Observational study finds low testosterone associated with 18% increased cancer mortality risk — Evidence Review
Published in Lancet Healthy Longevity, by researchers from The University of Western Australia
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Table of Contents
Men with very low testosterone levels face an increased risk of developing and dying from cancer later in life, according to a large international study; most related studies generally support an association between low testosterone and higher mortality, though details regarding specific cancer types—especially prostate cancer—are more nuanced (Lancet Healthy Longevity).
- Several large cohort and case-control studies have found that low testosterone levels in men are associated with higher all-cause and cancer-specific mortality, with risk thresholds similar to those identified in the new study 1 2 3 5.
- While the increased cancer mortality risk associated with low testosterone is consistently reported, findings regarding prostate cancer diverge: most studies, including recent meta-analyses, find no association or even an inverse relationship between natural testosterone levels and prostate cancer risk 6 10 11 12.
- Related research also raises ongoing questions about whether testosterone supplementation can mitigate these risks, as causality remains unproven and current evidence does not recommend supplementation solely for cancer risk reduction 4 10 11.
Study Overview and Key Findings
This large-scale observational study, led by Professor Bu Yeap at The University of Western Australia, sought to clarify the relationship between sex hormone levels and future cancer risk in men. The focus is timely, as rates of male hypogonadism (low testosterone) and cancer incidence both rise with age, yet the interplay between hormonal status and cancer outcomes remains incompletely understood. Notably, the study leveraged long-term, international data and included multiple sex hormones in its analysis, moving beyond the narrower focus on testosterone alone.
| Property | Value |
|---|---|
| Organization | The University of Western Australia |
| Journal Name | Lancet Healthy Longevity |
| Authors | Professor Bu Yeap |
| Population | Men with varying testosterone levels |
| Sample Size | n=26,000 |
| Methods | Observational Study |
| Outcome | Risk of dying from cancer associated with testosterone levels |
| Results | Men with low testosterone had an 18% higher risk of dying from cancer. |
Literature Review: Related Studies
To place this study in context, we searched the Consensus database of over 200 million papers using targeted queries. The following search queries were used:
- low testosterone cancer mortality risk
- testosterone levels cancer survival outcomes
- men testosterone deficiency cancer studies
Below, key themes emerging from the literature are summarized.
| Topic | Key Findings |
|---|---|
| Does low testosterone increase overall and cancer-specific mortality risk in men? | - Multiple cohort studies found that low testosterone is associated with higher all-cause and cancer mortality, independent of other health factors 1 2 3 5. - Some studies note particularly increased risks for cardiovascular and cancer-related deaths, suggesting testosterone as a possible biomarker for broader health vulnerability 2 3 5. |
| Is there a link between natural testosterone levels and prostate cancer risk? | - Large meta-analyses and cohort studies generally find no association, or even an inverse association, between natural testosterone levels and prostate cancer incidence 6 10 11 12. - Some studies suggest low free testosterone is linked to lower risk of overall prostate cancer, but the relationship with aggressive disease is less clear 12. |
| Does testosterone replacement therapy affect cancer outcomes or mortality? | - Observational studies show that testosterone therapy in men with low levels may be associated with decreased all-cause mortality, but causality is unproven due to possible confounding 4. - Evidence increasingly suggests that testosterone therapy does not increase prostate cancer risk or progression in appropriately selected men 10 11 14. |
| What other factors are associated with low testosterone and cancer risk? | - Low testosterone is more common in male cancer survivors and may be linked to adverse metabolic changes and higher mortality risk 13 15. - Hormonal regulators such as SHBG and luteinizing hormone may also influence specific cancer risks (e.g., prostate cancer), adding complexity to simple testosterone-cancer models 7 9. |
Does low testosterone increase overall and cancer-specific mortality risk in men?
A substantial body of evidence supports the association between low testosterone and increased risk of death from all causes, including cancer. The new study's finding of an 18% higher cancer mortality risk in men with low testosterone is consistent with earlier cohort and population-based studies, which have documented similar or even higher increased risks. Some studies specify that this risk persists after controlling for age, comorbidities, and lifestyle factors 1 2 3 5.
- Cohort and case-control studies found that men in the lowest quartile of testosterone had significantly higher mortality rates, including from cancer, than those with higher levels 1 2 3 5.
- The risk appears to extend across different age groups and is not limited to elderly populations 2 5.
- Some studies adjust for a wide range of confounders, strengthening the association between low testosterone and mortality 1 2 3.
