The Long-Term Harms Are No Longer Theoretical
A new review uncovers serious health risks linked to estrogen “therapy” in males.
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About the Author
Dr. Colin Wright is an evolutionary biology PhD, Manhattan Institute Fellow, and CEO/Editor-in-Chief of Reality’s Last Stand. His writing has appeared in The Wall Street Journal, The Times, the New York Post, Newsweek, City Journal, Quillette, Queer Majority, and other major news outlets and peer-reviewed journals.
In recent years, administering estrogen to males who identify as transgender women has become increasingly common, including among adolescents. Often paired with testosterone blockers, this treatment is marketed as part of “gender-affirming care”—a term used to describe medical interventions intended to “align” a person’s body with his or her “gender identity.” But as more young people pursue medical transition in the absence of long-term studies, concerns about safety, efficacy, and informed consent have grown more urgent.
A recent review article in Discover Mental Health, entitled “Emerging and accumulating safety signals for the use of estrogen among transgender women,” and authored by Lauren Schwartz and colleagues, tries to fill that gap. It compiles studies, case reports, and group data to spotlight a range of serious health risks—some well-known, others emerging—associated with long-term estrogen use in males.
Understanding the risks of cross-sex hormone therapy is important not only for clinicians and patients but also for policymakers, parents, and the broader public. Medicalized gender transition for minors is becoming increasingly common, even as major questions about long-term outcomes remain unanswered. That disconnect makes the work of Schwartz et al. especially important.
One of the best-known risks associated with estrogen use in males is infertility. In their new review, Schwartz et al. note that while some patients retain limited sperm production, many do not—and they exhibit “testicular atrophy, hyalinization, and fibrosis,” meaning shrinkage, scarring, and tissue changes that may signal elevated cancer risk. A recent systematic review cited in the paper found that taking estrogen alongside testosterone blockers was linked to “higher proportions of sperm abnormalities . . . or azoospermia” (complete loss of sperm). Some of these effects may be reversible, but others are not. Tissue studies following orchiectomies (surgical removal of the testes) show widespread damage.
Cardiovascular complications are another well-documented concern. Multiple studies cited in the review report higher rates of dangerous blood clots—known as venous thromboembolism (VTE)—and strokes among trans-identifying males taking estrogen. One meta-analysis found VTE incidence more than twice as high as in non-trans-identifying males. A cohort study showed that after two years of estrogen use, the risk of VTE was over five times higher; after six years, the risk of ischemic stroke was nearly ten times higher than in non-trans-identifying males. While some research suggests that transdermal estrogen (patches or creams) may carry a lower clotting risk than oral forms (pills), all delivery methods appear to elevate cardiovascular risk.
The paper also highlights potential cognitive risks, including memory loss and early-onset impairment. While short-term studies haven’t consistently shown problems, longer-term research on older transgender-identifying males taking hormones has found poorer performance on tasks involving memory and processing speed. In postmenopausal women, estrogen use has already been linked to a doubled relative risk of dementia—an effect that appears to extend to trans-identifying males. Survey data likewise show that trans- and nonbinary-identifying adults over 45 report more cognitive difficulties than their non-trans-identifying peers.
Perhaps the most alarming finding cited in the paper is the increased risk of early death. Schwartz and colleagues reference a Dutch cohort study of patients treated at a major gender identity clinic, which found that “the overall mortality risk of [trans-identifying men] . . . was higher compared to men in the general population . . . and even higher compared to women.” Leading causes of death included heart disease, cancer, and suicide. An earlier study found a 51 percent higher mortality rate in trans-identifying males than the general population. Notably, current estrogen use, rather than past use, was linked to these increased risks, suggesting long-term exposure to feminizing hormones may amplify health risks over time.
Beyond these headline findings, the paper outlines several additional risks. Autoimmune diseases such as lupus and systemic sclerosis have occasionally appeared or worsened following the initiation of estrogen therapy. One patient with a skin-limited autoimmune condition developed life-threatening kidney complications after starting hormones. At the population level, males with gender identity disorders have been found to have a more than sixfold increased risk of developing multiple sclerosis—raising the possibility that estrogen may act as a trigger for autoimmune responses in some individuals.
