind a doctor orders) did not show any relationship with breast volume. But, when we used a more advanced proteomic technique that measured thousands of proteins at once, we found that prolactin-related signals were linked with breast growth. This doesn’t mean that higher prolactin levels in a blood test cause breast development, or that taking medication to raise prolactin would help. In fact, high prolactin can sometimes indicate a medical problem.
The finding instead suggests that prolactin and related molecular pathways may play a role locally in the breast, rather than through changes in blood hormone levels. It’s an exciting scientific clue, but not something to act on medically. The safest and most effective approach remains following prescribed gender-affirming hormone therapy under your clinician’s supervision.
How might we use proteomics in the future?
This groundbreaking study is just the beginning, with the possibility for further proteomics research into other kinds of GAHT, such as testosterone (one previous study has shown testosterone-based GAHT reshapes immune function towards that of cis men). In the future, if proteomic testing becomes more affordable and accessible, it could play a key role in personalising GAHT.
By tracking thousands of proteins in the blood, clinicians could gain a detailed snapshot of how an individual’s body is responding, beyond just measuring hormone levels. This could help fine-tune medication doses, detect early signs of side effects such as changes in heart or immune health, and even identify who might benefit from one type of treatment over another.
As technology advances and costs fall, proteomics could become a powerful tool for tailoring care to each person’s unique biology, making hormone therapy safer, more effective, and more responsive to individual needs.
Links to Nature Medicine paper, and more
Read the paper: Plasma proteome adaptations during feminizing gender-affirming hormone therapy, published in Nature Medicine.
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