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Original Article |
Institute of Reproductive Medicine of the University, D-48129 Münster, Germany
Address all correspondence and requests for reprints to: Prof. Dr. E. Nieschlag, F.R.C.P., Institute of Reproductive Medicine of the University, Domagkstr. 11, D-48129 Münster, Germany. E-mail: nieschl{at}uni-muenster.de.
Abstract
The effect of testosterone (T) substitution therapy on blood vessel functions in relation to cardiovascular disease has not been fully elucidated. In 36 newly diagnosed nonsmoking hypogonadal men (37.5 ± 12.7 yr) endothelium-dependent flow-mediated vasodilatation (FMD; decreased in atherosclerosis) of the brachial artery was assessed before treatment and after 3 months of T substitution therapy (250 mg testosterone enanthate im every 2 wk in 19 men, human chorionic gonadotropin sc twice per week in 17 men). Twenty nonsmoking controls matched for age, low-density lipoprotein cholesterol (LDL-C), body height, and baseline diameter of the artery were selected for repeated measurements from a larger eugonadal control group (n = 113). In hypogonadal men, basal FMD (17.9 ± 4.5%) was significantly higher than in the large (11.9 ± 6.4%) and matched control (11.8 ± 7.1%, both P < 0.001) groups. Grouped multiple linear regression analysis revealed a significant negative association of T levels with FMD within the hypogonadal range, but no significant association was seen within the eugonadal range. During substitution therapy, T levels increased from 5.8 ± 2.3 to 17.2 ± 5.1 nmol/liter and FMD decreased significantly to 8.6 ± 3.1% (P < 0.001, analysis for covariance for repeated measurements including matched controls). LDL-C and advanced age contributed significantly to decrease FMD (P = 0.01, P = 0.04, respectively). Because T substitution adversely affects this important predictor of atherosclerosis, other contributing factors (such as smoking, high blood glucose, and LDL-C) should be eliminated or strictly controlled during treatment of hypogonadal men.
TESTOSTERONE (T) SUBSTITUTION in hypogonadal men receives wide recognition, and the number of men being treated with T is constantly increasing (1). Especially in these patients, the role of androgens concerning vascular functions deserves further evaluation. The effects of endogenous and, in the substituted patients, exogenous T on atherosclerosis and the development of cardiovascular disease (CVD) have not been fully resolved, which probably is due to multiple pathways of adverse or beneficial nature: T lowers visceral body fat mass and insulin resistance (2, 3) and exerts favorable influence on factors involved in hemostasis (4, 5). Simultaneously, T levels, at least when regarding exogenous T, are negatively associated with high-density lipoprotein cholesterol (HDL-C) levels, which is considered adverse (6, 7, 8).
Arterial functions, which are modulated by the endothelial cell layer, are also possibly subject to androgenic influence (9). Endothelial dysfunction is an early event in atherogenesis, appears to have detrimental functional consequences as well as adverse long-term effects including vascular remodeling, and seems to predict adverse coronary outcomes; thus, gender differences in endothelial function and the effects of hormonal therapy on vascular function have been the focus of considerable research interest (10, 11, 12, 13). Androgen receptors have been localized in endothelial and smooth muscle cells (14, 15, 16). T seems to be associated with shedding of endothelial adhesion molecules (17). Conflicting results concerning the nature of T influence on vascular reactivity have been published: a cross-sectional approach in androgen-deprived prostate cancer patients showed an increased flow-mediated dilatation (FMD) of the brachial artery reflecting enhanced endothelial function (18). Corresponding effects were seen in T-ablated male-to-female transsexuals (19). Conversely, acute high-dose iv T (with mean serum concentration around 20-fold of the upper normal range) improved FMD (20), coronary artery flow (21), and increased time to ST-segment depression in patients with CVD (22). However, a similar setting could not demonstrate increased myocardial perfusion (23). Administration of nonaromatizable dihydrotestosterone to men with T levels within the lower normal range did not alter FMD (24). Correspondingly, we have previously demonstrated that levels of total or free T within the normal range do not seem to play a major role in regulating vascular endothelial functions: in eugonadal men, other factors such as cigarette smoking, low-density lipoprotein cholesterol (LDL-C) levels, and the CAG repeat polymorphism of the androgen receptor influence vasoreactivity to a significant degree. In the latter, T effects are attenuated in longer triplet-repeat chains; this was associated with higher FMD (25).