Estrogen also appears to affect metabolism. Hormone therapy has been associated with increased fat mass, muscle loss, and reduced insulin sensitivity—an early warning sign for diabetes. In one study, insulin resistance rose by more than 80 percent over two years of use. Elevated triglycerides—a type of fat in the blood—have been linked to serious complications in trans-identifying males, including pancreatitis and gallstones.
The authors also review cancer risks. Trans-identifying males on estrogen are significantly more likely to develop breast cancer than non-trans-identifying men. One cited analysis estimated the risk to be 22 to 40 times higher. While breast cancer remains rare in men overall, such increases are noteworthy.
The paper also highlights elevated rates of thyroid and testicular cancers among trans-identifying males on estrogen. Some studies suggest a potential link between testicular cancer and long-term use of estrogen or testosterone blockers. Public drug safety databases in the U.S. and France reflect similar concerns, listing tumors, cardiovascular complications, and brain tumors—such as meningiomas—among the most frequently reported adverse events.
One especially unsettling section explores how estrogen may affect the male brain. A few small brain-imaging studies found that several months of estrogen use led to “an increase in ventricular volume and a decrease in brain volume.” Studies in male rats showed similar effects: estrogen and testosterone blockers reduced brain volume and altered brain chemistry. The authors suggest these changes may result from disruptions in how water is regulated in brain cells—potentially mimicking patterns seen in degenerative diseases.
The paper also notes that levels of BDNF—a brain chemical critical for mood and memory—tend to decline in patients on cross-sex hormones. Low BDNF is associated with depression and shrinkage of the hippocampus, a brain region essential for memory. Taken together, these findings raise the possibility that estrogen may produce lasting changes in male brain structure and function.
In the paper’s final section, the authors stress that even if some of these harms are based on limited evidence, they should still be taken seriously. “[M]edical decision-making tends to prioritize avoiding harm over achieving benefit,” the authors observe, “particularly when harms are severe and benefits are modest.” Many of the risks discussed here are life-altering or life-threatening, while randomized controlled trials showing long-term benefits of estrogen for this population are nonexistent. Some advocates argue that these treatments prevent suicide, but a recent major study found “no psychosocial improvement among natal males.” Earlier studies making stronger claims have since been corrected or discredited due to flawed methods.
The new paper’s authors call for more rigorous long-term research, especially studies that separate hormone effects from other factors like mental illness or previous treatments. They note that many systematic reviews gloss over side effects, and that some major safety reports commissioned by activist medical organizations like WPATH remain unpublished. Countries with national health databases—like Sweden and the Netherlands—could provide valuable longitudinal data for researchers willing to investigate these questions with scientific integrity.
Of course, the study has limitations. It’s not a formal systematic review, but rather a comprehensive summary of published evidence. Much of the data come from observational studies or case reports, which can’t prove cause and effect. But that’s true of most research in this field, as high-quality long-term trials don’t yet exist.
The value of this paper lies in its wide-angle view of risks that activist and medical circles have too often downplayed or ignored. While the findings don’t amount to conclusive proof of harm in every case, they make a compelling case for caution, transparency, and scientific integrity—qualities frequently missing in the rush to medicalize gender distress.
That this kind of research is only now being done—after thousands of teens have already started irreversible treatments—is troubling. That many of the safety signals are only now becoming detectable—because so many people have recently been exposed to these interventions—should be a sobering wake-up call.
Still, we have reason for hope. The voices of concerned clinicians, detransitioners, and independent scientists are becoming harder to dismiss. The public is asking tougher questions, and the medical establishment is beginning to confront the real costs of its rush to affirm identity over evidence. A better, safer, and more ethical path remains possible if we’re willing to follow the facts where they lead.
This article was originally published in City Journal on June 25, 2025.
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Our son received a letter from Planned Parenthood where (unbeknownst to us) he was getting estradaviol: the letter informed him that recent tests had found his risk of stroke and blood clotting is at dangerously high level and that he should see a primary care physician.. BUT THAT HE SHOULD FEEL COMFORTABLE CONTINUING HIS DRUG THERAPY!!!!! No mention made of what is clearly causing a perilous health condition in what was a perfectly normal and fully healthy body!!!!! EVIL!!!!!
None of these "discoveries" are surprising. Estrogen "therapy" is an all-out assault on the natural processes of the male body's chemistry. Literally, an aggressive suppression of everything the male body is hard-wired to do. Incredible that this must be pointed out.