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The International Journal of Molecular Sciences published the results of a randomized and controlled clinical trial evaluating the effects of varying doses of vitamin D supplementation on testosterone levels among breast cancer survivors. This analysis was part of the DEDiCa (Diet, Exercise, and vitamin D in Cancer) multicenter study in Italy, a randomized trial that is evaluating lifestyle changes in combination with vitamin D on breast cancer recurrence. Participants were included if they’d had breast cancer surgery within the past 12 months without evidence of metastasis and no contraindications for vitamin D supplementation.
Women were randomized into one of two groups: one in the “high-intensity” arm, which received structured counseling to follow a low-glycemic index Mediterranean diet, engage in regular physical activity, and supplement with sufficient vitamin D3 to maintain serum levels of 25(OH)D near 60 ng/mL. The “low-intensity” arm, serving as a positive control, received general advice to follow a Mediterranean diet, avoid sedentary behavior, and supplement with vitamin D3 only to maintain sufficiency (serum 25(OH)D levels of 30 ng/mL). Just over 125 women (at an average age of 52) in each group, roughly 90% of whom were post-menopausal, were followed for 2 years. Notably, baseline levels of 25(OH)D were below 30 ng/mL in about 2/3 of women.
Small rises in serum testosterone levels were noted in both groups, but no significant difference was observed between groups, and levels remained normal and within clinical thresholds. 25(OH)D levels increased in both groups, to a mean of 55 ng/mL and 29 ng/mL in the high- and low-intensity groups, respectively. Most women were taking hormone suppressive therapy (either selective estrogen receptor modulators or aromatase inhibitors), but among the small number of women not taking this therapy (20 and 26 women in the high and low-intensity groups, respectively), again, no significant difference was observed between treatments or within each treatment group.
A number of potential effect modifiers were also evaluated, including baseline levels of 25(OH)D, testosterone, body mass index, sex-hormone binding globulin (SHBG), the timing of hormone suppressive therapy, etc. Baseline 25(OH)D was not predictive of testosterone rise; for example, in women with severe vitamin D deficiency at baseline (≤10 ng/mL, 12% of women), there were no significant differences between groups or in testosterone levels over time. If supplementing with vitamin D were likely to increase testosterone levels, it’s plausible that these women would be the most likely to see an effect.
When stratified by baseline testosterone levels, those women with lower initial values (<0.150 ng/mL) did see a significant increase over time, but it was not different between groups, and remained within normal ranges. Women with higher baseline levels (≥0.150 ng/mL) had a slight but non-significant decline over the study period. Indeed, the main determinant of testosterone changes over time was a low baseline level, and at least 50% of this effect was thought to be mediated by hormone suppressive therapy. Increasing BMI and SHBG also influenced testosterone changes, suggesting that these other variables may be more relevant than vitamin D supplementation, which could potentially act to maintain normal levels of testosterone, rather than simply leading to an increase.
Overall, this study suggests that vitamin D supplementation, even at levels sufficient to raise 25(OH)D to more optimal levels (vs. deficiency prevention), is not likely to be responsible for a concerning rise in testosterone among survivors of breast cancer. The overall trial results for the effects of vitamin D in combination with other healthy lifestyle interventions on breast cancer recurrence have still not been published and are expected soon.
Testosterone levels have emerged as a concern for breast cancer risk; for example, a large Mendelian randomization analysis published in the American Journal of Cancer Research found that genetically determined higher testosterone levels were associated with a greater risk for breast cancer, though neither estradiol or progesterone were. Among post-menopausal but not pre-menopausal women it has been associated with a greater risk for breast cancer. And among women without obesity, higher testosterone levels have been associated with poorer outcomes.
Mixed associations between vitamin D and testosterone have been observed in the past, including results from the MESA (Multi-Ethnic Study of Atherosclerosis) cross-sectional analysis, suggesting that lower 25(OH)D were linked to lower SHBG levels, a higher free testosterone, and higher estradiol levels (note, MESA did not involve supplementation). The ambiguity about whether vitamin D supplementation could increase testosterone or influence SHBG levels (and thus affect free testosterone levels) prompted the analysis from the DEDiCa trial, and suggests that at least over a 2-year period, a concerning increase in testosterone is not likely. Given the many benefits of vitamin D supplementation, as well as a recent review suggesting that raising 25(OH)D levels to at least 40 ng/mL is likely to help suppress the risk of developing breast cancer, this recent analysis is encouraging. Finally, it’s important to note that unlike most studies with vitamin D, this one did not supplement with a fixed amount but instead supplemented based upon 25(OH)D levels. This personalization is welcome given the variable responses to vitamin D supplementation.
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