Assembling the pieces of this incomplete puzzle, it can be assumed that T deprivation and attenuation of T effects are associated with increased vascular endothelial functions. Endogenous or exogenous changes of androgen levels within the normal range are not likely to exert significant influence on vasoreactivity. Acute increment of T levels into the highly supraphysiological range seems to have, at least partially, positive effects. It is debatable whether these effects are endothelium dependent or rather smooth muscle cell dependent. It has to be mentioned that assessing FMD should always consider the baseline diameter of the artery (BDA) as a significant confounder of results: the greater the vessel diameter, the lower the dilatory response (12, 25). Additionally, changes of BDA have to be recognized when repeated assessments are performed (26).
Hypogonadism is, to date, the only indication to treat men with T. Still missing and of pivotal importance is realization of putative effects of clinically reasonable T doses on vascular endothelial functions in such patients. We, therefore, investigated the effects of exogenously and endogenously increased T levels in hypogonadal men on vascular functions in a controlled setting.
Patients and Methods
Patients
The 36 untreated hypogonadal men were patients aged 20–70 yr (mean 37.5 ± 12.7 SD years) presenting for examination and possible treatment of hypogonadism-related symptoms lasting for at least 2 yr. Such symptoms were fatigue, loss of libido, depressiveness, change in body composition/weight, decreased physical performance, decrease in aggressive behavior, disability to cope, and decreased performance at work. At least one of these symptoms had to be accompanied by low T levels (<12 nmol/liter). Previous androgen treatment or a history of cigarette smoking as well as diabetes mellitus, arterial hypertension, dyslipoproteinemia, medication of any kind, or drug abuse led to exclusion of patients. Hypogonadism was defined by the symptoms of androgen deficiency and morning total serum T levels less than 12 nmol/liter (25) (see also Hormone measurements). The threshold of 12 nmol/liter is in agreement with the World Health Organization consensus guidelines (27) and data obtained in a large trial involving older men (28). Hence, we did not perform an age-adjustment of the normal range for total T of 12–35 nmol/liter.
The diagnosis of primary hypogonadism (n = 11) was based on high normal to elevated gonadotropin levels (normal range for LH 2–10 IU/liter, for FSH 1–7 IU/liter) and included the determination of karyotype (Klinefelter patients, n = 7). Secondary hypogonadism (n = 25) was diagnosed in case of gonadotropin levels below the normal limit and also in hypogonadism in combination with gonadotropin levels within the low normal range, indicating a partial hypothalamic-pituitary insufficiency. There is evidence that this clinical entity often evolves with advancing age of men (29). A pituitary tumor was excluded by magnetic resonance imaging scans in those patients with subnormal gonadotropin levels or a blunted response to an LHRH challenge (n = 11). Especially in patients with secondary hypogonadism, other endocrine axes were regularly assessed. Subjects being additionally treated with L-thyroxine, hydrocortisone, and/or GH as well as patients with decreased levels of GH or IGF-I were excluded from this evaluation.
In summary, only subjects with isolated primary or secondary hypogonadism were included. Because of possible confounding effects, patients with other hormone deficits were excluded. Causes for primary hypogonadism were Klinefelter syndrome or Leydig cell insufficiency. In patients diagnosed according to the above-mentioned criteria with secondary hypogonadism, pituitary tumors were excluded. These men are best described as patients with a (partial) hypothalamic-pituitary insufficiency. Patients with Kallmann syndrome were not present in this study.
