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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6603-6608
Copyright © 2005 by The Endocrine Society

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

Michael Zitzmann, Michael Erren, Axel Kamischke, Manuela Simoni and Eberhard Nieschlag

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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 {alpha}-1 (r = 0.44; P < 0.001) and {alpha}-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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
STRONG EVIDENCE EXISTS that inflammatory mechanisms couple dyslipidemia to atheroma and plaque formation, hence, atherosclerosis. Leukocyte recruitment and expression of proinflammatory cytokines such as IL-6 characterize early atherogenesis. IL-6 modulates lipid homeostasis, vascular endothelial function, and plaque inflammation. The hepatic by-product of IL-6, C-reactive protein (CRP), has been named an independent risk factor for cardiovascular events. Moreover, concentrations of neutrophils and monocytes are related to cardiovascular risk, because these cells can promote endothelial damage mediated by inflammatory substances and adhesion molecules. Identifying the triggers for inflammation and unraveling the details of inflammatory pathways may furnish new therapeutic targets (1, 2, 3, 4).

Two major origins of an enhanced inflammatory condition have been identified. Dyslipidemia, especially low-density lipoprotein (LDL)-cholesterol species, can induce monocytes and endothelial cells to shed proinflammatory substances (3, 5). Fat tissue as an endocrine organ plays a relevant role as a source of ILs and immunomodulatory hormones such as leptin and adiponectin (6, 7).

Strong evidence exists that sex steroids influence the pattern of inflammatory substances in humans. The greater incidence of immune-mediated diseases in women or hypogonadal men compared with healthy men has been attributed to testosterone down-regulating proinflammatory cytokines in cross-sectional or intervention trials (8, 9, 10), whereas the role of estrogens is seen controversially (8, 11, 12). Moreover, in women, progestins can potentially stimulate monocyte production of proinflammatory cytokines as has been demonstrated (11, 12, 13). There are indications that the adverse cardiovascular events observed in postmenopausal women receiving a combined estrogen/progestin substitution therapy can be largely attributed to the latter hormone (14). Correspondingly, IL-6 concentrations increase during the luteal phase of the menstrual cycle, possibly being responsible for the increase of basal temperature (15, 16).

In men, the role of progesterone within the inflammatory system has not been elucidated. We report results of an extensive cross-sectional approach in healthy men investigating the association of endogenous progesterone levels to the inflammatory status. Because putative associations between two variable parameters cannot be distinguished in terms of cause and effect, we determined concentrations of IL-6 and antiinflammatory IL-10 in serum samples from a placebo-controlled trial for hormonal male contraception (17) involving administration of an exogenous progestin. In this trial, all subjects received additional androgen substitution to avoid the confounding effect of a progestin-induced hypogonadism because external progestins cause a marked decrease in gonadotropin and testosterone production (18, 19).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

For the cross-sectional approach, healthy male nonsmoking Caucasians aged 20–50 yr were recruited as volunteers willing to participate in a one-term clinical study (by local newspaper advertisements). Information concerning clinical, biochemical, and genetic investigations was provided. The study was approved by the Ethics Committee of the University and the State Medical Board, Münster, Germany. All volunteers gave written informed consent. Selection of participants followed the flow chart detailed in Fig. 1Go. In addition, a possible state of androgen deficiency (total serum testosterone < 12 nmol/liter or free testosterone < 250 pmol/liter) was taken as an exclusion criterion but not met by any of the men. All examinations and blood samplings were performed between 0800 and 1100 h after an overnight fast including abstinence from caffeine-based drinks for 12 h. Body fat content was assessed as previously described (20). The study was completed within 4 wk during summer. Subjects were all interested in obtaining the results and received reimbursement for transportation.



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  		FIG. 1. Screening procedures in relation to numbers of potential subjects excluded and subjects finally included.

