The aging male: testosterone deficiency and testosterone replacement. An up-date

Atherosclerosis 173 (2004) 157–169

Review

The aging male: testosterone deficiency and testosterone replacement. An up-date Peter Alexandersen∗ , Claus Christiansen CCBR, Ballerup Byvej 222, DK-2750 Ballerup, Denmark Received 5 November 2002; received in revised form 14 March 2003; accepted 21 May 2003

Abstract The significance of the age-related decline of androgens remains unclear in terms of cardiovascular risk, mood and cognition, and prostatic health. Although much research has been undertaken in this area and men’s health has received still more attention in the latest years, there are no data based on randomized controlled clinical studies in aging men investigating the long-term effects of androgen replacement therapy on various aspects of the cardiovascular system, the immune system, body composition, and the brain. In men receiving long-term androgen replacement therapy, the safety aspects regarding the prostate are also an area of clinical importance. In this paper we present an up-dated review of the experimental and clinical evidence of androgen deficiency and androgen replacement therapy on carbohydrate metabolism, on coagulation and fibrinolysis, inflammatory effects, effects on lipoprotein metabolism, direct arterial effects, effects on body composition, effects on cognitive function and mood, and prostatic effects. The evidence clearly shows that data for the most part are conflicting, with only very few randomized studies available. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Men; Androgens; Cardiovascular risk factors; Prostate; Brain; Review

1. Introduction With age healthy men experience a physiological but important decline in the plasma concentrations of bioactive androgens, although not as abrupt as described for the estrogen levels in women around menopause. This age-related decline in androgens is caused mainly by age-related impairment of testicular production and secretion of testosterone, but probably also through the aging hypothalamus that pulses more slowly with less luteinizing hormone-releasing hormone (LHRH) production. The precise role of androgens in the aging process of men remains unclear and controlled clinical studies in aging men investigating the effects of androgen replacement therapy on various organs and human functions known to deteriorate with age are few (except for studies on muscle and bone). These organs and functions include the mind, the cardiovascular system, the immune system, and the composition of body fat. In addition, the effect of androgen replacement therapy on the prostate is very important in terms of its safety in the ageing male.

∗

Corresponding author. Tel.: +45-44-68-4600; fax: +45-44-68-4220. E-mail address: [email protected] (P. Alexandersen).

Currently, the question of a male menopause (or andropause), by some termed the androgen deficiency of the aging male syndrome (ADAM), is a matter of intense debate [1]. The debate can be summarized into the following questions: Are symptoms like tiredness, decrease in muscle strength, lack of energy, decreased libido, insomnia, and cardiovascular symptoms in middle-aged men causally linked to the decrease in circulating levels of androgens (primarily testosterone and dehydroepiandrosterone sulfate) or are they merely a set of unrelated symptoms which have nothing to do with the changes in these sex hormone levels? Could androgen replacement have a beneficial influence on these organs and functions in the aging male? And finally, how safe are androgens in the aging male? These questions have huge clinical implications because populations in most industrialized and developing countries are older today than previously and because the number of elderly people is increasing at a fast rate. In this paper we review the evidence of androgen deficiency and androgen replacement therapy based on available experimental, clinical (epidemiological and cross-sectional) and clinical intervention data, based on published studies in English available at the PubMed (National Center of Biotehnology Information at the National Library of

0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0021-9150(03)00242-9

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Medicine, USA) with cross-reference to book chapters, particularly for older works. We will focus on metabolic effects of androgens upon tissues and metabolic systems believed to be implicated in the development of cardiovascular disease and other age-related changes in the aging male. This includes androgen effects on carbohydrate metabolism, on coagulation and fibrinolysis, inflammatory effects, effects on lipoprotein metabolism, direct arterial effects, effects on body composition, effects on the brain in terms of cognitive function and mood, and prostatic effects. Evidence of serum androgen levels in relation to CHD in men have been discussed elsewhere (see ref. [2] for review), and a recent study supported a large body of evidence that low circulating levels of total or free testosterone is associated with CHD in ageing men [3].