Treatment
Nineteen patients were treated with testosterone enanthate (TE; 250 mg in 1 ml oily solution) by im injections every 2 wk. Seventeen patients received treatment with human chorionic gonadotropin (hCG; 1000 IU in 1 ml 0.9% saline solution) injected sc twice per week. Continuity of treatment was confirmed by regular assessment of T levels. Reassessment of sex hormone levels, lipid parameters, and vascular functions was performed after 3 months. Patients treated with TE were seen 7 d after injection and those treated with hCG 2 d after the last application.
Controls
A larger control group of 113 eugonadal healthy men served for determination of normal values of vasoreactivity. Healthy male Caucasians aged 20–69 yr were recruited by local newspaper advertisements calling for volunteers willing to participate in clinical studies including the assessment of lipids, sex hormones, and other parameters. Subjects were all interested in obtaining results and received reimbursement for transportation. The studies were approved by the Ethics Committee of the university and the State Medical Board, Münster, Germany. All volunteers gave written informed consent.
After exclusion of previous androgen use, diabetes mellitus, arterial hypertension, dyslipoproteinemia, medication of any kind, drug abuse, and a possible state of androgen deficiency (total serum T, <12 nmol/liter; alcohol intake, >40 g/d; renal or hepatic illness by history, physical examination, and serum/blood analysis), 113 men were eligible to participate (8 men were excluded for taking medication for arterial hypertension, 3 for use of cholesterol-lowering drugs, 2 for extensive alcohol consumption, 1 for previously diagnosed and treated diabetes mellitus type 1). No exclusion was necessary because of abnormal laboratory findings or a physical examination revealing pathological entities of any kind. All examinations and blood sampling, in patients and controls, were done between 0800 and 1100 h after an overnight fast including abstinence from caffeine-based drinks for 12 h. Other results of these cross-sectional studies in healthy men have been previously published (25, 30, 31).
From these 113 men, a group of 20 nonsmoking controls matching the group of hypogonadal men in regard to age (25–69 yr; mean, 37.8 ± 11.7 SD years), LDL-C levels, body height, and BDA was selected for repeated measurements. Remeasurement was performed after 3 months. Tables 1
and 2 show data of patients and controls.
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Measurement of vascular reactivity
Doppler ultrasound was used to assess the vascular reactivity of the brachial artery. Endothelium-dependent FMD was induced by hyperemia, which triggers the release of nitric oxide from endothelial cells (32). For the assessment of endothelium-independent vasodilatation, the endothelium was bypassed by the exogenous application of glycerol trinitrate (GTN) (33). This method of assessing endothelial functions noninvasively was previously validated in studies of atherosclerosis (11, 12, 34) and is suitable for detecting the influence of androgens on the vascular endothelium (18, 20).
Before the start of the examination, the subjects rested in a room with a temperature of 20–24 C for 10–15 min. Subjects were investigated in a supine position. A high-resolution ultrasonography 7.5 MHz linear-phased array ultrasound transducer (Ultrasound Scanner type 2002 ADI; B-K Medical, Gentofte, Denmark) was used to image the dominant arm brachial artery longitudinally just above the antecubital fossa. The artery was identified by a pulsed Doppler signal at a 70-degree angle to the vessel with the range gate (1.5 mm) in the center of the artery. Additionally, color-coded duplex sonography was used. B-mode ultrasound images were used for measurements, the transmit zone was set to the depth of the near wall, and gain settings were not changed during the study. Digitalized motion sequences were saved for analysis. Arterial diameter was assessed over a 1-cm straight segment by measuring the distance from the anterior to the posterior wall (m-line, the interface between media and adventitia) at maximal resolution using the implemented software for distance measurements. After baseline images were obtained, a blood pressure cuff was placed over the ipsilateral upper arm just above the transducer, inflated for 4 min at 180 mm Hg, and then suddenly deflated. Images of the flow-mediated dilator response were obtained 1 min after cuff release (maximal arterial dilatation). The brachial artery diameter was then allowed to return to normal (8 min). New baseline images were recorded, and then 0.4 mg sublingual GTN was administered. Images from endothelial-independent vasodilation were obtained 3 min after application.
