NIH-Funded Study Finds Testosterone May Suppress Glioblastoma Growth in Men

A new National Institutes of Health (NIH)-funded study is challenging long-standing assumptions about testosterone and cancer biology by suggesting that loss of androgen signaling may accelerate the progression in preclinical male models of glioblastoma (GBM), the most aggressive primary brain tumor in adults.

The study, published in the journal Nature and led by researchers at Cleveland Clinic, found that androgen loss promoted glioblastoma growth in preclinical models through activation of stress-related hormonal pathways and inflammatory immune responses within the brain. The findings provide new insights into how hormonal signaling may influence brain tumor biology and could support future investigations into hormone-related therapeutic strategies for glioblastoma.

Glioblastoma Remains One of the Most Aggressive Brain Tumors

Glioblastoma is the most common malignant primary brain tumor in adults and remains one of the most difficult cancers to treat despite advances in surgery, radiation therapy, and chemotherapy. The disease is highly invasive, rapidly progressive, and frequently recurs even after aggressive treatment.

Patients diagnosed with glioblastoma typically undergo surgical resection followed by radiation therapy and temozolomide chemotherapy. However, treatment resistance and recurrence continue to limit long-term survival outcomes.

Because glioblastoma occurs more frequently in men than women, researchers have long investigated whether sex hormones influence tumor biology. Previous assumptions suggested that testosterone and other androgens might contribute to tumor progression. However, the new study indicates that androgen signaling within the brain may play a more complex regulatory role than previously understood.

Researchers Observed Accelerated Tumor Growth Following Androgen Loss

Using preclinical glioblastoma models, investigators observed that androgen deprivation accelerated intracranial tumor growth in male mice. Interestingly, tumors located outside the brain demonstrated different responses, where androgen reduction slowed tumor progression.

The findings suggest that androgen signaling may influence the brain tumor microenvironment differently from peripheral tissues. According to the researchers, androgen loss altered immune regulation within the brain and contributed to inflammatory conditions associated with tumor progression.

The study also demonstrated that androgen deprivation affected communication between immune cells and tumor cells, contributing to a more tumor-supportive microenvironment.

HPA-Axis Activation and Neuroinflammation Were Linked to Tumor Progression

One of the major findings of the study involved activation of the hypothalamic-pituitary-adrenal (HPA) axis, the body’s central stress-response system.

Researchers found that androgen loss increased glucocorticoid signaling, which was associated with suppression of anti-tumor immune activity and increased inflammatory responses within the brain.

The study also identified increased inflammatory signaling involving interleukin-1 beta (IL-1β) and tumor necrosis factor (TNF), both of which were associated with neuroinflammatory processes linked to glioblastoma progression.

Preclinical analyses further suggested inflammasome-related activation in microglial cells following androgen loss, indicating that dysregulation of the brain’s immune environment may contribute to accelerated tumor growth.

Investigators also noted that the immune environment within the central nervous system behaves differently from immune systems in other organs, which may partly explain the distinct effects observed in brain tumors.

Clinical Analysis Included More Than 1,300 Patients

To support their experimental findings, researchers performed retrospective clinical analyses involving more than 1,300 male glioblastoma patients.

The analysis suggested that androgen supplementation was associated with differences in survival outcomes compared with patients who did not receive supplementation. The analysis suggests a possible association between testosterone supplementation and improved outcomes, but the findings are observational and do not support testosterone as a standard glioblastoma therapy

“The brain has evolved to keep stuff out and that includes immune cells from elsewhere in the body. It’s a delicate tissue that often doesn’t want huge immune reactions,” said Justin Lathia, corresponding author of the study and scientific director of the Brain Tumor Center at Cleveland Clinic.

Researchers emphasized that larger prospective clinical studies will be necessary to determine whether hormone-related therapeutic approaches could eventually benefit selected glioblastoma patients.

Findings Challenge Traditional Assumptions About Hormones and Cancer

The findings challenge traditional assumptions that testosterone universally promotes cancer growth. Researchers reported that androgen signaling appeared to suppress glioblastoma progression within the brain’s unique immune environment, contrasting with observations seen in several hormone-sensitive cancers outside the central nervous system.

The study linked androgen loss with HPA-axis activation, glucocorticoid signaling, neuroinflammation, and reduced anti-tumor immune activity, providing new insight into biological differences observed in glioblastoma progression between males and females.

Potential Therapeutic Implications

Although testosterone supplementation is not considered a treatment for glioblastoma, the findings may support future research into hormone-related therapeutic strategies, immune modulation, glucocorticoid signaling, and neuroinflammation-focused interventions.

Researchers emphasized that larger prospective clinical studies will be required before hormone-related approaches can be considered for routine clinical use.

In Conclusion, The NIH-funded Nature study “Androgen loss accelerates brain tumour growth via HPA axis activation” suggests that androgen loss may accelerate glioblastoma progression through stress-hormone activation, neuroinflammation, and immune dysregulation within the brain.

If validated in future clinical studies, the findings could help guide development of new therapeutic strategies for glioblastoma, one of the deadliest forms of cancer.

Reference

NIH-funded study suggests that testosterone suppresses brain tumor growth in males | National Institutes of Health (NIH)

Androgen loss accelerates brain tumour growth via HPA axis activation | Nature

Testosterone slows glioblastoma growth in men • healthcare-in-europe.com