2. Effects on the carbohydrate metabolism Impaired glucose tolerance and abnormal insulin metabolism are important in the development of coronary heart disease (CHD). Few experimental studies have studied the effect on androgen replacement on insulin and glucose metabolism. A study in castrated male rats demonstrated that physiological doses of testosterone significantly improve insulin sensitivity to normal range whereas high doses of the hormone negate this beneficial effect [4]. Recent data also indicate that dehydroepiandrosterone (DHEA) treatment increases insulin sensitivity in old male rats [5]. In one intervention study on insulin sensitivity in healthy men, intramuscular injection of pharmacological doses of testosterone did not affect insulin sensitivity [6]. Other data have indicated that testosterone replacement increases insulin sensitivity [7,8]. For androgens, the route of administration is of great importance in terms of the biological effect obtained and this becomes clinically relevant since these hormones may be given either orally, transdermally, or intramuscularly. Estradiol (given either orally or transdermally) has been convincingly shown to improve insulin sensitivity in postmenopausal women [9]. Whether aromatization of testosterone in this respect is pivotal in men is not known. Hence, a number of cross-sectional studies have found a negative correlation between serum testosterone (total testosterone) and plasma insulin concentrations [10–14]. In one study, direct measures of insulin resistance using a hyperinsulinemic euglycemic clamp in obese men with non-insulin dependent diabetes mellitus (NIDDM) was used to study sex hormone and sex hormone-binding globulin (SHBG) concentrations [15]. The authors found a positive and strong correlation between insulin sensitivity and low SHBG levels (r = 0.74, P < 0.001), but not between SHBG concentrations and free testosterone concentrations (nor estradiol or free testosterone/estradiol ratio) [15]. Others have gone further and proposed that low SHBG levels and low testosterone concentrations may be markers of increased insulin resistance [16]. However, there are

data to suggest that both low testosterone and SHBG concentrations significantly increase the incidence of NIDDM in men [17]. In a recent prospective study of middle-aged and elderly men and postmenopausal women (not taking any estrogen-progestin replacement therapy) and followed for 8 years, age-adjusted correlation analyses showed that baseline total testosterone was inversely and significantly related to subsequent levels of fasting and postchallenge glucose and insulin in men (after oral glucose tolerance test), whereas baseline bioavailable testosterone and bioavailable estradiol were positively and significantly related to fasting and postchallenge glucose and insulin in women (all P < 0.05) [18]. It is therefore possible that testosterone replacement in men with low testosterone concentrations may prevent development of NIDDM. Nevertheless, it still remains unclear whether there are true causal relationships between low testosterone concentration and SHBG, and the development of NIDDM, or whether these are merely due to interrelated confounding factors. A single study on DHEA found that low levels of this steroid in diabetic men [19]. Table 1 summarizes the studies on androgens and carbohydrate metabolism.

3. Effects on body composition and fat distribution The issue of testosterone in relation to male body composition is closely linked to carbohydrate metabolism and the development of NIDDM. In studies where body composition (and particularly body fat) has been determined in relation to sex hormone concentrations in men, testosterone (or free testosterone) concentrations correlate significantly and inversely with measures of visceral fat accumulation (r = −0.21 to −0.26, P < 0.01) [10,20–23]. Testosterone replacement has also been shown to reduce fat tissue mass in hypogonadal and eugonadal men by 5–15%, depending on doses, duration of treatment, testosterone esters used, and route of administration [7–8,24–27], and even that long-term testosterone replacement also improves the lean/fat mass ratio in middle-aged men, partly by inhibition of lipoprotein lipase. However, the clinical data available are not unequivocal. For example, a placebo-controlled clinical study in middle-aged obese men found a neutral effect of testosterone on lean tissue mass after eight months of treatment and divergent effects on fat tissue mass depending on the region measured (visceral fat tissue mass decreased whereas subcutaneous fat tissue mass remained unchanged) [7–8,26]. A neutral effect of the weak adrenal androgen DHEA on lean tissue mass and fat tissue mass has been reported in the few clinical studies that have investigated this issue [28–30], similar to what is found in experimental studies [31]. Lean tissue mass and in particular muscular tissue, muscle size and strength usually increase significantly upon testosterone replacement in hypogonadal men (up to 15–20% depending on testosterone dose, duration of treatment, esters used,

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159

Table 1 Studies on androgens and carbohydrate metabolism Studies

Author and year

Findings

Experimental Clinical

Holmäng & Björntorp 1992, Mukasa et al. 1998 Seidell et al. 1990, Pasquali et al. 1991, Simon et al. 1992, Phillips 1993, Haffner et al. 1994a and 1996 Yamaguchi et al. 1998 Birkeland et al. 1993 Friedl et al. 1989 Marin et al. 1995 and 1996