The vessel diameter was assessed during maximal and minimal blood flow as indicated by the color-coded pulse wave of three cardiac cycles at each time point, and respective values were then averaged. This method captures the pulse-dependent maximum and minimum changes in vessel diameter. Body size (and, hence, distance from the aortic valve to the location of diameter assessment) does not influence the results as might be the case in electrocardiogram-triggered measurements. Flow-mediated and GTN-induced vasodilatation was calculated as the percent change in diameter, compared with baseline. All scans were performed by one investigator. Measurements were performed without knowledge of sex hormone levels. The procedures are in agreement with the guidelines for ultrasound assessment of endothelial-dependent FMD (26). Respective intraobserver variability for repeated measurements of the vessel diameter is 1.6%. When reactive hyperemia studies are performed on two separate days, the intraobserver coefficient of variation (CV) for FMD is 2.6% (based on 19 subjects).
Assessment of hormones
Serum T levels were measured with a commercial ELISA kit (DRG Instruments GmbH, Marburg, Germany) and serum levels of LH, FSH, prolactin, prostate-specific antigen, SHBG, and estradiol were measured with highly specific time-resolved fluoroimmunoassay (Autodelfia, Freiburg, Germany). Mean intraassay CV were less than 5%, and mean interassay CV less than 10%. Levels of free T were calculated from levels of SHBG and total serum T according to the law of mass action, using 3.6 x 104 liters/mol as the association constant of T with albumin and 1 x 109 liters/mol with SHBG. This method yields highly reliable values of free T levels (35). Levels of GH and IGF-I were assessed on an Advantage analyzer (chemoluminescent method; Nichols Institute, Bad Nauheim, Germany).
Assessment of lipids
A 917 autoanalyzer (Hitachi/Roche Diagnostics, Mannheim, Germany) was used for the quantification of serum concentrations of triglycerides and cholesterol with enzymatic tests, HDL-C with a homogenous assay, and apolipoprotein A-I with and lipoprotein (a) with (latex-enhanced) turbidimetric immunoassays (Hitachi/Roche Diagnostics). Imprecision was less than 5%. LDL-C was calculated using the formula of Friedewald et al. (36).
Statistics
All variables were checked for normal distribution by the Kolmogorov-Smirnov one-sample test for goodness of fit within each group for baseline data applying the calculated level of significance according to Lilliefors. When necessary, analysis was performed on logarithmically transformed data (data marked with #). Although FMD and GTN values were normally distributed, unequal variances occurred between groups, and arcsin transformation (because these were percentage data) was performed. All data are presented as mean ± SD.
Evaluation of baseline data
Pearson’s correlation coefficient was calculated for the putative association among the BDA, FMD, and GTN-induced dilatation for patients and controls. The matching criteria age, BDA, and height were compared among patients and controls as well as between treatment groups by analysis of covariance (ANCOVA) including covariates (BMI, age). Baseline functions of vascular reactivity were analyzed by ANCOVA including age, height, and baseline values for LDL-C and BDA as covariates. Serum levels of sex hormones and SHBG were compared among respective groups using multivariate analysis including total T, free T, SHBG, and estradiol as dependent variables and using age and BMI as covariates [multivariate ANCOVA (MANCOVA)]. Comparison of lipids (total cholesterol, its subfractions, and triglycerides) was performed accordingly.
Evaluation of repeated measurements
Putative treatment effects on vascular functions were analyzed by ANCOVA for repeated measurements including the control group. Treatment status (substitution or no substitution) was defined as intersubject factor. Age, body height, and BDA as well as changes in BDA between the two assessments, LDL-C levels, and baseline T concentrations were used as covariates. Changes in sex hormones and SHBG were assessed by MANCOVA for repeated measurements (age and BMI were used as covariates). Changes in lipid parameters were analyzed accordingly. Subgroups of patients were not separately compared with the matched control group, but treatment modality was used as intersubject variable in respective analyses.
