Prevention and Rehabilitation Oral testosterone supplementation and chronic low-grade inflammation in elderly men: A 26-week randomized, placebo-controlled trial Hamid Reza Nakhai-Pour, MD, PhD, a,b Diederick E. Grobbee, MD, PhD, a Marielle H. Emmelot-Vonk, MD, a,b Michiel L. Bots, MD, PhD, a Harald J.J. Verhaar, MD, PhD, b and Yvonne T. van der Schouw, PhD a Utrecht, The Netherlands Background To determine the effect of oral testosterone supplementation on systemic low-grade inflammation measured by high-sensitive C-reactive protein (hs-CRP) in aging men with low testosterone levels. Methods Two hundred thirty-seven men aged 60 to 80 years with a testosterone level of b13.7 nmol/L (below the 50th percentile of the population distribution) were recruited into a double-blind randomized placebo-controlled trial. Participants were randomized to either 4 capsules of 40 mg testosterone undecanoate (Andriol Testocaps, NV Organon, Oss, The Netherlands) or placebo daily for 26 weeks. Serum levels of hs-CRP were measured at baseline and at 26 weeks using a near-infrared particle immunoassay of the Synchron LX System (Beckman Coulter, Fullteron, CA). Results The median baseline hs-CRP level was 1.95 mg/L (0.30-6.43) in the testosterone group compared with 1.90 mg/L (0.40-5.91) in the placebo group. After 26 weeks of testosterone supplementation therapy, the 2 intervention groups were not statistically significantly different (median hs-CRP 2.20 vs 2.00 mg/L, interquartile range 0.40-6.54 vs 0.50-5.70, P = .36). In subgroup analysis, neither baseline testosterone level, nor age, nor baseline CRP-level modified the effect of testosterone supplementation on CRP levels. Conclusion Oral testosterone undecanoate supplementation, in dosage of 160 mg daily for 26 weeks, does not increase hs-CRP levels in elderly men. (Am Heart J 2007;154:1228.e1-1228.e7.) Aging is associated with a decrease in serum testoster- one levels. 1 At the same time, aging is accompanied by a pro-inflammatory state expressed by increasing levels of inflammatory cytokines. 2 Inflammation plays a crucial role in atherogenesis, 3 disability, 4 and mortality. 5 The age- associated decline in sex hormones may affect the development of mild pro-inflammatory state. 6 There is evidence suggesting that sex hormones may play a role in the regulation of inflammatory responses. For example, estrogen-based orally administered post- menopausal hormone therapy (HT) increases CRP levels in postmenopausal women. 7-9 C-Reactive protein (CRP), which is a prototypic acute phase reactant and probably an important defense protein during inflammation, also seems to be partly regulated by androgens in women. 10 In elderly men, evidence from a randomized clinical trial demonstrated no such effect after 13 weeks of testoster- one supplementation with dihydrotestosterone. 11 Also, short-term treatment with an aromatase inhibitor in elderly hypogonadal men, which increases testosterone levels, did not affect CRP levels. 12 On the other hand, 3-week testosterone treatment before intracoronary stenting resulted in a significant suppression in high- sensitive CRP (hs-CRP) and interleukin-6 (IL-6) levels after the stent implantation. 13 Given the controversial findings regarding the sex hormones effect in chronic low-grade inflammation and because of increased interest in the potential for testosterone supplementation in elderly men, the possibility of regulatory effect of testosterone on circulating CRP is of importance. We determined the effect of oral testosterone supplementa- tion on CRP levels in elderly men with moderately low testosterone levels. From the a Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands, and b Department of Geriatrics, University Medical Center Utrecht, Utrecht, The Netherlands. Clinical trial registration number [ISRCTN23688581]. The study was financially supported by grant 014-91-063 from the Netherlands Organization for Health Research and Development. Submitted April 4, 2007; accepted September 9, 2007. Reprint requests: Yvonne T. van der Schouw, PhD, Julius Center for Health Sciences and Primary Care, Room STR 6.131, PO Box 85500, Utrecht Medical Center, 3508 GA Utrecht, The Netherlands. E-mail: y.t.vanderschouw@umcutrecht.nl 0002-8703/$ - see front matter © 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.09.001