Response to: Emerging and accumulating safety signals for the use of estrogen among transgender women

A recent review claiming that estrogen harms cognition in transgender women is misleading and selective in how it uses the scientific evidence. The strongest type of evidence it cites — a meta-analysis that combines results from multiple studies — actually found no sign that estrogen harms cognition. In fact, it reported a small improvement in verbal working memory and no change in other cognitive skills.

The review then highlights weaker sources, including an unpublished and not peer-reviewed abstract and studies that were not designed to answer the question being asked. For example, one study looked at older cisgender women taking estrogen plus progesterone, and the authors concluded that their findings were due to progesterone, not estrogen.

The authors also suggest that estrogen reduces levels of a protein called brain-derived neurotrophic factor (BDNF), based on a longitudinal study of transgender women taking estrogen. However, the study did not find a correlation between estrogen and BDNF changes, only lower BDNF levels in transgender women one year after transitioning. There isn’t evidence that estrogen reduces BDNF levels; there is, however, evidence that estrogen increases BDNF (which Schwartz et al. do not mention). BDNF levels are particularly influenced by stress, which better explain the results of the study of transgender women.

The paper also points to a survey that found transgender people reported more subjective cognitive decline than cisgender people. But that survey included transgender people of all genders and did not ask about hormone use, so there is no way to know if estrogen caused changes to cognition. People in the sample may have been taking different hormones — or none at all — and self-reported cognitive decline is a very broad and nonspecific measure. A better explanation is that elevated stress, depression, and other factors associated with marginalization and health disparities caused increased levels of self-reported cognitive issues.

By contrast, other studies suggest estrogen may have neutral or even positive effects on cognition, but Schwartz and colleagues didn’t mention them. For example, one small study found improved emotional awareness after gender-affirming hormone therapy, and another found better scores on some memory and IQ tests after estrogen was stopped and then restarted in transgender women.

Overall, the evidence does not show that estrogen harms cognition in transgender women. The review’s conclusion appears to rest on selective citations and reporting of the literature. If you are interested in reading a more in-depth breakdown of the issues with the cognition portion of the Schwartz et al. review, click here.