Testosterone Suppresses Glioblastoma Growth in Males, NIH-Funded Study Finds
核心洞察
Cleveland Clinic researchers discovered that androgen hormones like testosterone suppress rather than promote glioblastoma (搜索) growth in male preclinical models, upending long-held assumptions about sex hormones and brain cancer.
Loss of androgens triggered HPA axis (搜索) overdrive, increasing stress hormones and creating an immunosuppressive brain environment that allowed tumors to progress unchecked.
A retrospective analysis of 1,333 male glioblastoma (搜索) patients found supplemental testosterone was associated with a 38% lower risk of death and extended median survival from 12 to 16 months.
In a striking reversal of conventional wisdom about sex hormones and cancer, scientists at Cleveland Clinic have discovered that testosterone—long considered a driver of tumor growth—actually suppresses glioblastoma (搜索) progression in males. The NIH-funded study, published in Nature, reveals that androgen hormones play a critical role in regulating the brain's immune environment, and their loss may accelerate the deadliest form of brain cancer.
The research team, led by Justin Lathia, Ph.D., professor of cancer sciences and scientific director of the Brain Tumor Center at Cleveland Clinic, found that reducing androgens in mouse models of glioblastoma (搜索) sent a neuroendocrine system called the hypothalamus-pituitary-adrenal (HPA) axis into overdrive. This triggered a spike in stress hormones that created an immunosuppressive environment in the brain, allowing tumors to grow largely unchecked.
"In many other systems, testosterone promotes tumor growth while suppressing the immune system," said lead author Juyeun Lee, DVM, Ph.D., now Assistant Staff at Cleveland Clinic's Florida Research & Innovation Center. "But in our study, we saw the complete opposite. Removing testosterone actually accelerating tumor growth."
A Brain-Specific Mechanism
The study highlights how the brain's unique biology demands a different lens for understanding cancer. Unlike tumors elsewhere in the body, glioblastoma (搜索) appears to be constrained by androgens rather than fueled by them.
"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 Lathia.
When the researchers castrated male mice to remove testosterone, they observed faster tumor growth—a result so unexpected they replicated the models multiple times and validated the findings by injecting exogenous testosterone to confirm the tumor activity was testosterone-dependent. Notably, testosterone did not produce the same effect in female mice.
The team further demonstrated the brain-specific nature of this mechanism by implanting tumors in the flank rather than the brain, where they observed opposite results. "The entire field of anti-androgen therapy and prostate cancer is based on the concept that when tumors are exposed to testosterone, they grow out of control. This work doesn't discredit that. It shows that there are major differences in how the brain responds to cancer compared to the rest of the body," Lathia explained.
Clinical Data Reinforces Preclinical Findings
Seeking to explore the relationship between androgens and brain cancer in humans, the researchers analyzed existing clinical data from the NIH/NCI Surveillance, Epidemiology, and End Results (SEER) database. Their analysis included 1,333 men with glioblastoma (搜索) who underwent surgical resection and radiation therapy.
The results were compelling: men receiving supplemental testosterone alongside temozolomide (N=61) demonstrated a median survival of 16 months, compared to 12 months for those receiving temozolomide alone (N=1,272). Overall, men on supplemental testosterone for reasons unrelated to cancer showed a 38% lower risk of death compared to patients not taking the supplements.
"This outcome is a welcome surprise and may potentially offer a lead for new treatments for a kind of cancer that is deadlier in men," said Anthony Letai, M.D., Ph.D., director of NIH's National Cancer Institute (NCI).
Toward Clinical Trials
Though the observational data does not establish a causal relationship, Lathia and his colleagues believe the convergence of preclinical and clinical findings warrants further investigation in humans. The team is now in discussions with colleagues in neuro-oncology and endocrinology to potentially study the question in an early-phase clinical trial.
"An obvious follow-up study would be to find out whether androgen deprivation, which is a common treatment for cancer, is actually detrimental for glioblastoma (搜索)," Lathia said.
The researchers also identified that the HPA axis (搜索) is likely triggered by inflammation in the hypothalamus caused by tumors in androgen-deficient mice. In future work, they intend to pinpoint exactly how tumors can induce this reaction in an entirely separate region of the brain, and to better understand the impact of testosterone on brain metastasis.
The study was supported by NIH through multiple NCI grants, along with funding from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.