Hypothyroidism and hyperthyroidism are common endocrine disorders with potentially damaging health consequences that affect all populations worldwide. Among them, hypothyroidism affects 0.6%-12% of women and 1.3%-4% of men (1, 2); In the general population, the frequency of hyperthyroidism ranges from 0.2% to 1.3% (3–5), is 1.48 times more prevalent in women than in males (6), and rises with age. Thyroid hormones are essential for growth, neuronal development, reproduction, and regulation of energy metabolism (7). Increased blood thyroid-stimulating hormone (TSH) levels in an iodine-rich environment cause hypothyroidism, which is most typically caused by Hashimoto’s thyroiditis. Hypothyroidism is widely established to be related to comorbidities such as diabetes, and cardiovascular and cerebrovascular illness (8). Graves’ disease accounts for 70%-80% of hyperthyroidism in countries with adequate iodine and around 50% of hyperthyroidism in places with insufficient iodine (5, 9).

Since thyroid hormone is crucial for physiological processes like growth, maturation, and human metabolism, it has been suggested previously that thyroid function may influence the development of cancer (10, 11). With inconsistent findings from past research, the precise relationship between thyroid function and cancer has been a matter of controversy for more than 200 years (12, 13). CMM, the most dangerous type of skin cancer, is becoming more common everywhere. According to recent statistics, men and women in the United States are more likely to develop CMM than any other type of cancer (14). For a long time, scholars have recognized the “thyroid-skin connection”, but there are few studies on the role of THs in the occurrence and/or progression of CMM. Early observations found that both abnormally low and excessive thyroid hormones (THs) can change the appearance and function of human skin and its appendages, leading to pretibial myxoedema and alopecia at rest (15, 16). Thyroid-stimulating hormone receptor mRNA was found to be highly expressed in cultured keratinocytes, epidermal melanocytes, and melanoma cells by Andrzej (16). Genes associated with the hypothalamic-pituitary-thyroid axis are also expressed in the skin but are selective in both cell type and gene type. Giacomo et al. described a case of melanoma onset after utilizing hormone, thyroid and growth hormone replacement therapy (17). Shah Monica et al. showed in a retrospective study that male melanoma patients had a substantially higher frequency of hypothyroidism than the overall population (18). Although the results of current observational studies are useful for researching thyroid function and CMM they are prone to be influenced by several confounding variables, making it difficult to draw reliable conclusions about the cause of an event. Therefore, more research into the causes of thyroid illness and malignant cutaneous melanoma is required.

Mendelian randomization (MR) is a data analysis method applied to the etiology inference of epidemics, which uses genetic variation to assess the causal relationship between exposure and outcome. It serves as a valuable tool, especially when randomized controlled trials are not feasible to examine causal relationships and observational studies deviate due to confounding factors or reverse causal relationships, which can be addressed by using genetic variation as a tool variable for testing exposure. Since alleles follow the principle of random allocation during gametogenesis, genotypes can be used as instrumental variables of intermediate phenotypes to be studied to infer their causal relationship with disease states, and the estimated effect value is not affected by confounding factors and reverse causality (19, 20).

Genome-wide association studies (GWAS) that have been widely disseminated in recent years have made it possible for researchers to examine complicated disorders, and the findings of many features have paved the path for rigorous and well-researched MR Analysis. Numerous MR studies have examined the link between cancer and thyroid function level in recent years. According to Lu et al.’s research, hypothyroidism has a protective causative association that is inversely correlated with the likelihood of developing hepatocellular carcinoma (HCC) (21). TSH levels were found to be inversely correlated with thyroid cancer by Yuan et al.’s MR Analysis, and thyroid dysfunction was found to be related to breast cancer (22).

However, more MR analyses are required to further examine more reliable results as the GWAS database grows. This investigation used a two-sample MR analysis to determine the possible causative link between thyroid illness and CMM.

GWAS data from two distinct consortiums with populations of European ancestry were included in this two-sample MR Study. By using two-sample MR analysis, we methodically evaluated the bidirectional causality between thyroid insufficiency and CMM. Although there is a causal link between hypothyroidism and a lower risk of CMM, there is no causal link between hyperthyroidism and an increased risk of the disease. Similarly to this, there is no conclusive proof that there is a hereditary link between the risk of cutaneous melanoma and the occurrence of thyroid dysfunction, according to additional sensitivity analysis, and the effect estimates were reliable.