 
Subjects participating in the pharmacological trial were 28 (two groups of 14) 18- to 45-yr-old healthy male Caucasians who were recruited as volunteers willing to participate in a clinical study for hormonal male contraception (by local newspaper advertisements). Groups did not differ in age, body mass index, or smoking habits. Subjects did not experience severe infections or inflammatory disease throughout the trial. The study was approved by the Ethics Committee of the University and the State Medical Board, Münster, Germany. All participants provided written informed consent. The trial and the participants have been described before in terms of contraceptive efficacy and effects on lipid metabolism (see discussion in Ref.17). We have also reported effects of this medication on hemostasis (see discussion in Ref.21). Every volunteer received im injections of 1000 mg testosterone undecanoate (TU) in study wk 0, 6, 12, and 18 plus either daily oral placebo treatment or im injections of norethisterone enanthate (NETE) (200 mg) in study wk 0, 6, 12, and 18. The total treatment phase lasted 24 wk, and oral medication was administered accordingly. Washout and follow-up lasted until wk 52.

Medication

TU (Nebido) was from Schering (Berlin, Germany). With an injection volume of 4 ml, the dose of 1000 mg TU in castor oil leads to maximal concentrations of 19.3 ± 2.1 nmol/liter after 11.4 ± 1.5 d. The terminal half-life was determined as 33.9 ± 4.9 d (22). The optimal injection interval for the treatment of hypogonadal men is set between 10 and 14 wk (23). In healthy volunteers receiving an additional gestagen that lowers SHBG concentrations and may thus enhance steroid metabolism, the injection interval was set to 6 wk (see above).

NETE (Noristerat) was also from Schering. NETE has a marked gestagenic potential but low androgenic and almost no estrogenic activity (24, 25). We had previously demonstrated that an im injection of 200 mg NETE in healthy men results in measurable concentrations of this synthetic hormone for about 6 wk; time to maximal concentration of NETE was achieved with a mean of 4.9 ± 1.1 d after injection. The terminal elimination half-life was 12.2 ± 1.7 d (26).

Biochemical analyses

All venous blood samples were obtained in a fasting condition under standardized conditions between 0800 and 1100 h after a 30-min rest. Serum or plasma was separated at 800 x g. Samples were immediately stored at –80 C. All assays were performed in one batch.

Serum progesterone was measured by RIA using the Coat-A-Count progesterone kit (Diagnostic Products Corp., Los Angeles, CA). Before measuring the study samples, the assay was carefully revalidated to assess its suitability for measuring progesterone in male serum. Linearity, assessed by measuring male serum samples (n = 11) at different dilutions (200, 100, and 50 µl) showed a recovery of 101.9 ± 11.5% (mean ± SD). Recovery of progesterone standard added to male sera within the relevant range (1.6–9.5 nmol/liter) was 108.2 ± 15.2% (n = 6). All serum samples (200 µl in duplicate) provided an analytical response with logit values ranging between +1 and –0.5, within the ED50 (3.75 nmol/liter) and the ED80 concentration (0.5 nmol/liter) of the standard curve. The sensitivity of the assay was 0.15 nmol/liter. The intra- and interassay coefficients of variation (CVs) were less than 4% and less than 6%, respectively. This assay was not compared against a standard involving mass spectrometry or HPLC, and thus, uncertainty concerning the assay specificity might persist. This may represent a source of error. Plasma 17-hydroxyprogesterone (17-OHP) was measured by RIA using the Coat-A-Count 17-OHP kit (Diagnostic Products) according to the instructions of the manufacturer. The sensitivity was 0.3 nmol/liter, and intra- and interassay CVs were less than 5%.

Serum testosterone levels were measured by a commercial ELISA kit (DRG Instruments GmbH, Marburg, Germany), and serum levels of SHBG and estradiol were measured by highly specific time-resolved fluoroimmunoassays (Autodelfia, PerkinElmer, Freiburg, Germany). For the above mentioned assays, the mean intraassay CVs were less than 5%, and mean interassay CVs were less than 10%. Levels of free testosterone were calculated from levels of SHBG and total serum testosterone according to the law of mass action, using 3.6 x 104 liter/mol as the association constant of testosterone with albumin and 1 x 109 liter/mol with SHBG. Calculation with this method yields highly reliable values of levels of free testosterone (27).

