Association between testosterone and cancers risk in women: a two-sample Mendelian randomization study

Abstract Objective Previous observational studies have explored the correlation between testosterone and cancer risk. However, the causal association between testosterone and various cancer types in women remains inconclusive. The objective of this Mendelian randomization study is to evaluate the causal links between total testosterone (TT) and bioavailable testosterone (BT) with cancer risk in females. Methods Initially, a rigorous quality control process was employed to identify suitable instrumental single nucleotide polymorphisms (SNPs) associated with the exposure under investigation that exhibited a significant association. The genetic causal relationship between female testosterone levels and the risk of developing cancers was examined through a two-sample Mendelian randomization. Various analytical methods, including inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, were applied in the investigation. Key findings were primarily based on the results obtained via IVW (random effects), and sensitivity analyses were conducted to assess the reliability of the obtained results. Furthermore, maximum likelihood, penalized weighted median, and IVW (fixed effects) methods were utilized to further validate the robustness of the results. Results Based on the results of IVW analysis, our study indicated a positive causal relationship between BT and breast cancer (OR = 1.1407, 95%CI: 1.0627–1.2244, P = 0.0015) and endometrial cancer (OR = 1.4610, 95%CI: 1.2695–1.6813, P = 1.22E-06). Moreover, our findings also showed a positive causal association between TT and breast cancer (OR = 1.1764, 95%CI: 1.0846–1.2761, P = 0.0005), cervical cancer(OR = 1.0020, 95%CI: 1.0007–1.0032, P = 0.0077), and endometrial cancer(OR = 1.4124, 95%CI: 1.2083–1.6511, P = 0.0001). Additionally, our results demonstrated a negative causal relationship between BT and ovarian cancer (OR = 0.8649, 95%CI: 0.7750–0.9653, P = 0.0320). However, no causal relationship was found between BT, TT and other types of cancer (corrected P > 0.05). Conclusions This study elucidates the role of testosterone on the development of breast cancer, endometrial cancer, ovarian cancer, and cervical cancer. It also hints at a potential but fragile link between testosterone and bladder cancer, as well as thyroid cancer. Nonetheless, it's worth noting that no statistically significant relationship between testosterone and various other types of cancer in females was identified.