There have been reports on the relationship between bioavailable testosterone levels and OA, but the causal relationship between them is still unclear. In this study, we conducted a bidirectional two sample MR analysis using the maximum GWAS data of genetic variation to evaluate the causal relationship between testosterone and OA, demonstrating strong genetic evidence. We found a positive causal relationship between bioavailable testosterone levels and the risk of OA.
Research on OA mainly focuses on estrogen, while research on androgens is relatively scarce. Research on OA mainly focuses on estrogen, while research on androgens is relatively scarce. Testosterone is mainly dissociated by binding to sex hormone binding protein (SHBG) and albumin, resulting in free testosterone, which is an important bioavailable testosterone in the human body and plays an important role in human growth and lipid metabolism [26, 27]. The lack of testosterone leads to disorders in lipid metabolism, protein metabolism, and glucose metabolism, resulting in a series of metabolic syndromes, obesity, and other conditions [28]. Biologically available testosterone is one of the most important androgens in the human body, and its concentration varies in a peak line with age [29, 30]. After the age of 40, there is a linear decline in testosterone levels in males and postmenopausal females [31]. Under normal circumstances, testosterone binds to specific receptors in the cell to form a testosterone receptor complex, and the active testosterone receptor complex binds to specific androgen response sheets (ARE) on the target gene to regulate gene expression. Studies have shown that both estrogen and androgen receptors exist in osteoblasts [32, 33]. In addition to its direct effects on bone and cartilage, testosterone not only binds to androgen receptors, but also to estrogen receptors to affect bone calcium metabolism balance [21]. In addition, testosterone can aromatise and convert into estradiol, which then binds to estrogen receptors and participates in the physiological regulation of bone and cartilage [34]. The decrease in testosterone levels affect cartilage metabolism through androgen receptors and ion channels, as well as leading to decreased in estradiol conversion rate, which leading to cartilage degeneration and the formation of OA [35]. When testosterone is at normal levels in men but there is an aromatase deficiency in the body, most of the androgens cannot be converted into estrogen, which often results in lower levels of estrogen in the body, which leads to joint cartilage degeneration and the development of OA [36]. This indicates a significant correlation between androgens, especially testosterone, and OA. In a study of male calf knee joint cartilage, it was found that testosterone increased the content of glycosaminoglycans in the extracellular matrix of chondrocytes, promote the coverage of type II collagen on the cartilage surface and the growth of cartilage fiber structure in joint cartilage [37]. Currently, clinical studies on the correlation between testosterone levels and OA are mainly case reports. A study of the correlation between hormone levels and hand OA in 573 premenopausal women found a significant correlation between lower levels of serum testosterone and the prevalence of hand OA [38]. In another study targeting men, serum testosterone levels were found to be positively correlated with cartilage thickness [39]. Testosterone can increase male muscle strength and is often recommended for the treatment of male musculoskeletal pain, its also can effective to reduce fat content and inhibit inflammatory reactions [40, 41]. In the study of serum testosterone levels and OA symptoms, it was found that higher levels of serum testosterone can reduce the joint osteoarthritis index (WOMAC) [42]. These studies have shown a significant correlation between serum testosterone levels and OA, but the causal relationship remains unclear. Our study suggests a causal relationship between bioavailable testosterone levels and OA from a genetic perspective, providing indicative evidence for the prevention and treatment of OA.
In this study, we had sufficient samples for MR analysis to explore the causal relationship between bioavailable testosterone levels and OA, and found a causal relationship between bioavailable testosterone levels and OA. This study has several advantages. Firstly, the data is sourced from the GWAS database, which can exclude the interference of confounding factors. Secondly, we use bidirectional MR analysis to study the impact of causal relationships on causal inference. We also used sensitivity analysis using multiple methods to exclude bias caused by related and unrelated pleiotropy.
In summary, we demonstrate a potential causal relationship between bioavailable testosterone levels and OA, whereas OA is the cause and bioavailable testosterone levels are the result, and there is no causal relationship between the two. However, our research still has certain limitations. Firstly, the study population is of European ancestry, and the scope of the study is relatively limited. Secondly, due to the lack of raw data from the WGAS database, subgroup analysis was not conducted. Finally, we only found a causal relationship between bioavailable testosterone levels and OA from a genetic perspective, and the mechanism of its occurrence is still unclear. Nevertheless, this study provides new insights into the causal relationship between bioavailable testosterone levels and OA from a genetic perspective, thereby providing new insights into the study of OA.