Because of previous results (7) and because it is largely hormone receptor mediated, the relationship between T levels and vascular functions can be assumed to be nonlinear. Because pooling hypogonadal and eugonadal men for regression analysis is statistically questionable, especially in the light of unequal variance of FMD among the groups, we chose a multiple linear regression model involving the large control group and the patients using a group indicator variable and correcting for log age, log LDL-C, body height, and smoking status to determine the putative association between total T levels and FMD. Variance of FMD was positively dependent on T levels; therefore, a correspondingly weighted model was used: The weight was 1/FMD-0.5 x T. This weight was obtained by using the respective function of SPSS, Inc. (Chicago, IL). For this analysis, FMD values were not arcsin transformed. The linear model followed the general equation: FMD = ß0 + ß1 x group + ß2 x T + ß3 x group x T (group = 0, controls; group = 1, hypogonadal men). Significance of ß2 would then show an association of T and FMD in the eugonadal group alone, and significance of slope ß2 + ß3 would reflect the same for the hypogonadal group. Significance of intercept ß1 and slope ß3 would then demonstrate a differential association of T and FMD among the groups.
Computations were performed using the statistical software package SPSS (SPSS, Inc., release 10.0.1.).
Results
All anthroprometrical data, baseline values, and parameters assessed after 3 months are shown in Tables 1
and 2 together with levels of significance. In patients with secondary hypogonadism, levels of GH and IGF-I were found within the normal range (0.1–2.1 ng/ml and 72–207 ng/ml, respectively). Blood pressure levels were not significantly different between patients and controls and did not change during treatment (Table 1). Neither systolic nor diastolic blood pressure was associated with FMD or GTN-induced dilatation. The BDA showed a significant negative correlation with FMD (r = -0.48, P = 0.003) and endothelium-independent GTN-induced dilatation (r = -0.48, P = 0.003, correlations for patient group, similar results in controls). Therefore, it was introduced as a covariate in all further analyses. BDA as confounder of FMD did not change significantly during treatment (Table 2, ANCOVA for repeated measurements using age as covariate, P = 0.21), but the marginal fluctuations were used as covariate in respective analyses, nevertheless. The patient groups treated with TE and hCG did not differ in any baseline or posttreatment parameter nor did patients with primary or secondary hypogonadism. Matching criteria between patients and controls were not different, but weight and BMI were significantly higher in hypogonadal men (Table 1). Baseline weight or BMI was not associated with FMD (patients, r = -0.03 and r = -0.1; both not significant, similar results for controls and GTN-induced vasodilatation) and did not change significantly during the trial (Table 1). Baseline sex hormone levels in patients were significantly lower than in controls (MANCOVA, see Table 2).
Analysis of baseline vascular functions
ANCOVA revealed baseline FMD to be significantly higher in hypogonadal men (P < 0.001) than in controls (Table 2 and Figs. 1 and 2). Significant negative confounders of initial FMD were BDA (P = 0.001) and, as a trend, age (P = 0.06), body height (P = 0.05), and LDL-C (P = 0.07). The default vascular dilatory response to GTN was slightly higher in patients than in controls (P = 0.03, Table 2). BDA was the only significant confounder of baseline values of GTN-induced vasodilatation (negative association, P < 0.001).
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Analysis of treatment effects
After 3 months of therapy, levels of total T in all hypogonadal men had increased to levels within the normal range (Table 2). MANCOVA for repeated measurements revealed the increment to be highly significant for both total T and free T (both P < 0.001) and for estradiol (P = 0.004), but SHBG concentrations did not change (P = 0.97). Levels of total T, free T, and estradiol in treated hypogonadal men were no longer different from eugonadal controls (MANCOVA controlling for age and BMI).
