Table 1.

Effects of testosterone deficiency (hypogonadism) on the expression and/or function of inflammatory markers.

Study	Study Design	Major Findings	Authors Comments
Maggio et al., 2006 [11]	This study included 497 male participants, aged 65 years and older, excluded 22 men taking glucocorticoids, exogenous androgens, or antibiotic treatment and eight who had been recently hospitalized. The final analysis included 467 men (mean age, 74.8 ± 7.0 years; range, 65–97 years).	Older men tended to have higher levels of IL-6, TNF-α, IL-1β, and C-reactive protein (CRP), but the levels of soluble IL-6 receptor (sIL-6r) were not different. Levels of sIL-6r were inversely related to total testosterone and bioavailable testosterone. IL-6 was not associated with total testosterone or bioavailable testosterone. After adjusting for age and multiple confounders, the negative correlation between sIL-6r and testosterone and bioavailable testosterone was maintained. No independent association of testosterone or bio-availability with TNF-α or IL-1β CRP was found.	Testosterone was significantly, inversely and independently associated with sIL-6r, but not with IL-6, IL-1β, TNF-α, or CRP. Study findings suggest that testosterone may decrease inflammation by reducing the production of sIL-6r.
Kupelian et al., 2010 [12]	Cross-sectional observational survey of a random sample of 2301 racially and ethnically diverse men aged 30–79 years. Analyses were conducted on 1559 men, with complete data on CRP and sex hormone levels.	About 40% of men were overweight with body mass index (BMI) of 25.0–29.9 and one-third were obese (BMI ≥ 30). Over half of the analysis samples reported the use of anti-inflammatories or other medications that could affect CRP levels. One-third of men were at moderate cardiovascular risk (CRP levels 9.5–28.5 nmol/L) while almost 20% were at high risk (CRP >28.5 nmol/L). Strong correlation between testosterone/SHBG (sex hormone binding globulin) and CRP.	A robust inverse correlation of testosterone and sex hormone-binding globulin with CRP levels. These findings provide evidence supporting the hypothesis that modulation of inflammatory processes is a potential pathway by which androgens could affect cardiometabolic risk and associated conditions such as metabolic syndrome, diabetes, and cardiovascular disease.
Bobjer et al., 2012 [13]	Sub-fertile hypogonadal men (n = 20) and eugonadal men (n = 20) (mean age 37 years, standard deviation (SD) = 4.3 and age-matched controls (n = 20) were assessed for the levels of inflammatory markers.	Macrophage inflammatory proteins a and 1b (MIP1a & MIP1b and TNF-α all showed negative associations with testosterone levels, while MIP1a and TNF-α also showed negative association with calculated free testosterone (cFT) levels. Compared with men exhibiting normal testosterone and cFT levels, TNF-α levels were higher in men with subnormal levels of testosterone and cFT. Also, MIP1 levels were higher in men with subnormal levels of testosterone.	Higher levels of proinflammatory biomarkers were noted in young men with reduced testosterone, even in the absence of concurrent metabolic disease. These findings suggest that testosterone levels are directly associated with low grade systemic inflammation, which may contribute to the development of several adverse health effects previously associated with androgen deficiency. It appears that TNF-α and MIP1 are strongly associated with low testosterone in men not suffering from serious systemic disease.
Tsilidis et al., 2013 [14]	Data from 809 adult men in the National Health and Nutrition Examination Survey 1999–2004 were analyzed by geometric means and 95% confidence intervals for CRP and white blood cell (WBC) concentrations by sex steroid hormones and sex hormone binding globulin (SHBG), using weighted linear regression models.	Total and calculated free estradiol (E2) were positively associated with both CRP and WBC concentrations. SHBG concentrations were inversely associated with WBC count, but not with CRP. These cross-sectional findings are consistent with the hypothesis that higher androgen and lower estrogen concentrations may have an anti-inflammatory effect in men.	Testosterone and cFT are modestly inversely associated with CRP concentrations, and that total and calculated free estradiol are modestly positively associated with CRP and WBC.
Burney et al., 2012 [15]	Patients with cancer cachexia (n = 45) and cancer without cachexia (n = 50), as well as non-cancer controls (n = 45). Total testosterone, bioavailable testosterone, CRP, and IL-6 were measured in plasma. Functional performance was assessed by the Eastern Cooperative Oncology Group and Karnofsky Performance Scales, and sexual function was assessed by the International Index of Erectile Function (IIEF).	Low testosterone-levels were noted in more than 70% of cancer cachexia cases. Total testosterone was lower in cancer cachexia compared to cancer without cachexia. Cancer cachexia patients had lower bioavailable testosterone (BAT) and grip strength, IIEF scores, appendicular lean body mass, and fat mass, and higher IL-6 and CRP compared to controls.	Patients with cancer cachexia have lower grip strength, testosterone, fat mass, and a lean body mass with higher bone resorption, high sensitivity-CRP (hs-CRP), and IL-6, and poor functional status and erectile function, suggesting that cancer cachexia patients exhibited higher degrees of inflammation.
Tremellen et al., 2017 [16,17]	Men (n = 50) aged between 21 and 50 years (mean 35.1 ± 6.8 years) recruited from a private fertility clinic. BMI, waist circumference and % body fat, inflammatory status (serum CRP, IL-1β, IL-6, TNF-α, and lipopolysaccharide-binding protein (LBP)) and testicular endocrine function (serum testosterone, estradiol, anti-Mullerian hormone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured.	The mean (± SD) age, BMI, percentage body fat, and waist circumference of participants was 35.1 ± 6.8 years, 26.96 ± 3.5 kg/m2, 23.6 ± 6%, and 93.2 ± 9.5 cm, respectively. Inflammatory status and all three measures of adiposity, were positively correlated with serum IL-6 and CRP, but not with IL-1β or TNF-α. CRP was an overall marker of inflammation, and a positive correlation was observed between both CRP and the cytokines IL1β and IL-6, but not with TNF-α, CRP was negatively correlated with total testosterone (r = −0.471, p = 0.001,) but not calculated free testosterone (r = −0.238, p = 0.11). A significant negative relationship between serum IL-6 and testosterone (r = −0.516, p < 0.001), was observed.	Male adiposity was associated with both metabolic endotoxemia and an increase in serum IL-6, with this heightened inflammatory response being associated with a decline in both Leydig (testosterone) and Sertoli cell (anti-Mullerian hormone) function.