- The magnitude of risk reported in previous studies (hazard ratios ranging from 1.3 to over 2 for cancer mortality) is broadly similar to the 18% relative risk increase seen in the new study 1 2 3 5.
Is there a link between natural testosterone levels and prostate cancer risk?
Contrary to earlier assumptions, most large epidemiological studies and meta-analyses do not find a positive association between higher endogenous testosterone and prostate cancer risk. The new study's finding—that low testosterone does not increase prostate cancer risk, and that other hormones may be more relevant—aligns with this body of research 6 10 11 12.
- Meta-analyses indicate that endogenous testosterone levels are not associated with increased risk or aggressiveness of prostate cancer 6 11 12.
- Some evidence suggests that men with low free testosterone may have a lower risk of developing prostate cancer overall, though this may not apply to aggressive subtypes 12.
- Recent population-based and systematic reviews show that testosterone therapy in hypogonadal men does not increase prostate cancer progression risk 10 11 14.
- The "saturation model" has been proposed to explain the lack of a linear relationship between testosterone and prostate cancer growth, suggesting that only very low levels may matter biologically 11.
Does testosterone replacement therapy affect cancer outcomes or mortality?
The role of testosterone therapy in men with low testosterone and its impact on cancer outcomes is still debated. Observational studies suggest possible benefits for overall mortality, but limitations such as residual confounding persist. There is growing consensus that testosterone therapy does not increase prostate cancer risk when appropriately prescribed 4 10 11 14.
- Observational data indicate lower mortality among men with low testosterone who receive replacement therapy versus those who do not, but randomized controlled trials are lacking 4.
- Testosterone therapy appears not to increase the risk of prostate cancer progression in men on active surveillance or after treatment for localized disease 10 11 14.
- The longstanding prohibition against testosterone therapy in men with a history of prostate cancer is being reevaluated, as several recent reviews and cohort studies find no increase in recurrence or aggressiveness 10 11.
- The new study notes that its findings should not be interpreted as a call for testosterone supplementation to prevent cancer, echoing the caution in the literature 4 10 11.
What other factors are associated with low testosterone and cancer risk?
Research shows that low testosterone is more likely in male cancer survivors, especially following certain treatments. Additionally, metabolic changes such as increased fat mass and insulin resistance are common in hypogonadal men and may contribute to broader health risks, including cancer 13 15. The relationship between other sex hormones (SHBG, luteinizing hormone) and cancer risk is also under exploration 7 9.
- Male survivors of testicular and other cancers are at increased risk of testosterone deficiency, especially after chemotherapy or radiation 13 15.
- Low testosterone in cancer survivors is associated with adverse metabolic profiles, which may contribute to increased mortality risk 15.
- Beyond testosterone, variations in SHBG and luteinizing hormone may influence risk for specific cancers, such as prostate cancer, suggesting a role for broader hormonal panels in risk assessment 7 9.
- The new study's finding of SHBG and luteinizing hormone associations with prostate cancer risk highlights the complexity of hormonal interactions in cancer biology 7 9.
Future Research Questions
Despite advances, important gaps remain in our understanding of testosterone, cancer risk, and mortality. Future research is needed to determine causality, clarify the role of testosterone supplementation, and explore the mechanisms linking hormonal status and cancer outcomes.
| Research Question | Relevance |
|---|---|
| Does testosterone replacement therapy reduce cancer mortality in men with low testosterone? | Observational studies suggest possible mortality benefits, but randomized controlled trials are needed to determine if supplementation can reduce cancer risk or mortality 4 10 11. |
| What mechanisms link low testosterone and increased cancer mortality risk? | Understanding biological pathways could identify modifiable risk factors and new interventions; current studies show association but not causation 1 2 5. |
| How do other sex hormones (SHBG, luteinizing hormone) influence specific cancer risks in men? | The new study and others highlight the potential importance of these hormones, especially for prostate cancer, but their independent effects remain unclear 7 9. |
| Does testosterone therapy impact prostate cancer progression or outcomes in men on active surveillance? | Recent studies suggest no increased risk, but larger prospective trials are needed to confirm safety and identify subgroups that may benefit or be at risk 10 11 14. |
| Are there lifestyle interventions that can raise testosterone levels and reduce cancer mortality risk in men? | Since factors like BMI and physical activity influence testosterone, research could identify preventive strategies that target both hormonal health and cancer risk 1 2 5 15. |