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Endogenous Progesterone and the Exogenous Progestin Norethisterone Enanthate Are Associated with a Proinflammatory Profile in Healthy Men

Institute of Reproductive Medicine (M.Z., A.K., M.S., E.N.) and Institute of Laboratory Medicine and Leibniz Institute of Atherosclerosis Research of the University (M.E.), D-48129 Münster, Germany

Address all correspondence and requests for reprints to: Prof. Dr. E. Nieschlag, FRCP, Institute of Reproductive Medicine of the University, Domagkstrasse 11, D-48129 Münster, Germany. E-mail: Eberhard.Nieschlag{at}ukmuenster.de.

Context: Inflammatory processes are related to atherosclerosis. Identification of inflammation triggers may furnish new therapeutic pathways. In women, progestins can have a marked inflammatory capacity.

Objective and Design: We investigated the effects of progesterone in men within the setting of two independent trials. First, the relation of endogenous progesterone levels to inflammation markers was assessed in 67 healthy nonsmoking Caucasian men (age, 20–50 yr) on a cross-sectional basis. Second, in a longitudinal controlled trial (52 wk) involving 28 healthy men receiving im medication, we determined the effects of an exogenous progestin (norethisterone enanthate 200 mg) in combination with a long-acting testosterone preparation (testosterone undecanoate 1000 mg) administered to avoid androgen deficiency caused by pituitary-hypothalamic feedback. Controls received testosterone plus placebo.

Results: In the cross-sectional study, progesterone levels were positively related to concentrations of IL-6 (r = 0.41; P < 0.001), C-reactive protein (r = 0.37; P = 0.007), soluble vascular cell adhesion molecule 1 (r = 0.28; P = 0.02), E-selectin (r = 0.45; P < 0.001), leptin (r = 0.42; P < 0.001), neutrophils (r = 0.62; P < 0.001), and serum protein fractions -1 (r = 0.44; P < 0.001) and -2 (r = 0.36; P = 0.002). During the pharmacological trial, the testosterone/progestin group exhibited a marked increase of IL-6 concentrations (P < 0.001), whereas these decreased in the testosterone/placebo group (P = 0.03). Antiinflammatory IL-10 levels decreased in the group receiving testosterone/progestin (P = 0.01) but did not change in the testosterone/placebo group.

Conclusion: Progesterone concentrations correspond to an inflammatory profile in healthy men, and external progestins elicit a similar effect. Men receiving regimens for hormonal male contraception involving progestins should be monitored for inflammatory effects. Speculatively, testosterone treatment decreasing endogenous progesterone production may facilitate beneficial effects on inflammation profiles even in eugonadal men.

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