TRT or DHEA RT →insulin sensitivity ↑ S-T↑ → insulin ↓

Clinical, intervention

S-DHEA ↓ → insulin ↑ S-T ↑ → insulin sensitivity ↑ TRT → insulin sensitivity ↔ TRT → insulin sensitivity ↑

S-T, serum testosterone; S-DHEA, serum dehydroepiandrosterone; S-X ↑ → Y ↓, serum X is inversely associated with Y; S-X ↑ → Y ↔, serum X is not associated with Y; TRT →, testosterone replacement therapy results in . . . DHEA RT→, dehydroepiandrosterone replacement therapy results in . . . ↑, increase in; ↓ decrease in; ↔ no change in. Table 2 Studies on androgens and body composition Studies

Author and year

Findings

Experimental

Alexandersen et al. 2001

Clinical

Seidell et al. 1990, Khaw and Barrett-Connor 1992, Zmuda et al. 1997, Tsai et al. 2000 Rebuff´e-Scrive et al. 1991, Marin et al. 1992, 1995 and 1996, Haffner et al. 1993a, Young et al. 1993, Katznelson et al. 1996, Wang et al. 1996a and 2000 Brodsky et al. 1996, Bhasin et al. 1996 and 1997, Wang et al. 2000, Ly et al. 2001 Vogiatzi et al. 1996, Flynn et al. 1999 Morales et al. 1998

TRT→→ fat tissue mass ↓ DHEA RT → lean and fat tissue mass ↔ S-T ↓ → fat tissue mass ↑

Clinical, intervention

TRT → fat tissue mass ↓ TRT → lean tissue mass ↑, muscle strength ↑ DHEA RT → lean and fat tissue mass ↔ DHEA RT → fat tissue mass ↓

Symbols as in Table 1.

and route of administration) [32–37]. The mechanism of action of androgens on body composition remains largely unknown. Some data suggest that natural androgens, i.e. testosterone and DHEA, may exert their actions trough binding to the androgen receptor (AR) (both testosterone and DHEA bind to the AR), which is present in skeletal muscle and sensitive to androgen replacement [38–39]. Table 2 summarizes the studies on androgens and body composition.

4. Effects on coagulation and fibrinolysis It is well established that the plasma clotting factors fibrinogen and factor VII are major independent risk factors of CHD in men [40]. In addition, decreased fibrinolysis and increased activity of plasminogen activator inhibitor 1 (PAI-1) are also shown to be risk factors of CHD. Evidence suggests that the endogenous sex hormone milieu may affect the concentrations of these clotting factors involved in the coagulation/fibrinolysis balance and thus the risk of atherothrombogenesis [41]. Experimental data have suggested enhanced aggregation of platelets in mesenteric arterioles of testosterone-treated males mice [42]. However, a cross-sectional study in non-obese and obese middle-aged men found that PAI-1 correlated significantly and negatively with total testosterone levels (r = −0.49, P < 0.01), but positively with the estradiol/testosterone ratio and with

the free testosterone/total testosterone ratio (r = 0.43 and r = 0.46, respectively, P < 0.01 for both) [43]. The authors concluded that PAI-1, factor VII, and fibrinogen are related to other risk factors of CHD and that changes in the sex hormone milieu could be the underlying factor linking them together. Thus, if true, low testosterone concentrations in men would increase the activity of PAI-1, factor VII and fibrinogen and in turn could predispose to atherothrombolic events mediated by an enhancement of fibrinolytic inhibition. Cross-sectional [44–45] have yielded similar results. However, as pointed out by Winkler [46] data on the effects of androgens on hemostasis and fibrinolysis are limited and probably often confounded due to interference with other sex steroids. Recent evidence from intervention studies also supports a beneficial role of testosterone on fibrinolysis. Anderson et al. showed that testosterone replacement in healthy men decreased plasma fibrinogen levels significantly by 16% (P < 0.01) [47], a decrease also demonstrated more than 40 years ago by Fearnley & Chakrabarti [48]. In addition, it has been suggested that testosterone augments the fibrinolytic system and antithrombin III activity and prevents the clotting system by increasing thromboxane A2 receptor activity and platelet aggregability [49]. Some clinical observations support that androgen replacement in men reduce PAI-1 activity (reduction of the fibrinolytic inhibition) and lipoprotein a (Lp(a)), both of which are considered favorable in terms of CHD risk. A simultaneous change in the insulin/insulin-like growth factor 1 (IGF-1) system may

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Table 3 Studies on androgens and hemostasis

