The Effect of Testosterone Replacement on Endogenous Inflammatory Cytokines and Lipid Profiles in Hypogonadal Men

The Effect of Testosterone Replacement on Endogenous Inflammatory Cytokines and Lipid Profiles in Hypogonadal Men
Chris J. Malkin, Peter J. Pugh, Richard D. Jones, Dheeraj Kapoor, Kevin S. Channer and T. Hugh Jones

Department of Cardiology, Royal Hallamshire Hospital (C.J.M., P.J.P., K.S.C.), Sheffield, United Kingdom S10 2JF; Academic Unit of Endocrinology, Division of Genomic Medicine, University of Sheffield (R.D.J., D.K., T.H.J.), Sheffield, United Kingdom S10 2RX; and Center for Diabetes and Endocrinology, Barnsley District General Hospital (D.K., T.H.J.), Barnsley, United Kingdom S75 2EP

Address all correspondence and requests for reprints to: Dr. Chris J. Malkin, Cardiology Department, Royal Hallamshire Hospital, Sheffield, United Kingdom S10 2JF. E-mail: chris.malkin@sth.nhs.uk.

Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNF{alpha}, IL-1ß, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 ± 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 ± 1.2 nmol/liter; bioavailable testosterone, 2.4 ± 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNF{alpha} (–3.1 ± 8.3 vs. 1.3 ± 5.2 pg/ml; P = 0.01) and IL-1ß (–0.14 ± 0.32 vs. 0.18 ± 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 ± 1.8 vs. –1.1 ± 3.0 pg/ml; P = 0.01); the reductions of TNF{alpha} and IL-1ß were positively correlated (rS = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (–0.25 ± 0.4 vs. –0.004 ± 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.

The men in this study have been tracked for the last 18 years.

“We have followed these men for an average of 18 years and our study strongly suggests that the association between testosterone levels and death is not simply due to some acute illness,” said Laughlin.

In the study, Laughlin and co-workers looked at death, no matter the cause, in nearly 800 men, ages 50 to 91 years, who were living in Rancho Bernardo, California. The participants have been members of the Rancho Bernardo Heart and Chronic Disease Study since the 1970s. At the beginning of the 1980s, almost one-third of these men had suboptimal blood testosterone levels for men their age.

The group with low testosterone levels had a 33 percent greater risk of death during the next 18 years than the men with higher testosterone. This difference was not explained by smoking, drinking, physical activity level or pre-existing diseases (such as diabetes or heart disease).

In this study, "low testosterone" levels were set at the lower limit of the normal range for young adult men. Testosterone declines slowly with aging in men and levels vary widely, with many older men still having testosterone levels in the range of young men. Twenty-nine percent of Rancho Bernardo men had low testosterone.


Men with low testosterone were more likely to have elevated markers of inflammation, called inflammatory cytokines, which contribute to many diseases.* Another characteristic that distinguished the men with low testosterone was a larger waist girth along with a cluster of cardiovascular and diabetes risk factors related to this type of fat accumulation.

* Cytokines contribute more-so to disease symptomology rather than the cause of the disease in my opinion.