Gender-affirming therapy reshapes the immune systems of trans men (2024)

Gender-affirming therapy reshapes the immune systems of trans men (1)

When trans men receive testosterone therapy, their bodies begin to resemble those of cis men in many ways — including their immune systems. That’s according to a study published today in Nature1, one of the largest yet to examine how gender-affirming hormone therapy (GAHT) affects the immune system over time.

The results provide much-needed insight and could help to explain why men tend to be more susceptible to viral infections than women and women are often more susceptible to autoimmune conditions.

The study is important because physicians want GAHT “to be safe, of course”, says co-author Mats Holmberg, an endocrinologist at the Karolinska Institute in Stockholm, who provides gender-affirming care. It is a step towards being able to administer the best treatment possible, Holmberg says.

An immune balance point?

During their study, Holmberg and his colleagues collected blood samples from 23 trans men (who were assigned female at birth but sought masculinizing GAHT) at three time points: before they began GAHT, three months into treatment and one year into treatment. Over time, the researchers observed a shift in the participants’ immune response, from a type characterized by high levels of immune-signalling proteins called type I interferons, which specialize in fighting viral infections, to one featuring an abundance of an inflammatory protein called tumour necrosis factor (TNF), which is associated with muscle growth.

What’s new here is that sex hormones seem to cross-regulate immunological pathways, says study co-author Petter Brodin, a paediatric immunologist at the Karolinska Institute. As testosterone levels go up and oestrogen levels go down, it seems as if the immune system passes through a balance point, Brodin adds.

“This is a very interesting new finding that will trigger a lot of research,” says Marcus Altfeld, an immunologist at the University Medical Center Hamburg–Eppendorf in Germany. In particular, Altfeld wants to understand whether rising TNF levels reduce the amount of type I interferons directly, or whether testosterone mediates both of these effects independently.

Disease implications

The researchers point out that their molecular-level findings echo real-world susceptibility to infection and disease. For instance, during the early days of the COVID-19 pandemic, men infected with the coronavirus SARS-CoV-2 had about a 50% higher death rate than did women who were infected. This makes sense, Brodin says, because women typically have high levels of type I interferons, helping them to fight off infections.

Heed lessons from past studies involving transgender people: first, do no harm

On the flip side, women develop long COVID more frequently than do men — about 76% more often, according to one study2. This could be because long COVID bears a resemblance to autoimmune diseases, some of which are associated with overactivation of the type I interferon system.

Other research also points in this direction. A preprint posted ahead of peer review3 in March shows that low levels of testosterone are a predictor of whether women will develop long COVID. “The importance of sex hormones in both acute, severe COVID and long COVID is becoming more appreciated,” says preprint co-author Akiko Iwasaki, an immunologist at Yale University in New Haven, Connecticut.

But hormones are probably not the whole story when it comes to differences in susceptibility to COVID-19 or other diseases, researchers say. The X-chromosome — of which females typically have two copies, and males one — also deserves consideration, says Sabra Klein, an immunologist at Johns Hopkins University in Baltimore, Maryland. The X-chromosome is rich in genes related to the immune system so, for instance, attributing sex differences in COVID-19 outcomes to hormones alone is “probably simplifying something that’s more complex”, she says.

Autoimmune risk

Trans men need not be too concerned that testosterone therapy will raise their risk of viral infections. “Most of the normal infections, they are common in both sexes,” Altfeld says, and people get over them. Autoimmune disorders, by contrast, can be severe, and Holmberg is concerned that oestrogen therapy, which reduces testosterone, might increase the risk of developing these conditions.

The fraught quest to account for sex in biology research

But the study didn't examine oestrogen therapy or safety directly. Klein thinks it’s too early to say whether the link between autoimmune diseases and GAHT warrants consideration. “These are small sample sizes,” she says — 23 people isn’t a lot. “This is pointing towards the need for more research.”

Some physicians already warn their patients about the link. Altfeld, who studies the effect of GAHT on the immune system, says he works with clinicians who inform trans women that oestrogen therapy comes with a risk of developing an autoimmune disease. The potential downside is “well known in the community”, he says.

But not everyone has such well-informed doctors. It’s “really hard” to find a medical provider who specializes in multiple disciplines, such as immunology and gender-affirming care, and can treat “intersectional needs”, says Jamie, a transmasculine person (assigned female at birth but identifying with masculinity) who has an autoimmune condition called Sjögren’s syndrome, and who asked to be identified by a pseudonym because not everyone in their life is aware of their gender identity.

Jamie decided to undergo testosterone therapy both for gender affirmation and to treat Sjögren’s syndrome — a course of action they undertook on the basis of their own reading of the scientific literature, rather than because of a physician’s advice. Since then, Jamie has traded testosterone therapy for an immunosuppressant called adalimumab (sold as Humira) in an effort to improve their health. Adalimumab inhibits TNF, which is elevated in people with Sjögren’s. Holmberg and Brodin’s work makes Jamie wonder whether returning to testosterone therapy would make the adalimumab they are taking less effective, given that their TNF levels could rise as a result. “My god, I wish there were studies on this so that we knew how the interactions worked instead of just having to guess,” they say.

