Zhang C, Bian H, Chen Z et al: The Association between Dietary Inflammatory Index and Sex Hormones among Men in the United States. J Urol 2021; 206: 97.

Introduction

Testosterone (T) is a fundamental male sex hormone that is produced by the testicular Leydig’s cells and is primarily regulated through the drive of hypothalamic-pituitary-luteinizing hormone.¹ T plays essential roles in reproduction and sexual function; however, testosterone deficiency (TD) is prevalent in 20–50% of males in the U.S.² Both animal and human studies demonstrate that TD is related to an increased level of pro-inflammatory cytokines.³ Higher intake of specific pro-inflammatory dietary components, such as total fat and refined carbohydrates, are associated with a decrease in T levels.⁴ The Dietary Inflammatory Index (DII) was developed to measure the inflammatory potential of the diet.⁵ However, literature about the relationship among the inflammatory potential of diet, T level, and TD is scarce.

Hence, the primary aim of our study is to assess the association between DII and sex hormones in a large, nationally representative adult male sample.

Materials and Methods

We utilized data from the 2013–2014 and 2015–2016 National Health and Nutrition Examination Survey (NHANES). All men aged ≥20 years who completed the full 24-hour dietary history and underwent sex hormone testing were included in the cohort. Participants with incomplete data on sex hormones and dietary recall assessments were excluded. At last, 4,151 participants were included after further exclusion of men who were taking sex hormone medication including T, progesterone, estrogen, or “other sex hormones” noted in the NHANES questionnaire. Weighted proportions and multivariable analysis controlling for age, race, energy, smoking status, education level, body mass index (BMI), and time of venipuncture were used to evaluate the associations between DII and sex hormones. Multivariate models included the nonadjusted model (Model I), minimally adjusted Model II (only age, race, energy, smoking status and time of venipuncture were adjusted), and fully adjusted Model III (age, race, energy, smoking status, education level, BMI, cardiovascular disease score and time of venipuncture were adjusted). The primary outcome was the association between DII and total testosterone (TT) less than 300 ng/dL, which was accepted as the TD threshold in the American Urological Association (AUA) guidelines on TD.⁶

Results

For 4,151 participants, prevalence of TD was 25.7%. Mean DII was 0.71±1.97, with scores ranging from −5.05 (most anti-inflammatory) to +5.48 (most pro-inflammatory). Mean±SD TT was 419.30±176.27 ng/dL. Mean TT was lower among men in the highest tertile compared with men in the lowest tertile group (410.42±171.97 vs 422.71±175.69, p <0.001). A per unit increase in DII was related to 4.0% (95% CI 0.5–7.6) higher odds of TD. In the fully adjusted multivariable model (Model III), males in DII tertile 3 (the most pro-inflammatory) had 29.6% (3.1–63.0%) higher odds of TD than those in tertile 1 (P trend=0.025, table 1). Furthermore, the association was still pronounced when analyzing only males with obesity (Table 2). After accounting for all potential confounders, we found that higher DII (continuous) was associated with a significantly higher risk of TD among males with obesity (OR 1.10; 95% CI 1.02–1.19). Participants in tertile 3 had a 59% higher risk of TD (OR 1.59; 95% CI 1.13–2.24; P trend=0.007) than men with obesity in the most anti-inflammatory DII group (tertile 1). In addition, males with obesity having a higher DII score were associated with lower TT levels (β –5.80; 95% CI −10.89–−0.70), and men in tertile 1 had a mean 26.75 ng/dL decrease in TT compared with those in tertile 3 (β −26.75; 95% CI −49.63– −3.86; P trend=0.022).

Discussion

To our knowledge, this is the first study assessing an association between the inflammatory potential of overall dietary patterns and sex hormones. Our results indicated that higher pro-inflammatory dietary intake was positively associated with TD. When we limited the participants to males with obesity, the risk for TD was also significant.⁷ Emerging evidence showed that one possible mechanism for our results could be the effect of diet on pro-inflammatory markers such as IL-1, IL-6, IL-17, and TNF. These markers severely impair T secretion by activating inflammation and reactive oxygen species production by interstitial macrophages residing adjacent to Leydig cells.⁸ In addition, some experimental studies also demonstrated that these pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, could modulate the hypothalamic-pituitary-gonadal axis to inhibit T secretion.⁹ For males with obesity, excessive visceral adipose tissue was a cause of chronic inflammation because fat tissue was the main source of pro-inflammatory mediators.¹⁰ As it has been reported that excessive inflammation had the potential to negatively influence Leydig cell function and reduce the production of T (which were particularly sensitive to inflammation), it was reasonable to consider that an anti-inflammatory treatment could prevent TD. Our findings suggested that a more anti-inflammatory diet could be a feasible method to reduce the accumulated inflammatory burden; hence, leading to an increased T level.

Conclusions

In conclusion, men adhering to a more pro-inflammatory diet have a higher risk of TD, especially men with obesity, indicating the important role of inflammatory diet in male reproductive health. Large, well-designed prospective research studies are warranted in the future to verify the causal relationship between DII and TD.