A highly significant decrease of FMD of the brachial artery was seen in the treated hypogonadal men in comparison to controls (Table 2, Fig. 2, ANCOVA for repeated measurements, P < 0.001). The statistical model included putative confounders: Higher baseline BDA, baseline LDL-C, and age contributed significantly to the decrement (P = 0.006, P = 0.01, and P = 0.04, respectively). The nonsignificant fluctuations of BDA during treatment were included in this model and showed a trend in influencing the result (P = 0.07). The amount of increase in levels of total T or free T did not influence the effect (P = 0.7, P = 0.6). FMD of substituted hypogonadal men showed even slightly but significantly lower values than controls (Table 2 and Fig. 2, ANCOVA, P = 0.04; covariates are age, height, BDA, and LDL-C). Treatment effects on FMD were not different between primarily and secondarily hypogonadal patients or TE- and hCG-treated men (Table 2, ANCOVA for repeated measurements, P = 0.71 and P = 0.31, respectively).
Endothelium-independent GTN-induced vasodilatation was not significantly influenced by treatment (Table 2, ANCOVA for repeated measurements, P = 0.45). Likewise, no difference for this parameter was seen among the above-mentioned subgroups of patients during treatment.
Concentrations of total cholesterol and triglycerides decreased with marginal significance during treatment (Table 2, MANCOVA for repeated measurement, P = 0.03 and P = 0.05, respectively). Age was a significant confounder of this result (P = 0.001). These changes were not reflected by significant fluctuations of cholesterol subfractions (albeit HDL-C levels decreased during T substitution, this was not significant because of unidirectional changes in the control group, see Table 2).
Discussion
This study provides novel information on three different aspects of T influence on vascular functions: 1) endothelium-dependent FMD is elevated in hypogonadal men in comparison to eugonadal controls; 2) the association of endothelial functions with T is different between hypogonadal and eugonadal men; and 3) therapeutic elevation of T levels in hypogonadal men decreases endothelium-mediated vascular reactivity into the range of eugonadal men.
Higher FMD in a hypogonadal state in comparison with eugonadal T levels has been described before in men with artificially lowered T concentrations (prostate cancer patients) (18). Animal models using androgen receptor blockade could confirm such observations as well (37). Here we report corroborating results in men with inherent hypogonadism, who are those patients likely to receive substitution therapy. The hypotheses are that T might enhance apoptosis-related damage in human vascular endothelial cells (38) and androgen exposure increases human monocyte adhesion to vascular endothelium and induces shedding of vascular cell adhesion molecules from damaged endothelium (17). In combination with environmental tobacco smoke and high LDL-C levels, T had a synergistically detrimental effect on endothelial functions of cultured rabbit aorta (39). In contrast, T has been demonstrated to relax canine coronary arteries by initiating nitric oxide release (40).
Androgen receptors have been localized in endothelial and vascular smooth muscle cells (14, 15, 16). We have previously shown that within the eugonadal range, androgenic effects on FMD are modulated by the CAG repeat androgen receptor polymorphism and, only to a very marginal extent, by T concentrations themselves (25). These results are corroborated by findings in testicular-feminized rats with defect androgen receptors (41). In an androgen-deprived state, a different picture emerges as only a fraction of available androgen receptors can be activated. The differential association of T and FMD depending on the range of T levels described here is in good agreement with the understanding of hormone receptor-mediated effects: after a saturation level is reached, other factors and receptor polymorphisms gain significance. Such has been observed for other androgen effects as well (7). In the case of T influence on vascular endothelium, no significant association with FMD is seen within the eugonadal range, but FMD decreases significantly with increasing T levels in the hypogonadal range. It has to be considered that these results were obtained from a cross-sectional analysis of baseline data. This may not reflect within-patient effects of alterations of T levels. Nevertheless, the results reported here suggest a plateau effect of T on vascular endothelium and one might assume, although with a mathematical demur, that this is one reason studies examining normally dosed androgen treatment in healthy men with normal or low normal T levels could not demonstrate any change in FMD (24, 42). During the trial reported here, treatment caused androgen levels to increase into the normal range in all subjects; the extent of increased T concentrations did not influence the effect on vascular endothelial functions. In support of our findings, a Cochrane database metaanalysis on T treatment for lower limb atherosclerosis shows that there is no effect of short-term T treatment in subjects with this disorder (43).