IL-10 was determined by Biosource International (Camarillo, CA) (human IL-10 US ultrasensitive) and IL-6 by R&D Systems (Wiesbaden, Germany) (Quantikine HS high-sensitivity human IL-6). The intra- and interassay CVs were 4 and 6% for the IL-10 assay, respectively, and 3.5 and 6% for the IL-6 assay, respectively. CRP was determined nephelometrically on a BNII analyzer with an ultrasensitive method (Dade Behring, Bad Schwalbach, Germany). The lower detection limit was 0.02 mg/liter; the upper normal value was 0.5 mg/liter.

An Hitachi 917 autoanalyzer was used for the quantification of serum concentrations of triglycerides and cholesterol by enzymatic tests, of high-density lipoprotein cholesterol by a homogenous assay, and of apolipoprotein A-I with and lipoprotein (a) by (latex-enhanced) turbidimetric immunoassays (Hitachi/Roche Diagnostics, Mannheim, Germany). Imprecision was less than 5%. LDL-cholesterol was calculated using the Friedewald formula.

Plasma concentrations of soluble E-selectin (sE-selectin) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were determined in duplicate by the use of enzyme immunoassays from Bender Medsystems Diagnostics (Vienna, Austria). The interassay CV was less than 10%.

Serum levels of insulin and C-peptide were assessed by solid-phase, two-site chemoluminescent enzyme-labeled immunometric assays (Immulite insulin/C-peptide, Diagnostic Products Corp.). The intraassay CVs were 3.8 and 7.5%, respectively, and the interassay CVs were 4.8 and 8.4%, respectively.

Leptin serum levels were measured using RIA (Mediagnost, Reutlingen, Germany) with intra- and interassay CVs being 5 and 7.6%, respectively.

Serum protein fractionation was performed by one-dimensional serum protein electrophoresis on an Olympus Hite 320 system (Olympus, Hamburg, Germany). Five-part differential hematology analysis was performed on a Sysmex SE 9500 system (Sysmex Europe, Hamburg, Germany).

Statistics

All variables were checked for normal distribution by the Kolmogorov-Smirnov one-sample test for goodness of fit. When necessary, analysis was performed on logarithmically or, for percentage values, on arcsine-transformed data. For the cross-sectional approach, Pearson’s correlation coefficient was calculated as well as partial correlations after correction for age alone or age and body fat content. These parameters were chosen because age was negatively related to progesterone levels and body fat content is likely to influence inflammation parameters. For analysis of data from the placebo-controlled trial, one-way ANOVA was performed to detect changes from baseline. Treatments were compared by two-way ANOVA. Using two groups of 14 volunteers, a power of 80% was calculated to detect changes of 1 SD in cytokine concentrations at the 2P < 0.05 level. Computations were performed using the statistical software package SPSS (release 11.0; Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Characteristics of the subjects participating in the cross-sectional approach are detailed in Table 1Go. Correlations of progesterone to various inflammation-associated parameters are given in Table 2Go. Highly significant positive associations of progesterone levels to IL-6 and CRP as well as cell-adhesion molecules and leptin were seen. Similarly, progesterone concentrations correlated with total protein concentrations and the inflammation-associated subfractions of {alpha}-1 and {alpha}-2 globulins, whereas an inverse relation to albumin could be described. Progesterone was positively related to total leukocyte counts, especially to the relative neutrophil fraction, as well as to absolute neutrophil counts (r = 0.42; P = 0.001). The relative lymphocyte fraction was strongly inversely associated with progesterone (Table 2Go), but absolute lymphocyte numbers were not related to concentrations of this hormone (r = 0.12; P = 0.33). Because progesterone levels decreased with advancing age (r = –0.36; P = 0.002), respective partial correlations were calculated. The results remained stable, also after additional inclusion of body fat content as a potential confounder of inflammation markers (Table 2Go).


