Cadmium is a widespread toxic and carcinogenic metal with numerous adverse health effects in humans 1. In the general population, environmental exposure to cadmium occurs primarily through smoking, the consumption of contaminated food and water, and inhalation of contaminated air 23.

Cadmium shows androgen and estrogen-like activities in vitro and in vivo, and it disrupts the male endocrine system in animal models. There is conflicting evidence regarding whether cadmium increases or decreases testosterone production in experimental models 456, with decreases more commonly seen after a single, large dose injection of cadmium and increases more commonly seen after chronic oral cadmium exposure 7. Studies investigating the association of cadmium and sex steroid hormones in men have been inconsistent, finding either no association 8910, or a positive association between cadmium and testosterone levels 111213. Inconsistencies in these studies may be due to small sample sizes, to differences in study design, or to inadequate control of confounders such as tobacco use, a major source of cadmium 14 that is also associated with higher testosterone levels in men 1516.

The purpose of the current analysis was to evaluate the association of urinary cadmium levels, a biomarker of long term and ongoing cadmium exposure, with serum concentrations of sex steroid hormones (total testosterone, total estradiol, androstanediol glucuronide [AAG], estimated free testosterone, and estimated free estradiol) and sex hormone-binding globulin (SHBG) in the Third National Health and Nutrition Examination Survey (NHANES III).

The median level (range) of urinary cadmium in the study sample was 0.34 μg/g creatinine (0.003–4.22 μg/g). Participants with higher cadmium levels were more likely to be older, to be non-Hispanic black, to be current smokers, to have household incomes < $20,000, not to exercise, and to have higher blood lead levels (Table 1). The median levels (range) of urinary cadmium among never (n = 436), former (n = 416), and current (n = 410) smokers were 0.21 μg/g (0.003–4.22 μg/g), 0.42 μg/g (0.004–2.32 μg/g), and 0.56 μg/g (0.004–4.02 μg/g), respectively.

After adjustment for age and race-ethnicity, higher cadmium levels were associated with higher levels of total testosterone, total estradiol, SHBG, estimated free testosterone, and estimated free estradiol (each p-trend < 0.05), but not with AAG or any of the molar ratios (Table 2). After additionally adjusting for smoking status and serum cotinine, the associations of urinary cadmium levels with sex steroid hormones and their molar ratios were small and not statistically significant (each p-trend > 0.05). After stratifying by smoking status, the associations of urinary cadmium levels with sex steroid hormones and their molar ratios were small and not statistically significant for never, former, and current smokers (each p-trend > 0.05; Table 3). However, among never smokers there was a marginally significant, negative association between urinary cadmium and total testosterone (p-trend = 0.06) and among current smokers there was a marginally significant, positive association between urinary cadmium and free testosterone concentrations (p-trend = 0.09).

In this large, representative sample of US adult men, urinary cadmium levels were not associated with sex steroid hormone levels after adjustment for confounders. In our analysis, smoking was an important confounder of the association between cadmium and sex steroid hormone levels. The lack of association between cadmium and sex steroid hormones was also evident after stratifying by smoking status, although we identified a marginally significant association between cadmium and total testosterone among never smokers and free testosterone among current smokers. These findings may be explained as chance findings or a result of residual confounding, although we cannot exclude a modest association.

Four previous studies have evaluated the association of urine or blood cadmium with sex steroid hormone levels in men 10111213. In a cross-sectional study of Chinese men with environmental exposure to cadmium, blood and urine cadmium did not meet the criteria for inclusion in stepwise models predicting testosterone levels 10. Blood cadmium was positively associated with testosterone in two separate studies of Croatian men who had never been occupationally exposed to cadmium 1112 and in a study of Chinese male smelter workers 13. These studies were relatively small: the largest study included 263 participants, and their combined sample size was 701. Additionally, three of these studies did not report smoking adjusted results 101112, although smoking was included in stepwise regression algorithms. The importance of tobacco use as a confounder of the cadmium-sex hormone relationship may differ across populations due to varying levels of cadmium in tobacco, prevalence of tobacco use, and exposure to cadmium from other sources (e.g., occupational exposure, food, air pollution). However, our analysis indicates that studies of the association of cadmium with sex steroid hormones need to carefully control for tobacco use.

Our findings pertain to low-level chronic environmental cadmium exposure and may not be generalizable to environmental or occupational settings involving higher dosages of cadmium. Indeed, differences in cadmium levels may account for the inconsistent results in previous research. Additionally, urinary cadmium reflects predominantly cumulative long-term exposure and we cannot rule out short-term effects of cadmium exposure on sex steroid hormone levels. Our analysis was based on single measures of sex steroid hormones in plasma and of cadmium in spot urine samples, all of which were subject to substantial within person variability and laboratory measurement error. Consequently, we cannot exclude the existence of a modest association between urine cadmium and sex steroid hormone levels. However, the inconsistent findings in experimental models and the lack of a clearly delineated biological mechanism that could explain an effect of chronic environmental cadmium exposure on sex steroid hormone concentrations support our findings of no association.

Cadmium binds with high affinity to the androgen receptor, where it inhibits the binding of androgens and induces androgen-like effects 29. While cadmium itself may exert androgen-like effects, our analysis indicates that urinary cadmium is not an important determinant of sex steroid hormone levels in adult men at the range of exposure evaluated in the general US population.

AAG – androstanediol glucuronide; SHBG – sex hormone-binding globulin; NHANES III – Third National Health and Nutrition Examination Survey

The author(s) declare that they have no competing interests.

AM, EG, MSS, and EAP were responsible for the conception and design, analysis and interpretation of data. AM drafted the manuscript, that was edited by EG, MSS, and EAP. SR, SB, NR, and WGN were responsible for interpretation of the data and revising the manuscript. All authors read and approved the final manuscript.