Male use of estrogen is associated with a range of diseases and health complications.
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 notâand they exhibit âtesticular atrophy, hyalinization, and fibrosis,â 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 âhigher proportions of sperm abnormalities . . . or azoospermiaâ (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 clotsâknown as venous thromboembolism (VTE)âand 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 havenât 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 dementiaâan 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 âthe overall mortality risk of [trans-identifying men] . . . was higher compared to men in the general population . . . and even higher compared to women.â 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 sclerosisâraising 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 sensitivityâan early warning sign for diabetes. In one study, insulin resistance rose by more than 80 percent over two years of use. Elevated triglyceridesâa type of fat in the bloodâhave 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 tumorsâsuch as meningiomasâamong 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 âan increase in ventricular volume and a decrease in brain volume.â 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 cellsâpotentially mimicking patterns seen in degenerative diseases.
The paper also notes that levels of BDNFâa brain chemical critical for mood and memoryâtend 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 paperâs final section, the authors stress that even if some of these harms are based on limited evidence, they should still be taken seriously. â[M]edical decision-making tends to prioritize avoiding harm over achieving benefit,â the authors observe, âparticularly when harms are severe and benefits are modest.â 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 âno psychosocial improvement among natal males.â Earlier studies making stronger claims have since been corrected or discredited due to flawed methods.
The new paperâs 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 databasesâlike Sweden and the Netherlandsâcould provide valuable longitudinal data for researchers willing to investigate these questions with scientific integrity.
Of course, the study has limitations. Itâs 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 canât prove cause and effect. But thatâs true of most research in this field, as high-quality long-term trials donât 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 donât amount to conclusive proof of harm in every case, they make a compelling case for caution, transparency, and scientific integrityâqualities frequently missing in the rush to medicalize gender distress.
That this kind of research is only now being doneâafter thousands of teens have already started irreversible treatmentsâis troubling. That many of the safety signals are only now becoming detectableâbecause so many people have recently been exposed to these interventionsâshould 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 weâre willing to follow the facts where they lead.