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  		TABLE 1. General data of the 67 subjects recruited for the cross-sectional assessment

 

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  		TABLE 2. Progesterone correlated with parameters associated with inflammation

 
Concentrations of 17-OHP were closely related to progesterone levels (r = 0.83; P < 0.001). Within the setting of this marked dependency, 17-OHP exhibited significant associations with concentrations of CRP (r = 0.28; P = 0.02), the relative neutrophil count (r = 0.53; P < 0.001) and the {alpha}-1 fraction of electrophoresis (r = 0.27; P = 0.03) but not the other inflammation parameters given in Table 2Go. Moreover, the significant associations of 17-OHP lost significance when controlled for progesterone concentrations.

Total testosterone showed a significant inverse association with concentrations of fasting insulin and C-peptide (r = –0.273, P = 0.03; and r = –0.28, P = 0.02, respectively). Other relevant associations of total/free testosterone or estradiol with the parameters detailed in Table 2Go were not seen.

During the pharmacological trial, the testosterone/progestin group exhibited a marked increase of IL-6 concentrations (P = 0.009), whereas these decreased in the testosterone/placebo group (P = 0.02). Antiinflammatory IL-10 levels decreased in the group receiving testosterone/progestin (P = 0.01) but did not change in the testosterone/placebo group (P = 0.32; Fig. 2Go, A and B). Two-way ANOVA demonstrated that the treatment effects were significantly different over time between the two groups (IL-6, P < 0.001; IL-10, P = 0.03).



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  		FIG. 2. Changes from baseline for IL-6 (A) and IL-10 (B) concentrations during the pharmacological trial (mean ± SE). P values of two-way ANOVA are given and represent significant differences between treatment groups over time. One-way ANOVA revealed that the testosterone/progestin group exhibited a marked increase of IL-6 concentrations (P = 0.009), whereas these decreased in the testosterone/placebo group (P = 0.02). Antiinflammatory IL-10 levels decreased in the group receiving testosterone/progestin (P = 0.01) but did not change in the testosterone/placebo group (P = 0.32).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Progesterone in men, produced by testicular and adrenal steroidogenesis, is not an unimportant by-product because it exerts effects on several organ systems (for review see Ref.28). Progesterone levels reported here are in agreement with previous results (29, 30). The lowest progesterone concentration in this study is a quarter of the maximal value (Table 1Go), which explains associations of inflammatory markers to progesterone levels.

There is a strong indication that the cross-sectional observation is not an epiphenomenon, because the exogenous progestin NETE increases IL-6 production. In addition, because 17-OHP does not compete with progesterone for the progesterone receptor (31), the lack of independent association of 17-OHP as the next step of steroidogenesis with inflammation markers is in agreement with the assumption that progesterone itself has the described effect. This knowledge may have implications on the cardiovascular risk assessment in men and on the use of progestins in males. A recent study demonstrates the adverse effect of a synthetic progestin (medroxyprogesterone acetate) on coronary vessel function in a male monkey model (32). Nevertheless, significant scatter exists in the association of endogenous progesterone levels with IL-6 concentrations.

ILs exert pleiotropic activities within several organ systems and initiate several inflammatory pathways related to atherosclerosis (7). A starting point is monocyte activity (33). Monocyte-derived macrophages exhibit a sex-differential behavior in relation to progesterone and lipid accumulation (34), and shedding of proinflammatory cytokines is increased by progesterone (11, 12, 13, 14, 35). Correspondingly, we observe a marked association of progesterone levels in men with parameters representing steps of the inflammatory cascade but not with monocyte concentrations.

Another observation in our study was the positive association of progesterone levels with leukocyte counts, especially with the neutrophil section. This cell-based aspect of inflammation is linked to the chemokine pathways. Several studies demonstrate a clear and positive correlation between leukocyte/neutrophil count and risk of atherosclerosis (for review, see Refs.2 and 36).