Table 4 Studies on androgens and inflammation

Studies

Author and year

Findings

Studies

Author and year

Findings

Experimental Clinical

Rosenblum et al. 1987 Caron et al. 1989, Yang et al. 1993, Glueck et al. 1993, De Pergola et al. 1997 Fearnley and Chakrabarti 1962, Anderson et al. 1995

TRT → fibrinolysis ↓ S-T↓ → fibrinolysis ↑

Experimental

McCrohon et al.1999 and 2000 Keller et al. 1996, Mukherjee et al. 2002 Straub et al. 1998 Ng et al. 2002

TRT → inflammation ↑

Clinical, intervention

TRT → fibrinolysis ↑

Clinical Clinical, intervention

TRT → inflammation ↓ S-DHEA ↓ → inflammation ↑ TRT → inflammation ↔

Symbols as in Table 1.

Symbols as in Table 1.

however somewhat counteract the beneficial effects [46]. Nevertheless, real evidence of a cause-effect relationship between degree of activation of fibrinolysis/coagulation and CHD can only be come from randomized studies demonstrating that androgen-mediated changes in markers of fibrinolysis/coagulation reflect in a significant reduction in clinical manifestations of CHD. Table 3 summarizes the studies on androgens and coagulation/fribrinolysis.

5. Effects on inflammation Inflammation plays a crucial role in atherogenesis [50]. Experimental studies investigating the effect of dehydroepiandrosterone and testosterone on inflammation have yielded divergent results [51–54]. Some evidence of androgen regulation of the inflammatory response comes from observations that testosterone (among other factors, including also estrogen) down-regulates the cytokine interleukin 6 (IL-6), a potent stimulator of inflammation [55] and increasing plasma concentrations of IL-6 have been demonstrated in women after menopause and in aging men, also in the absence of infection. There seems however to be an inhibitory feedback mechanism present at the adrenal gland level, since IL-6 in turn stimulates androgen secretion [56]. C-reactive protein (CRP), a prototypic acute phase reactant and probably an important defense protein during inflammation, also seems to be partly regulated by androgens. Thus, studies in transgenic mice infected with Streptococcus pneumoniae have revealed a testosterone-dependent expression of CRP [57]. Some in vitrodata however suggest that exposure of human umbilical vein endothelial cells to dihydrotestosterone (that cannot be metabolized further into estrogens by aromatase) increases monocyte adhesion as well as endothelial cell expression of the vascular cell adhesion molecule-1 (VCAM-1), both of which are considered proatherogenic events [52]. In contrast, an elegant study by Mukherjee and co-workers recently showed that testosterone attenuates the expression of VCAM-1 by conversion of testosterone to estrogen [54]. There are some few data indicating that the AR expression is higher in macrophages from men than from women that may contribute to the greater foam cell formation and hence predisposition to atherosclerosis in men

than in women [53]. A recent prospective study in healthy middle-aged men found no change in CRP, VCAM-1, or inter cellular adhesion molecule 1 (ICAM-1) following treatment with dihydrotestosterone for 3 months [58]. A recent uncontrolled study in transsexual males-to-females treated with estrogens and antiandrogens and females-to-males treated with androgens found that estrogens combined with antiandrogens in males-to-females may affect the immune system by decreasing the number of natural killer cells significantly and slightly inhibiting a shift towards a T helper type 1 lymphocyte (TH1) profile of peripheral blood, whereas androgens in females-to-males stimulated a shift towards a TH1 profile [59]. Regarding DHEA, a single study found that serum levels correlated negatively with IL-6 [60]. Androgens may play a role in modulating the inflammatory response to cytokines and CPR. Again, ultimate evidence of a beneficial effect of androgens in terms of CHD would come from randomized studies in aging men with CVD demonstrating that the androgen-mediated decrease in these markers results in a reduction in CHD. Table 4 summarizes the studies on androgens and inflammation.

6. Effects on lipoprotein metabolism Data on androgenic effects on serum lipid and lipoprotein metabolism in men are not unequivocal. Several clinical studies of endogenous testosterone concentrations have shown a positive correlation to HDL-C concentrations in most men [61–66], whereas other early studies have not [67–68]. The discrepancy may in part be due to a concomitant alteration in insulin sensitivity that may be an important confounding factor. Furthermore, enzymes involved in the metabolism of high-density lipoprotein cholesterol (HDL-C) and triglycerides seem to be sensitive to sex hormones, since gender differences are known in relation to lipoprotein lipase (higher activity in women than in men) and hepatic triglyceride lipase (higher in men than in women) [69]. However, as argued by Friedl and co-workers, aromatisation of testosterone into 17␤-estradiol may also be of importance in this respect since administration of non-aromatizable androgens results in an increase in hepatic triglyceride lipase

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161

Fig. 1. It shows changes in serum total cholesterol (top panel), low-density lipoprotein (LDL) cholesterol (second panel from top), high-density lipoprotein (HDL) cholesterol (second panel from bottom) and serum triglycerides (bottom panel) in elderly men before and during three months of treatment with either ditestosterone gel (70 mg/day) (solid circles) or placebo gel (open circles) and during one month of follow-up. Values are mean ± SEM. Asterisks indicate statistically significant difference from placebo (P < 0.05). Printed with permission from the author and the copyright owner, the Endocrine Society [37].

and a simultaneous decrease in HDL-C, whereas testosterone administration does not alter HDL-C levels [70]. An elegant study by Bagatell and co-workers provided evidence that suppressing endogenous estradiol concentrations in men may in a significant decrease in HDL-C, particularly, in the HDL2 subfraction, whereas the low-density lipoprotein cholesterol (LDL-C) and triglycerides are not affected [71]. With regard to LDL particle size in men, few data are available. Indirect evidence comes from observations that in most populations, women having lower triglyceride concentrations than men of similar age, which may in part explain the difference in LDL particle size, of which small dense LDL particles are considered to be atherogenic [72]. Endogenous total testosterone concentrations correlated significantly and inversely to serum total cholesterol and LDL-C levels (r = −0.17, and r = −0.15, respectively, P < 0.05) and positively to HDL-C levels (r = 0.17, P < 0.05) in a group of 178 non-diabetic men by Haffner’s group [65] and these results are in accordance with data reported by others [66]. Thus, these studies indicated a more atherogenic lipoprotein profile with decreasing testosterone concentrations. Data on androgens in relation to Lp(a) are also conflicting. A recent

controlled intervention study [73] found no association with androgens and Lp(a) in agreement with observational data [74], whereas another intervention (but uncontrolled) study reported a 25–59% decrease in Lp(a) in after testosterone administration in men with a Lp(a) concentration >25 nmol/l (P < 0.05), but no change in Lp(a) when the level was <25 nmol/l prior to testosterone administration [75]. Regarding exogenous androgens, two factors are crucial: the route of administration and whether the administration results in physiological or supraphysiological (i.e. pharmacological) concentrations. Oral testosterone (e.g. testosterone undecanoate) and transdermal testosterone result in high dihydrotestosterone concentrations (the active metabolite), also a non-aromatizable synthetic androgen (stanozolol) has been shown to significantly decrease HDL-C by as much as 50% (P < 0.01) [76]. The mechanism behind this HDL metabolism is due to a high degree of intestinal hydrolyzation after which free testosterone reaches the liver. Serum total cholesterol decreased almost 10% from baseline (P < 0.01) in a group of middle-aged obese men after 8 months of oral testosterone undecanoate treatment (resulting in physiological testosterone concentrations) [26].

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In that study, total fat mass and visceral fat mass were also significantly reduced by 5.5% (P < 0.05) and the glucose disappearance rate (during glucose clamp) significantly improved (P < 0.01). In an early randomized, 4-weeks study by Conway and colleagues, hypogonadal men were given a combination of testosterone esters (oral testosterone undecanoate, intramuscular testosterone enanthate, or subcutaneous testosterone pellets), serum total cholesterol did not significantly change in the intramuscular and subcutaneous groups (lipoprotein levels were not determined in this study). However, in the orally treated group, the authors observed a 6% (P = 0.005) and 50% (P < 0.0001) decline in total cholesterol and in SHBG, respectively [77]. Again the route of administration may be important. In the study by Friedl [70], HDL-C was not decreased by administration of an aromatizable androgen (testosterone enanthate), in contrast to what was found if the androgen was administered in the presence of an aromatase inhibitor. In an elegant study by Tenover, testosterone enanthate was given intramuscularly for 3 months to hypogonadal men [78]. Serum total cholesterol and LDL-C both decreased significantly (by approximately 11-12%, P < 0.05 for both) whereas HDL-C remained unchanged. Others have reported similar data [37,79,80] (Fig. 1). The use of testosterone replacement in hypogonadal men (to obtain physiological concentrations) is quite different from using testosterone (and other anabolics) in healthy men (where supraphysiological concentrations are achieved). This situation is similar in comparison of postmenopausal women using hormone replacement therapy (HRT) to that of premenopausal women using oral contraceptives. In a study of healthy men, administration of testosterone enanthate in high doses was found to decrease HDL-C and apolipoprotein A1 by 26 and 17% (P < 0.05 for both), increase serum total cholesterol by 12% (P < 0.05), but had a neutral effect on LDL-C and triglycerides. All lipid and lipoprotein changes normalized within 1 month after discontinuation of testosterone replacement [81]. Others have published similar results using other high doses of testosterone or synthetic anabolic steroids [82]. A recent randomized controlled study of transdermal testosterone or placebo for 3 years in middle-aged healthy men showed no net change in either total cholesterol, LDL-C, or Lp (a) [73]. The conflicting evidence for lipids and lipoproteins in relation to androgens in men may in part be explained by the confounding effect of sex hormone binding globulin (SHBG) as pointed out by Gyllenborg et al. [83]. Table 5 summarizes the studies on androgens and lipids/lipoproteins.

7. Direct arterial effects Accumulating evidence from experimental and clinical studies suggests a direct effect of androgens on the arterial wall, in line with what is known for estrogens [84,85]. Direct actions of testosterone on the arterial wall are probably im-

portant in relation to its antiatherogenic properties. Several clinical studies have investigated the acute effects of testosterone on ischemic symptoms in middle-aged men (angina pectoris) and found a favorable influence [86–88], probably through nongenomic mechanisms action on vasomotor regulation in view of the immediate effect obtained. However, as to what mechanism(s) of action that is working, data are sparse, but may be distinct for short-term (acute) as well as for long-term (chronic) androgen replacement therapy. Aromatisable androgens may exercise their influence on the cardiovascular system by conversion into estrogen by aromatase, which has been located in the arterial wall of human coronary arteries [89]. It remains unclear at present whether this enzymatic process takes place in the healthy or diseased male coronary arteries to an extent where it becomes biologically significant. A recent study in cholesterol-fed LDL receptor deficient male mice indicated that testosterone is able to attenuate early atherogenesis (by approximately 40%, P < 0.05 compared to untreated controls) by its conversion into estrogen by aromatase present in the vascular wall [90]. Estrogen causes vasodilatation in arteries with intact endothelium by production and secretion of nitric oxide (NO) [91] and this could explain the clinically significant effects observed by testosterone in men with angina [86,87]. Studies of cholesterol-fed male rabbits treated with long-term testosterone (>30 weeks) suggested that the AR in the arterial wall probably was not directly involved in the anti-atherogenic effect observed since the concentration of this receptor remained unchanged in testosterone and control animals [92]. Recently, a nice study by Hanke et al. found a 50% increase in the expression of AR in the arteries of rabbits treated with testosterone (P < 0.05) [93], and the few data available are thus conflicting on this matter. Nevertheless, it is possible that testosterone (as well as other androgens) may act directly on the arterial wall through a variety of other ways, for instance via the citric acid cycle by enhancing the enzymatic activity of dehydrogenase and possibly via activation of ATP-sensitive potassium channels causing vasodilator actions as observed in clinical studies [86,87,94]. Early uncontrolled reports suggested that testosterone therapy had a beneficial effect on angina pectoris in men [95,96]. These findings have since been documented in a well-conducted clinical randomized, placebo-controlled, and double blind study of low dose testosterone showing that treated men had significantly longer time to 1 mm of exercise-induced ST depression on ECG after 6 and 14 weeks of treatment compared to placebo [97] (Fig. 2). Similar data have been confirmed in other studies of testosterone treatment on exercise-induced ST-segment depression in men with angina pectoris [86,87,98]. Direct effects of testosterone on the male vasculature could thus account for these beneficial observations. These results have however been questioned by data obtained in male rabbits which have showed a vasoconstricting effect of physiological levels of testosterone [99]. Indeed, studies on animal vascular smooth muscle cells (VSMCs) and on vasomotor function

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Table 5 Studies on androgens and lipid metabolism Studies

Author and year

Findings

Clinical

Gutai et al. 1981, Dai et al. 1983, Duell and Bierman 1990, Khaw and Barrett-Connor 1991, Haffner et al. 1993b*, Ooi et al. 1996* Semmens et al. 1983, Stefanik et al. 1987 Friedl et al. 1990

S-T ