The relationship between circulating testosterone and inflammatory cytokines in men

Figures & data

Table 1. Summary of the association between testosterone level and supplementation with inflammatory markers in animals and humans with hypogonadism.

Reference (year)	Animal model (hypogonadism)	Treatment	Treatment duration	Findings
Negative relationship between testosterone and inflammatory markers
Kelly et al. (2012) [16]	Testicular-feminized mice fed with high cholesterol diet (n = 28, 8 weeks old)	Testosterone esters (10 μL of 100 mg/mL, i.m.)	28 weeks	↓ IL-6. ↔ IL-1β, IL-10, MCP-1, and TNF-α
Jia et al. (2015) [17]	Castrated male Sprague-Dawley rats (n = 48)	Estrogen (0.25 mg/kg/day) + testosterone (0.25, 0.50 or 1.0 mg/kg/day, s.c.)	30 days	↓ TNF-α
Papadopoulos and Wardlaw (2000) [18]	Adult male Sprague-Dawley rats; Intact (n = 9) Orchiectomized rats with testosterone replacement (n = 5) Orchiectomized rats without testosterone replacement (n = 7)	Two 20-mm silastic capsules (i.d., 0.062 in; o.d., 0.125 in) filled with crystalline testosterone – s.c. implantation First day: 0, 20, 40, 60, 120, and 180 min after intravenous injection of 500 ng of recombinant human IL-6 Second day: 0, 1, 2, 3, 4, and 6 h after intravenous injection of 10 ng of endotoxin		Testosterone attenuates the response of the HPA axis to IL-6 in the rat
Demirtas Sahin et al. (2017) [20]	Aging male Wistar albino rats (n = 27) Control (4 months old) Aged (24 months old + etanercept)	Etanercept (a TNF-α inhibitor; 0.8 mg/kg per week, s.c.)	12 weeks	Normalized testosterone, TNF-α, CRP MCP-1, and ICAM-1 levels
Wang et al. (2005) [19]	Normal male Sprague-Dawley rats (n = 17, 9–10 weeks old)	(i) Castrated group (ii) Flutamide (anti-testosterone) (10 mg; s.c. implantation)	21 days	↓ TNF-α, IL-1β, and IL-6
Reference (year)	Study design	Group characteristic (hypogonadism)	Treatment	Outcomes
Negative relationship between testosterone and inflammatory markers
Maggio et al. (2005) [1]	Cross-sectional study	Elderly male participants of the InCHIANTI population (n = 473; aged >65 years old)	NA	Significant inverse relationship between testosterone and sIL-6r levels.
Maggio et al. (2006) [5]	Cross-sectional study	Elderly men participants of the InCHIANTI population (n = 467; age: >65 years old)	NA	sIL-6r was inversely correlated with total and bioavailable testosterone. No correlation with any other inflammatory markers (TNF-α, IL-1β, and CRP).
Bobjer et al. (2013) [4]	Nested cross-sectional study	Hypogonadal men (n = 20) Eugonadal men (n = 20; Mean age: 37 ± 4.3 years old)	NA	Negative association between testosterone and inflammatory markers (MIP1a, MIP1B, and TNF-α)
Malkin et al. (2004) [2]	Randomized, single-blind, placebo-controlled, crossover study	Symptomatic androgen deficiency men (n = 27; age: 62 ± 9 years old)	Testosterone replacement (Sustanon 100) – 1 month	↓ TNF-α and IL-1β ↑ IL-10
Kaplan et al. (2010) [21]	Cross-sectional study 8 weeks	Men participated in a lipid treatment study (n = 467; mean age: 52 years old)	NA	Hypogonadal men (low testosterone) had higher hsCRP level.
Kalinchenko et al. (2010) [22]	Randomized, placebo-controlled, double-blinded, phase III trial	Men with MetS and hypogonadism (n = 184; age: 35–70 years old)	Parenteral testosterone undecanoate (1000 mg, i.m.) – 30 weeks	↓ IL-1β, TNF-α, and CRP ↔ IL-6 and IL-10 levels.
Negligible relationship between testosterone and inflammatory markers
Reference (year)	Animal model (hypogonadism)	Treatment	Treatment duration	Findings
Chin and Ima-Nirwana (2017) [23]	Orchidectomized male Sprague Dawley rats (n = 18, 3 months old)	Testosterone enanthate (7 mg/kg/weekly; i.m.)	8 weeks	↑ Testosterone ↔ IL-1α, IL-1β, IL-6, and TNF-α
Reference (year)	Study design	Group characteristic (hypogonadism)	Treatment	Outcomes
Ng et al. (2002) [24]	Randomized double-blind placebo-controlled trials	Healthy men with partial androgen deficiency (n = 73; age: >60 years old)	DHT (70 mg/day, transdermal) or rhCG (250 mg twice weekly) – 3 months	↔ ICAM-1, CRP, and VCAM-1
Dougherty et al. (2005) [25]	Placebo-controlled randomized trial	Men with mild hypogonadism (Testosterone level <350 ng/dL; n = 37; age: 62–74 years old)	Anastrozole (1 mg daily or 1 mg twice weekly) – 12 weeks	↑ Testosterone ↔ IL-6 and CRP
Reference (year)	Study design	Group characteristic (hypogonadism)	Treatment	Outcomes
Kapoor et al. (2007) [26]	Double-blinded placebo-controlled crossover study	Hypogonadal men with type 2 diabetes (n = 20; age: > 30 years old)	Sustanon – containing 30 mg testosterone propionate, 60 mg testosterone phenylpropionate, 60 mg testosterone isocaproate intramascular, and 100 mg/mL testosterone decanoate (200 mg, i.m.) – 6 months	↔IL-6, TNF-α, and CRP
Maggio et al. (2006) [12]	Cross-sectional study	Men with prostate cancer undergoing ADT (12 months prior to the onset of the study; n = 20) Non-metastatic prostate cancer patients and had not yet received ADT (n = 18) Healthy eugonadal men (n = 20; Age: 69.9 years old)	Androgen deprivation therapy	↔ Pro-inflammatory or anti-inflammatory cytokines serum levels between the 3 groups.

CRP: C-reactive protein; hsCRP: high sensitivity C-reactive protein; IL-1β: interleukin-1 beta; IL-6: interleukin; IL-10: interleukin; i.m.: intramuscular; s.c.: subcutaneous; TNF-α: tumor necrosis factor alpha; ICAM: intracellular adhesion molecule; VCAM: vascular cell adhesion molecule; MIP: macrophage inflammatory protein; NA: not applicable; Suffix – s: serum.

Table 2. Summary of the association between testosterone level and supplementation with inflammatory markers in animals and humans with metabolic disorders.

Reference (year)	Animal model (MetS and associated disease)	Treatment	Treatment duration	Findings
Negative relationship between testosterone and inflammatory markers
Vignozzi et al. (2012) [28]	Male New Zealand white rabbits feed with MetS and hypogonadism (n = 27, 15 weeks old)	Testosterone (30 mg/kg/week, oral)	12 weeks	↓ IL8, IL6, IL1β, and TNFα
Credit et al. (2002) [29]	Male Sprague Dawley rats	Testosterone, DHT or AED (TCPL drug delivery 40 mg)	90 days	↓ IL-6 ↔ IL-1 and TNF-α
Reference (year)	Study design	Group characteristic (MetS and associated disease)	Treatment	Outcomes
Negative relationship between testosterone and inflammatory markers
Nettleship et al. (2007) [3]	Cross-sectional study	Men with stable CAD (n = 69; mean age: 59 ± 1 years old)	NA	↑ IL-1β and IL-10 in men with 1, 2, 3 vessel CAD ↑ IL-6 only with 3 vessel CAD Level of IL-1β (eugonadal < borderline hypogonadal < hypogonadal men)
Yang et al. (2005) [30]	Case control study (20 months)	Elderly men selected based on Doppler’s method: i. Control group (n = 32; mean age: 66.2 ± 7.3 years old) ii. Case group: atherosclerosis old-age men (n = 38; mean age: 64.6 ± 9.1 years old)	NA	Free testosterone in the case group was lower than in the control group. Free testosterone was negatively correlated with CRP, IL-6, and sICAM-1
Corrales et al. (2006) [31]	Prospective study	Type 2 diabetic men with partial androgen deficiency (n = 13; age: 52–76 years old)	Testosterone enanthate (150mg every 15 days, i.m.) – 1 year	↑ Total testosterone, free testosterone, and LH ↓ IL-1β, IL-6, and TNF-α
Corrales et al. (2009) [32]	Prospective intervention study	Type 2 diabetic men with partial androgen deficiency (n = 13; age: >55 years old)	Testosterone enanthate (150mg every 15 days, i.m.) – 1 year (after a 3-month testosterone withdrawal period)	↓ IL-1β, IL-6, and TNF-α

CRP: C-reactive protein; IL-1β: interleukin-1 beta; IL-6: interleukin; IL-8: interleukin; i.m.: intramuscular; s.c.: subcutaneous; TNF-α: tumor necrosis factor alpha; CAD: coronary artery disease; ICAM: intracellular adhesion molecule; NA: not applicable; Suffix – s: serum.

Table 3. Summary of the association between testosterone level and supplementation with inflammatory markers in animals and humans with other pathologies.

Reference (year)	Animal model (other pathological disease)	Treatment	Treatment duration	Findings
Negative relationship between testosterone and inflammatory markers
Angele et al. (2001) [33]	Castrated male C3H/HeN mice (n = 56, 7 weeks old)	(i) 5α-DHT (7.5 mg) – s.c. implantation (ii) 5α-DHT (7.5 mg) + 17β-estradiol (0.5 mg) – s.c. implantation	14 days	DHT-treated mice ↓ IL-2, IL-3, and IFN-γ ↑ IL-10
Gilliver et al. (2006) [34]	Male Sprague Dawley rats with four 1-cm incisional wounds (n = 5–7/group, 8 weeks old)	MK-434 (a 5α-reductase inhibitor which blocks the conversion of testosterone to 5α-DHT; 1 mg/day prior to wounding, oral)	10 days	↓ IL-6 ↔ TNF-α.
Poutahidis et al. (2014) [38]	Genetically outbred CD-1 male mice (n = 7/group; 8 weeks old)	Drinking water containing Lactobacillus reuteri	8–36 weeks	↓ IL-17 ↑ IL-10 ↑ testosterone
Mendes et al. (2014) [35]	Chronic Ethanol Consumption (UChB) rats (n = 40, 60 days old)	Testosterone cypionate (Deposteron; 5 mg/kg body weight, s.c)	180 days	In plasma:
				↔ IL-6 and IL-10 ↑ TNF-α and TGF-β1 levels In ventral prostate: ↔ IL-6, IL-10, TNF-α, and TGF-1β
Guo et al. (2016) [36]	Female C57BL/6NCrl mice with anemia induced by Brucella abortus (n = 41, 10 weeks old)	Testosterone (40 µg/g b.w./week, s.c.)	6 weeks	↑ TNF-α ↓ IL-6
Patil et al. (2016) [37]	Renal ischemia-reperfusion of male Sprague-Dawley rats (8–10 weeks old)	Intravenous infusion of testosterone (20, 50, or 100 μg/kg; 3 h postreperfusion)	24 hours	Low-dose testosterone (20 µg/kg) ↓ Renal T-cell infiltration ↑ Intrarenal IL-10 ↓ Intrarenal TNF-α High-dose testosterone (100 µg/kg) ↑ Intrarenal IL-10 ↑ Intrarenal TNF-α
Reference (year)	Study design	Group characteristic (other pathological disease)	Treatment	Outcomes
Negative relationship between testosterone and inflammatory markers
Burney et al. (2012) [10]	Cross-sectional study (2006–2010)	Men with cancer-cachexia (n = 45) Male with cancer without cachexia (n = 50) Non-cancer control (n = 45; Age: >18 years old)	NA	Male with cancer-cachexia had lower bioavailable testosterone but higher IL-6 and CRP
Kaparianos et al. (2011) [39]	Case control study	Male non-COPD smokers (n = 80; mean age: 59.32 years old) Male COPD smokers (n = 82; mean age: 63.41–64.15 years old)	NA	Levels of testosterone and free testosterone were lower in the COPD group. Inverse correlation between testosterone and CRP levels.
Bini et al. (2015) [40]	Cross-sectional study	Men with active untreated pulmonary tuberculosis (n = 36) Healthy control (n = 21; Mean age: 40 ± 16.8 years old)	NA	↓ Testosterone ↑ IFN-γ, IL-6, TGF-β, IL-1β, and TNF-α
Negligible relationship between testosterone and inflammatory markers
Maggio et al. (2014) [27]	Placebo-controlled Randomized trial	Healthy males with serum T concentration <475 ng/dL (n = 108; age: >65 years old)	Testosterone patch (60 cm^2, ∼6 mg testosterone/day) – 36 months	↔ CRP, TNF-α, soluble TNF-α receptor-1 (TNFR1), IL-6, and soluble IL-6 receptors (sIL6r and sgp130)
Zhao et al. (2015) [41]	Cohort study (51 weeks)	Young Chinese men - genetically predicted testosterone (n = 289; mean age: 21 years old) Elderly Chinese men - genetically predicted testosterone with inflammation markers (n = 4,212; age: >50 years old)	NA	No association between endogenous testosterone with hsCRP.
Huang et al. (2016) [42]	Placebo-controlled, double blind randomized trial	Non-diabetic men using opioid analgesics for chronic non-cancer pain (n = 64; age: 18–64 years old)	Testosterone (5 g once daily, transdermal gel) – 14 weeks	↑ Testosterone ↔ CRP

IFN-γ: interferon-gamma; IL-1β: interleukin-1 beta; IL-2: interleukin; IL-3: interleukin-3; IL-6: interleukin-6; IL-8: interleukin-8; IL-10: interleukin-10; IL-17: interleukin-17; i.m.: intramuscular; s.c.: subcutaneous; TNF-α: tumor necrosis factor alpha; TGF-1β: transforming growth factor-1beta; CRP: C-reactive protein; hsCRP: high-sensitivity CRP; COPD: chronic obstructive pulmonary disease; NA: not applicable; Suffixes – r: receptor; s: serum.

Figure 1. Interactions between testosterone and inflammation.

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