There is evidence for a relationship between obesity and inflammation (37, 38) because fat tissue plays a role as the source of atherogenically relevant cytokines (6, 7). These processes are linked to sex steroids, and respective receptors exist in adipose tissue (39). We have previously demonstrated that testosterone influences adipokine secretion (40) and that an androgen-receptor polymorphism affects leptin and insulin concentrations (20). This study corroborates previous findings of progestins elevating leptin levels in women (35). Thus, our results can be explained by three coexisting, interrelated pathways of progesterone on inflammation: monocyte function, neutrophil recruitment, and adipocyte activity.

There are few reports on the metabolic effects of exogenous gestagens in men. In this placebo-controlled setting, we demonstrate an up-regulation of IL-6 in those men receiving NETE, whereas concentrations of the antiinflammatory IL-10 are decreased. If changes in IL-6 concentrations were attributable to the external progestin, associations of parameters further down the inflammatory signal chain can also be explained. Within the same setting, we have previously shown that NETE has unfavorable effects on lipid constellations and hemostasis in men (17, 21).

In comparison with progesterone, synthetic progestins have various affinities to the progesterone receptor and to the other sex steroid receptors, which may be, for example in the case of the androgen receptor, agonistic (e.g. levonorgestrel) or antagonistic (e.g. cyproterone acetate). Thus, the effects on inflammation may vary between different synthetic progestins. NETE has low androgenic and almost no estrogenic activity combined with a marked gestagenic potential and was thus ideal for the purposes of this investigation focusing on progesterone effects (24, 25). It is possible, however, that different amounts of NETE given at various intervals may result in differential effects on inflammation.

Although clinical effects of progestins used as oral contraceptives by nonsmoking women have not been demonstrated, there are indications that progestins antagonize the protective effects of estrogens on cytokine production in postmenopausal women (14). In addition, the male is probably not comparable to the female in regard to progesterone action (see above) (32).

The progestin megestrol is sometimes used in elderly men to overcome cachexia. Although these desired effects are observed, they are largely a result of an increase of body fat and a decrease of muscle mass relating to the induced hypogonadism. A respective trial demonstrated a decrease of IL-6 in those men receiving additional androgens (41). In principle, this trial demonstrates androgen effects in progestin-induced hypogonadism rather than gestagen action.

External administration of sex steroids will suppress gonadotropin secretion and testicular, but not adrenal, steroidogenesis. Testosterone administration, which has favorable effects on inflammatory processes in hypogonadal patients (10), should suppress the testicular proportion of progesterone production also in eugonadal men. In this case, eugonadal men at cardiovascular risk as mediated by a proinflammatory profile could benefit from testosterone substitution. The men reported in this trial receiving testosterone plus placebo exhibited a decrease in concentrations of IL-6.

In conclusion, we describe a positive relation of progesterone concentrations with an inflammatory profile in healthy men. External progestins elicit a corresponding effect. Men receiving regimens for hormonal male contraception involving progestins have to be monitored in this regard. Speculatively, testosterone treatment decreasing endogenous progesterone production by suppressing the testicular part of steroidogenesis (the adrenal production would remain intact) may facilitate beneficial effects on inflammation profiles even in eugonadal men.


   Acknowledgments
 
We thank Susan Nieschlag, M.A., for editing the manuscript.


   Footnotes
 
Medication was provided by Schering AG, Germany.

First Published Online October 4, 2005

Abbreviations: CRP, C-reactive protein; CV, coefficient of variation; LDL, low-density lipoprotein; NETE, norethisterone enanthate; 17-OHP, 17-hydroxyprogesterone; sE-selectin, soluble E-selectin; sVCAM-1, soluble vascular cell adhesion molecule 1; TU, testosterone undecanoate.

Received April 19, 2005.

Accepted September 22, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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S. T. Page, J. K. Amory, and W. J. Bremner
Advances in Male Contraception
Endocr. Rev., June 1, 2008; 29(4): 465 - 493.
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