The effects of feminising gender-affirmative hormone therapy (GAHT) are more than skin deep, new research in Nature Medicine has reported, with the changes going down to the very proteins circulating in a person’s blood.
University of Melbourne endocrinologist Ada Cheung, who co-led the study, has called the findings “a world-first”.
Sanjay Kalra, an endocrinologist and the former president of the Indian Professional Association for Transgender Health, added that the study “sheds light on a new aspect of transgender medicine”.
Effects of GAHT
Transgender people are those whose gender identity differs from the sex they were assigned at birth.
Transgender women, who are assigned male sex at birth but identify as women, may opt for GAHT to help align their bodies with their gender identity. Feminising GAHT typically involves a combination of the hormone estrogen and an antiandrogen like cyproterone acetate (CPA) or spironolactone (SpiroL). Antiandrogens block the effects of testosterone and dihydrotestosterone, hormones that play key roles in the development of male sexual characteristics, muscle growth, and in determining how fat is deposited in the body.
Scientists and physicians have known since the 1970s that GAHT redistributes fat, reduces facial and body hair growth, and develops breasts in transgender women’s bodies. The new study has now shown that GAHT also shifts the profile of proteins circulating in a transgender woman’s blood towards levels observed in cisgender women.
It took researchers this long to find this because “transgender health has historically been under-researched,” Dr. Cheung said.
Also, the technology required to measure thousands of proteins in the body at the same time “has only been around for 2-3 years, and is very expensive,” Boris Novakovic, a team leader at the Murdoch Children’s Research Institute in Australia and who collaborated with Dr. Cheung on the study, said.
These deeper biological changes may also increase the long-term susceptibility of transgender women to asthma and autoimmune disorders, the study added. While experts said these risks have yet to be clinically observed, cisgender women are known to be moresusceptible to them than cisgender men.
Changing protein levels
The study recruited 40 transgender women in Melbourne and placed half on a combination of estrogen + CPA and the other half on estrogen + SpiroL. The researchers collected their blood samples once before they began GAHT and after six months on the therapy.
The team then isolated plasma, the liquid component of blood, from the samples and measured the levels of over 5,000 proteins. By comparing their levels in samples collected before and after GAHT, the researchers could estimate the therapy’s effects.
Their analysis identified 245 proteins whose levels had changed in the group that received CPA and 91 proteins in the group that received SpiroL. In both the groups, GAHT had decreased the levels of most of these proteins.
Using statistical methods, the researchers were able to attribute GAHT’s effects on the protein levels to three factors: decreased testosterone concentration, increased body fat percentage, and higher breast volume.
Beneath the surface
The team also checked proteins whose levels had already been reported to vary with sex in a cisgender population using the UK Biobank’s Pharma Proteomics project. In 2023, this project profiled nearly 3,000 proteins from around 54,000 UK-based participants and identified those most strongly associated with sex.
Using a computational technique, they discovered that the levels of 36 such proteins were correlated with GAHT involving CPA use. For GAHT that involved SpiroL, the list numbered 22. For both groups, GAHT led to a noticeable change in these proteins’ levels towards the pattern generally observed in cisgender women.
The findings suggest feminising GAHT “changes thousands of proteins in the blood, aligning the body’s biology more closely with a person’s gender identity,” Dr. Cheung said. “The changes go far beyond what we see on the outside; they happen deep inside the body’s cells and systems.”
In the long-term
The study’s results also suggested that using either CPA or SpiroL might shift protein profiles towards those consistent with increased risks of allergic asthma and autoimmune diseases.
Only CPA use shifted protein levels to those suggestive of lower atherosclerosis risk, i.e. the risk of blood vessels narrowing and hardening due to fat deposits.
That said, Dr. Cheung warned that the risks are “only possibilities, not proven. We don’t yet have clinical evidence showing higher rates of these diseases in trans women on hormones.”
Dr. Kalra also said he hadn’t observed transgender women being more susceptible to autoimmune diseases in his clinical practice.
The difference between clinical observations and the study’s findings might arise because “autoimmune or allergic conditions take years to develop, and depend on multiple genetic and environmental factors,” Dr. Cheung said. The protein-level changes observed are “early molecular shifts, not diagnoses”.
She also stressed the need for longitudinal studies that track transgender women’s health over a period of time to understand whether these “biological patterns translate into real-world health effects”.
Future possibilities
For the team, the study is one of many that could help researchers “build a complete picture of how gender-affirming hormones influence health for everyone.”
They are already extending their work to masculinising GAHT, which involves administering testosterone to transgender individuals assigned female at birth.
Dr. Kalra expressed hope that the study will prompt similar ones in India, where transgender women’s access to GAHT is often inconsistent and without regular clinical monitoring. Such studies could help clinicians make more informed decisions in the long run, Richie Gupta, senior director and head of the Department of Plastic Surgery and Gender-Affirmation Clinic at Fortis Hospital in New Delhi, said.
But the effort’s biggest contribution, Dr. Cheung said, is highlighting “the need for high-quality, inclusive science so that trans people can receive the best possible care based on real data.”
Sayantan Datta is a faculty member at Krea University and an independent science journalist.
Published – November 28, 2025 07:30 am IST
