Hormone Therapy Shifts Biomarkers in Transgender Women

When transgender women undergo feminizing hormone therapy, the physical changes become visible – but what happens beneath the surface?

Researchers at the Murdoch Children’s Research Institute (MCRI) and the University of Melbourne found that the therapy shifted many biomarker levels toward those typically seen in cisgender women, suggesting that hormone therapy does much more than alter appearance 

Hormone therapy and disease risk

Biological sex has a strong influence on disease risk: women are more likely to develop autoimmune disorders, while men face higher rates of cardiovascular disease. These patterns arise in part because sex hormones such as testosterone and estrogen help shape body composition, immune function and metabolism. These hormones act beyond their roles in reproduction, influencing multiple physiological systems.

When individuals undergo gender-affirming hormone therapy (GAHT) to align physical traits with gender identity, the primary focus is often on visible outcomes and changes in hormone levels.

“Despite the clear physical changes induced by GAHT, little is known about how it affects underlying physiological and biochemical processes,” said the authors.

Prior studies have documented metabolic changes and shifts in DNA methylation in people receiving GAHT. However, large-scale biochemical profiling, especially of blood proteins that reflect many body systems, is still largely missing.

Blood plasma proteins provide a snapshot of diverse processes such as fertility, immune response and cardiovascular health. Mapping how GAHT affects this proteome could help better understand how hormone therapy reshapes physiology.

The new study examined how feminizing GAHT over six months alters blood proteins in transgender women and asked whether their proteomic profiles begin to resemble those of cisgender women.

“Studying proteins could help with the development of personalized treatment approaches by monitoring the effectiveness of GAHT in trans women and help us with early detection of potential side-effects on heart health or immune function,” said co-author Dr. Ada Cheung, a research fellow at the University of Melbourne.

How hormone therapy changed protein profiles

The study involved 40 transgender women, who were all beginning feminizing GAHT combining estradiol with either cyproterone acetate (CPA) or spironolactone (SPIRO) – standard anti-androgen medications. Blood samples were collected before treatment and again after six months. The team measured more than 5,000 plasma proteins and compared these results with blood-protein data from over 54,000 UK Biobank participants to see how closely the changes matched typical cisgender male and female profiles.

After six months, the therapy had reshaped the plasma proteome. In the CPA group, 245 proteins changed significantly and in the SPIRO group, 91 proteins changed, with over 95% decreased in abundance.

The proteins most affected were those tied to male reproductive biology, such as SPINT3 and INSL3, which are linked to sperm production and testicular function.

At the same time, proteins involved in body fat regulation and breast tissue growth rose, including leptin and prolactin. Participants who reached lower testosterone levels showed the largest shifts.

In the CPA group, 36 of the 100 most sex-specific proteins moved toward female-typical levels and 22 were altered in the SPIRO group. Nearly half of the CPA-related protein changes also mirrored those seen in menopausal hormone therapy, implying shared hormonal mechanisms.

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Proteins linked to immune activity, such as CXCL13, increased in those on CPA. Patterns associated with asthma and autoimmune disease also rose, while those tied to atherosclerosis declined.

Hormone therapy implications on health

Within six months of treatment, GAHT altered hundreds of circulating proteins, shifting many toward a cis-female profile. This molecular change helps explain why long-term health risks for transgender women may begin to align with those of cisgender women, with a greater tendency toward autoimmune conditions but a lower risk of cardiovascular disease.

“For transgender women we found GAHT alters the levels of many protein biomarkers that reflect what happens clinically. This may go onto impact the risk of allergic and autoimmune diseases, which tend to affect more females, but decrease the risk of heart disease, more commonly seen in males,” said corresponding author Dr. Boris Novakovic, a senior research fellow at MCRI.

“This highlights that human biology is malleable and that even in adulthood, our bodies respond to sex hormone changes,” he added.

The work highlights the need for personalized health monitoring during hormone therapy, particularly for heart and immune function. Proteomic markers such as leptin and INSL3 could help clinicians track treatment effects and fertility changes more precisely.

The study’s size limits how broadly the results can be applied, and only feminizing GAHT was studied. Larger and longer studies, including masculinizing therapy, are needed to capture the full picture.

“We need to improve the way gender-affirming hormone therapy is managed. This study gives us a glimpse into how personalized treatment may work as technology advances,” said Cheung.

Reference: Nguyen NNL, Celestra D, Angus LM, et al. Plasma proteome adaptations during feminizing gender-affirming hormone therapy. Nat Med. 2025. doi: 10.1038/s41591-025-04023-9

This article is a rework of a press release issued by Murdoch Children’s Research Institute. Material has been edited for length and content.