An autoimmune condition known as thyroid dysfunction includes both hyperthyroidism and hypothyroidism. Although the pathophysiology of the two diseases is distinct, clinical work makes it simpler to diagnose and treat the disease by enhancing the serological assessment of thyroid function in conjunction with clinical symptoms. However, growing clinical evidence in recent years has demonstrated that even small changes in thyroid function, such as subclinical dysfunction and changes within the reference range, can have a significant effect on clinical endpoint outcomes like bone mineral density, depression, metabolic syndrome, and cardiovascular disease (28). Cancer is one of the common diseases with the highest incidence rate and mortality in the world. The International Agency for Research on Cancer (IARC) predicts that there will be 18.1 million new cancer cases worldwide in 2020 (29). In addition, the American Cancer Society predicts that 1.95 million new cancer cases and 600,000 cancer deaths are expected in the United States in 2023 (30). Current research on the connection between thyroid health and cancer is contradictory. According to studies, there is no connection between SCH and breast or prostate cancer (12). The relative risk (OR) for cancer in 2,414,165 adults with diagnosed hypothyroidism compared to those without hypothyroidism was 1.73(1.72-1.74) based on the 2019 Spanish population-based statistics (p<0.0001). In addition, patients aged 65 years or older with hypothyroidism have a reduced risk of bladder, colorectal, gastric, pancreatic, and prostate cancers (31). Although existing studies have analyzed the causal relationship between thyroid dysfunction and other cancers, there has been no MR analysis of the causal relationship between thyroid dysfunction and CMM, and the exact relationship between the two has not been clarified by existing clinical and basic research.

Studies using epidemiological data have demonstrated a favorable correlation between hypothyroidism and the advancement of CMM (31–33). In line with the findings of the aforementioned epidemiological data, a retrospective analysis from the Israeli National Cancer Registry indicated that elevated Log-TSH was linked to a higher risk of CMM (HR: 1.11) (34). In contrast to the epidemiological data of the Israeli population mentioned above, our MR analysis, which was focused on a European population, revealed the opposite conclusion from a genetic point of view, which may have skewed the statistical results due to the Israeli population’s small size. In contrast to these investigations, our MR analysis comprised a considerably bigger population. Our work is more trustworthy because of our more stringent genetic instrument inclusion criteria and the removal of potential confounding variables. Furthermore, the aforementioned Israeli research discovered a link between hyperthyroidism and melanoma mortality (adjusted HR: 2.20) (35). Our MR analysis, however, could not identify a genetic link between hyperthyroidism and CMM. Since drug therapy alters the body’s initial immune status, more studies have recently focused on thyroid dysfunction in people with CMM caused by the use of immune checkpoint inhibitors (36), which is distinct from the causal relationship between thyroid dysfunction and CMM investigated in this study.

The advantage of our study is that we are the first to use a two-sample MR analysis to explore the bidirectional causal link between thyroid dysfunction and CMM. MR analysis is able to minimize the interference of confounding factors. Additionally, the genetic techniques that we developed by combining numerous separate data sets allowed us to reduce the possibility of biased outcomes as a result of under-enrollment. This MR analysis still has several limitations, such as the fact that the research population was chosen because it was European, which may have led to outcome bias. To generalize this analysis to other populations, more research is required.

We could have been unable to identify variations in thyroid dysfunction in the initial data set due to the heterogeneity of the included data sets.

Our research demonstrates that hyperthyroidism does not raise the risk of CMM, whereas hypothyroidism is causally linked to a decreased risk of the disease. In addition, we found no clear evidence of genetic causality between CMM and the risk of thyroid dysfunction.

The Supplementary Materials section of this paper contains the original data and photographs used in this research. Please get in touch with the authors of this manuscript if you require any further original information.

The studies involving humans were approved by Medical Ethics Committee of the First People’s Hospital of Jiashan. The studies were conducted in accordance with the local legislation and institutional requirements. This study's exposure and result samples were human individuals, and it was a secondary analysis of already published data, thus no ethical approval was required. The Ethics Committee of the First People's Hospital of Jiashan granted us an exemption because all datasets utilized in this study were public domain.

YF: Participating in the topic selection and writing of the study. HD: Writing the Manuscript. LP: Participating in the interpretation of the results of the MR Analysis. YS: Data Collection. JH and QX, ZH: Drawing the Figures and Tables. HD1†, LP2†, these authors contributed equally to this work and share first authorship. All authors contributed to the article and approved the submitted version.