We read with great interest the elegant article by Lipscombe et al in a recent issue of Cancer.1 The authors concluded that older women who are taking tamoxifen may have an increased risk of developing diabetes. However, we believe that the article has some shortcomings that can be misleading. Lipscombe et al have proposed that tamoxifen can result in weight gain, which was one of the suggested mechanisms for the increased risk of diabetes in these patients. However, the article provides no information regarding the weight of the patients in either group and the results have not been adjusted for weight that was proposed as a risk factor for diabetes, which is a methodological weak point of the study. In addition, the suggested mechanism does not appear to be true because several studies have shown that tamoxifen has no significant effect on weight gain2 and Lipscombe et al. also demonstrated that the risk of diabetes increased only during tamoxifen treatment and not after the cessation of therapy.
The most important mechanism that was suggested by the authors for the increased risk of diabetes in tamoxifen users was the estrogen inhibitory effects of tamoxifen. However, it is not clear what it meant exactly by “estrogen inhibition.” Tamoxifen is a selective estrogen receptor modulator and acts as an estrogen agonist, partial agonist, or antagonist in different tissues. For example, although tamoxifen acts against the effects of estrogen in breast tissue, it acts similar to estrogen in many other tissues such as the endometrium and liver,3 and there is no evidence in the literature that it works as an estrogen antagonist in pancreatic cells. There is even some evidence of a positive correlation between serum concentrations of tamoxifen and estrogen.4 Thus, this suggested mechanism does not appear to be true.
The other mechanisms proposed, such as an increase in beta-cell apoptosis by tamoxifen, lack evidence to support them. Thus, if further studies support the finding that tamoxifen therapy can result in diabetes, similar to what is observed in androgen deprivation therapy for prostate cancer, then we will need to determine proper mechanisms to explain this association. A recent review article has suggested that tamoxifen has extensive modulatory effects on immunity and most likely confers these effects through an estrogen-independent mechanism.5 This could mean that tamoxifen use could result in the alteration of the cytokine environment and many other immunity cell-related derivatives, which may be related to the etiology of many diseases such as diabetes.