Is there an association between levothryoxine and breast cancer?
The short answer is that there is not sufficient evidence to draw any conclusion at this time. Patients who require levothyroxine should continue to take their medication as prescribed by their doctor. The risk of ultimately fatal myxedema due to severe untreated hypothyroidism is proven and real. The risk of cancer is speculative and not definitively proven.
When this question came up at the end of the lecture, my initial thought was that an association between levothryoxine and cancer is highly improbable. Oral levothyroxine essentially replaces your own endogenous thyroxine (T4). Treatment normalises T4 levels but should not cause supraphysiological levels of T4. Even the route of absorption is largely physiological as endogenous T4 is recycled through enterohepatic circulation and is absorbed in the small intestine after being excreted in the bile. The only potentially “unnatural” exposure is as the levothryoxine tablet passes from the mouth to the stomach. In theory, there is no reason why taking levothyroxine should expose anyone to greater risk than having physiologically normal thyroid function would.
However, some papers have reported a possible association between levothyroxine exposure and cancer risk. A study in Taiwan reported an increased risk of breast cancer associated with levothyroxine use, especially in those over 65-years-old (Wu et al., 1998). A study in Sweden reported an association between levothyroxine prescription and increased risks for cancers of the thyroid gland and other endocrine glands in men and cancers of the breast, endometrium, other female genitals (ovaries not included), stomach, colon, liver, pancreas, urinary bladder, skin, leukaemia, and unspecified primary tumour in women (Wändell et al., 2020). The group in Taiwan then published another paper reporting association of levothyroxine use with increased risk of cancer at any site, particularly brain, skin, pancreatic, and female breast cancers (Wu et al., 2021). However, it is important to note that the authors of these studies themselves conclude that more research is needed as the studies on the association between levothyroxine use and cancer risk to date are still inadequate. An earlier study even suggested that levothyroxine might protect against colorectal cancer risk (Rennert et al., 2010).
There are many potential confounding factors in these risk association studies. It is important to remember that an association shows that two things occurred together, but it does not prove that one caused the other. Endogenous thyroid hormones are essential for normal growth and development and therefore it is not surprising that they are also unfortunately likely associated with increased growth of certain cancers (Bolf et al., 2019). Meanwhile, the development of subclinical hypothyroidism is fairly common in the chronically ill and the aged. Therefore, unless thyroid function is accounted for in studies, the apparent increased risk of levothyroxine could simply be the same risk associated with having normal healthy endogenous thyroid function. Also, autoimmune thyroid disease is associated with an increased risk of subsequently developing thyroid cancer (Dias Lopes et al., 2020) and is likely also genetically associated with increased risk of other cancers, including breast cancer (Bolf et al., 2019). Therefore, the reported increased cancer risk in patients prescribed levothryoxine might be because many of them are prescribed levothryoxine for autoimmune thyroiditis, which is itself associated with increased cancer risk, not because the levothyroxine causes cancer.
Therefore, further studies are required before any conclusion can be drawn on whether levothyroxine causes an increase in cancer risk.
References:
Wu CC, Islam MM, Nguyen PA, Poly TN, Wang CH, Iqbal U, Li YJ, Yang HC. Risk of cancer in long-term levothyroxine users: Retrospective population-based study. Cancer Sci. 2021 Jun;112(6):2533-2541. doi: 10.1111/cas.14908.
10/09/2021
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