New research has ruled out hormone signaling as the reason why men with acute myeloid leukemia (AML) tend to have poorer outcomes than women, even when treated with the same intensive chemotherapy—a finding that helps refine future research and could influence clinical trial design.
The study—published by Miraki-Moud et al in Leukemia—found that although AML cells express high levels of androgen receptors, they do not appear to influence how the cancer grows or responds to treatment. The findings suggest that hormone signaling is not responsible for the sex-based survival gap in AML, and that other biological factors are likely at play.
Study Methodology and Findings
To explore whether hormone signaling might explain the survival gap between male and female patients with AML, the research team analyzed more than 4,000 patients enrolled in two major UK clinical trials, alongside lab experiments on AML cells for androgen receptor expression. They found high levels of these receptors in both male and female patients and observed that these levels were associated with worse survival, even if the receptors themselves weren’t helping the cancer grow.
However, when AML cells were exposed to testosterone-like hormones in the lab, the hormones had no effect on cell growth, survival, or response to chemotherapy. Blocking the receptors with drugs commonly used to treat prostate cancer also failed to improve outcomes, either alone or in combination with chemotherapy. Even when studying the disease in preclinical models, the combination therapy did not outperform standard treatment.
The researchers also discovered that a common immune signal, called IL-6, may drive up these receptor levels—suggesting that inflammation, rather than hormones, may play a role in AML outcomes.
The team also investigated estrogen signaling, given its potential relevance to female biology. While AML cells expressed some estrogen receptors, the hormone had no impact on cell viability or treatment response.
The research team found that men had a lower remission rate of 86%, and a slightly higher relapse rate of 43% than female patients—whose rates were 89% and 40%, respectively—and that male sex remained an independent risk factor for poorer survival, even after accounting for genetic profile differences.
While the findings do not point to a new treatment strategy, they help clarify a key question in AML and rule out a previously plausible explanation. The study suggests that other factors—such as differences in drug metabolism, immune responses, or mutation patterns—may be more important in driving sex-based differences in AML outcomes.
Previous research has shown that men may clear chemotherapy drugs more quickly than women, potentially reducing their effectiveness. Women also tend to have stronger immune responses, which could help control leukemia more effectively. These areas now warrant closer investigation.
The study also highlights the importance of considering sex as a biological variable in future AML research and clinical trial design. Understanding how sex interacts with treatment could lead to more personalized and effective therapies for all patients.
Expert Point of View
Senior author David Taussig, PhD, Associate Honorary Faculty in Leukaemia at the Institute of Cancer Research (ICR) and Consultant Haematologist at The Royal Marsden, said: “We found that AML cells express high levels of androgen receptors, but these receptors don’t seem to help the cancer survive. That’s an important finding—it tells us that hormone signaling isn’t the reason men do worse with AML, and helps us focus on other, more promising areas.”
The team is now exploring how factors such as immune function and drug clearance contribute to AML outcomes, and whether these can be targeted to improve survival.
First author Farideh Miraki-Moud, PhD, Higher Scientific Officer in Cancer Biology at the ICR, said: “While much work remains, the findings mark a valuable step in refining our understanding of the biology of AML—and guiding future research towards the mechanisms that matter most. We hope this will ultimately lead to more effective, personalized treatments for patients.”
Disclosure: Funding for the study was provided by Cancer Research UK, the National Institute for Health and Care Research Biomedical Research Centre, and Bayer, who also provided the drug. The study was supported by The Royal Marsden Cancer Charity. For full disclosures of the study authors, visit nature.com.