Elevation of T levels in hypogonadal men, whether endogenously by Leydig cell stimulation or exogenously by injection of TE, caused endothelium-dependent vasoreactivity to decrease into the range of eugonadal men. The observed decrement in FMD is in agreement with some studies in women receiving T treatment (44, 45). However, postmenopausal women on hormone replacement therapy seemed to profit from additional T medication in regard to vascular functions (46). There are also reports on positive effects of T on vascular functions in patients with CVD. These reports involve acute effects of iv T. Thereby, levels of about the 20-fold of the upper normal limit were achieved (20, 21, 22). One study arm in these assessments included lower-dosed iv T; no effect could be observed in the respective subjects with T levels remaining within the normal range (20), which is in agreement with the above-mentioned plateau effect. The results involving high-dosed iv T are not consistent because a similar approach could not demonstrate any effect on myocardial perfusion (23).
Notwithstanding, high-dose T effects lead to another aspect of androgen influence on vascular functions: endothelium-independent vasodilation. This seems to directly involve smooth muscle cells in which ATP-sensitive calcium-activated potassium channels are susceptible to T influence (40, 47). Androgens may have dilatory effects in this case (48). We did not see major effects of T levels or their alterations in endothelium-independent GTN-induced vasodilatation.
Vascular effects induced by T could be partly mediated via local aromatization to estradiol, but although aromatase has been identified in vascular smooth muscle cells, it could not be demonstrated in endothelial cells (49). Furthermore, T effects could not be blocked by estrogen antagonists in previous studies (40). Additionally, estrogen seems to exert positive effects on the endothelium, not only in postmenopausal women receiving hormone replacement therapy (50), but also in healthy men (42). Thus, the decrement in vascular reactivity induced by therapeutical elevation of androgen levels is unlikely to be attributable to estrogen activity.
The clinical relevance of these findings has to be judged from the general perspective of other known effects of T on cardiovascular risk factors. In men, the influence of androgens on body composition and insulin resistance and modulation of factors involved in clotting and fibrinolysis have to be considered beneficial. The decreasing effect of androgen substitution on HDL-C has, at least theoretically (8), to be regarded as adverse, although clinical evidence is lacking. As demonstrated in this trial, the endothelial function in hypogonadal men is reduced to normal by elevation of T levels. It is debatable whether the initially increased FMD is of any advantage over normal values or the decrement into the range of eugonadal men is adverse. For the time being, our results strongly support the demand for intense monitoring and/or elimination of other factors exerting negative influence on endothelial functions, such as elevated LDL-C (25, 51) and glucose levels (52) and cigarette smoking (34) during treatment of hypogonadal men. We do not consider the results a significant argument to refrain from androgen substitution in hypogonadal patients, especially taking further beneficial effects into account, such as improvement of psychological and sexual functions, restored hematopoiesis, and elevation of bone density.
Acknowledgments
We thank Susan Nieschlag, M.A., for language editing.
Footnotes
Abbreviations: ANCOVA, Analysis of covariance; BDA, baseline diameter of the artery; BMI, body mass index; CV, coefficient of variation; CVD, cardiovascular disease; FMD, flow-mediated vasodilatation; GTN, glycerol trinitrate; hCG, human chorion gonadotropin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MANCOVA, multivariate ANCOVA; T, testosterone; TE, testosterone enanthate.
Received March 31, 2002.
Accepted August 5, 2002.
References
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, Baseline values, with SD; 
, reassessment after 3 months, with SD. The negative influence of age and LDL-C levels on the T-induced decrement of FMD is indicated by the arrow (also see Results).