Epidemiological surveys indicate that ED is a prevalent global health issue. Survey data suggests that over half of men experience mild to moderate ED at some stage in their lives, imposing significant psychological and physiological burdens on patients and their families (6, 36). Furthermore, ED is considered a potential warning sign for other chronic diseases, especially cardiovascular conditions (37). This close association underscores the importance of researching ED. In our study, through a Mendelian randomization investigation, we found that the use of atorvastatin may increase the risk of developing ED. In addition, colocalization analysis did not find a common genetic factor between the two.
Atorvastatin, as a commonly used lipid-lowering medication, is widely prescribed for the treatment of hypercholesterolemia and hyperlipidemia to prevent the occurrence and progression of cardiovascular diseases (38). However, past studies have yielded disparate conclusions regarding the relationship between atorvastatin use and ED, prompting deeper inquiry. Therefore, this study investigates the potential causal relationship between atorvastatin use and ED from a novel perspective using a MR study design based on genetic variation.
The results of this study are consistent with some previous studies. Data from the Boston Area Community Health (BACH) Survey suggest that lipid-lowering drugs (including statins) may be associated with ED in men under 55 years of age with diabetes and/or cardiovascular disease (39). Catherine Do et al. investigated the relationship between statins and ED using the French Pharmacovigilance System database by calculating the reporting odds ratio (ROR) and its 95% confidence interval (CI) for each drug exposure. The results indicated a significant association between atorvastatin and ED (40). Mustafa Suat Bolat et al. found through animal experiments that atorvastatin can reduce testosterone levels in rats and the intracavernosal pressure under 10v stimulation, suggesting that the drug may affect the rearrangement of collagen and elastic fibers in the corpus cavernosum, ultimately impacting penile erection (41). Currently, most studies indicate that atorvastatin, while lowering cholesterol levels, can also affect testosterone synthesis and libido, ultimately leading to ED (10). Roger D Stanworth et al. discovered in a cross-sectional study of 355 type 2 diabetic male patients that atorvastatin can reduce total testosterone (TT) and sex hormone-binding globulin (SHBG), with a significant dose-response effect (42). Similarly, a meta-analysis of placebo-controlled randomized trials evaluating the impact of statins on male testosterone levels also showed a decrease in testosterone levels (43). Osman Baspınar et al. treated 11 hypercholesterolemia patients with atorvastatin, and the results showed that along with reducing LDL-C levels, peak levels of TT and FT hormones decreased, the latency of penile dorsal nerve somatosensory-evoked potentials prolonged compared to normal, and the International Index of Erectile Function-5 score significantly decreased (44).
However, some research findings regarding the relationship between atorvastatin and ED contradict our results. Benedetta Fibbi et al. found that atorvastatin may improve the response to sildenafil in spontaneously hypertensive rats by intervening in the RhoA/ROCK signaling pathway within the penis (45). Similarly, Annamaria Morelli et al. validated this conclusion in diabetic rats, diabetic rabbits, and human fetal penile smooth muscle cells, proposing that atorvastatin can inhibit RhoA membrane translocation, ROCK activity, and RhoA-dependent cellular migration and proliferation, thereby improving diabetes-related ED (46). A clinical observational study on males with hypercholesterolemia as the sole risk factor for ED showed that using atorvastatin not only reduced total cholesterol and low-density lipoprotein cholesterol levels but also increased penile erection hardness and improved International Index of Erectile Function-5 scores. Moreover, studies have found that the effects are more significant in elderly patients, those with moderate to severe ED, and those with higher baseline LDL levels (47). Z. Zhang et al. explored the mechanisms involved by inducing atherosclerosis in rats with high cholesterol, administering different drug treatments, and observing changes after 8 weeks of treatment. They found that rats in the atorvastatin group exhibited reduced expression of oxidative stress biochemical markers, restoration of endothelial nitric oxide synthase (eNOS) and extracellular superoxide dismutase (SODEX) mRNA expression to normal levels, suggesting that atorvastatin's protective effect on high cholesterol-induced erectile dysfunction is attributed to its endothelial protection, thereby improving nitric oxide bioavailability (48). In addition to its antioxidant and endothelial function-preserving effects, atorvastatin also plays a role in anti-inflammation and neuroprotection, which may be beneficial for preserving early spontaneous erections after radical prostatectomy (49, 50).
This study has several strengths. Firstly, both the GWAS datasets for atorvastatin use and ED were selected from European populations, which helped avoid potential biases due to population stratification. Secondly, the study utilized MR analysis, a data analysis technique commonly used in epidemiological research for causal inference assessment. This technique used genetic variants as instrumental variables to investigate the causal relationship between exposure (atorvastatin use) and outcome (ED), thereby reducing confounding factors and reverse causation effects. Thirdly, the GWAS datasets included a large number of samples, enhancing the reliability of the results.
However, our study has certain limitations. Firstly, the samples studied were individuals of European descent, and future research should expand to other populations. Secondly, the study did not differentiate ED cases into subgroups, and future research could focus on analyzing the relationship between atorvastatin and these different subgroups. Thirdly, the study can only provide evidence supporting a causal relationship between the two, without clearly delineating the complex mechanistic links. Fourthly, we only used summary-level statistics and were unable to perform stratified analyses.