Gender-affirming therapy reshapes the immune systems of trans men (2024)

FAQs

Gender-affirming therapy reshapes the immune systems of trans men? ›

Gender-affirming therapy reshapes the immune systems of trans men. Testosterone treatment boosts levels of an inflammatory protein to those typically seen in cis men, study finds. When trans men receive testosterone therapy, their bodies begin to resemble those of cis men in many ways — including their immune systems.

Does HRT change your immune system? ›

The activity of the female immune system varies throughout the life cycle, peaking at puberty, being suppressed during pregnancy, rebounding after pregnancy, and decreasing once again at the onset of menopause [5]. There is evidence that HRT may further depress several cellular immune responses.

What happens if a woman stops taking testosterone? ›

If you stop taking testosterone you'll probably start to have periods. You may also notice changes in your body shape around your hips, chest and thighs. You should not notice any changes to your tone of voice or facial hair.

Do you have to take testosterone forever in FTM? ›

Often, people who are looking to sustain certain changes will take testosterone therapy for the rest of their lives. Some people will only take testosterone for as long as it takes to develop changes that are usually considered permanent, like a deeper voice and increased body hair.

What happens when you go off testosterone ftm? ›

Some of the physical changes caused by masculinizing hormone therapy can be reversed if you stop taking testosterone. Others, such as a deeper voice, a larger clitoris, scalp hair loss, and more body and facial hair, cannot be reversed.

Does estrogen weaken your immune system? ›

Estrogen has a strong effect on the immune system. When levels are high, the immune system is more likely to trend towards an autoimmune response. This is because estrogen tends to push immune system signals towards autoimmunity through stimulation of antibodies.

What is the long term damage of HRT? ›

HRT can slightly increase the risk of breast cancer. If you've had breast cancer you'll usually be advised not to take HRT. The increased risk is low: there are around 5 extra cases of breast cancer in every 1,000 women who take combined HRT for 5 years. The risk increases the longer you take it, and the older you are.

Does HRT make you infertile in MTF? ›

Can Hormone Replacement Therapy (HRT) Make You Sterile? For some transfeminine individuals who are transitioning, the hormones you take during your transition may make it impossible for you to have biological children. Procedures like orchiectomies (removing your testicles) can also cause fertility problems.

Does TRT change your face? ›

You may also gain fat around your abdomen. Your eyes and face will begin to develop a more angular, male appearance as facial fat decreases and shifts. Please note that it's not likely your bone structure will change, though some people in their late teens or early twenties may see some subtle bone changes.

What are the side effects of gender affirming hormone therapy? ›

While gender affirming hormone therapy usually results in an improvement in mood, some people may experience mood swings or a worsening of anxiety, depression, or other mental health conditions as a result of the shifts associated with starting a second puberty.

Does testosterone age your face? ›

The higher your testosterone, the firmer and tighter your skin appears. In men, low testosterone (low-T) is associated with wrinkles, muscle loss, thinning hair, and weight gain. Although testosterone levels are thought to be most important for men, these levels are important for women also.

Why can't I cry on testosterone? ›

And, as it turns out, there could be a biological reason behind it: some research has suggested that higher levels of testosterone could inhibit crying. Crying as a response to strong emotions appears to be a uniquely human thing.

What are the permanent effects of testosterone FTM? ›

Some changes are PERMANENT and will not go away, even if you decide to stop taking testosterone or take a lower amount: Deepening of the pitch (sound) of your voice. Growth, thickening, and darkening of hair on the body.

Can Transmen get erect? ›

Can I get an erection after phalloplasty? In stage 3 phalloplasty, a urologist can place a prosthetic erectile device which will allow you to maintain an erection. As of September 2022, no implantable prosthetic devices have been FDA-approved for phalloplasty.

Does your body go back to normal after stopping testosterone? ›

Stopping TRT can lead to the return of symptoms of low testosterone, such as fatigue, mood changes, bone density changes, and decreased libido. Natural testosterone production may take time to resume after stopping TRT, especially for those who have used TRT for an extended period of time.

Is testosterone bad for your liver FTM? ›

Can gender-affirming hormone therapy damage my liver? High doses of testosterone or estrogen may damage the liver. If you take hormone therapy, you should receive regular monitoring by your health care team.

Can HRT trigger autoimmune disease? ›

Hormone replacement therapy (HRT)

Research studies suggest that estrogen therapy may modulate the immune system in ways that either increase or decrease the risk of autoimmune conditions. This depends on various factors, such as the type of hormone therapy or the dose.

Does HRT deplete nutrients? ›

Vitamin C – This water-soluble nutrient may be depleted by HRT and the contraceptive pill. Vitamin C is important for the immune system, for collagen formation, is a powerful antioxidant and also helps the body to utilise iron.

Does hormone replacement therapy change your body? ›

You can also expect your muscle mass and strength to decrease. To maintain muscle tone, and for your general health, I recommend you exercise. Overall, you may gain or lose weight once you begin hormone therapy, depending on your diet, lifestyle, genetics and muscle mass.

How does HRT affect lifespan? ›

Effects of HRT.

Although HRT was associated with a decrement in life expectancy across the majority of the analyses, HRT became associated with an increase in life expectancy when its effect on breast cancer risk was relatively small and its effect on CHD risk was relatively beneficial.

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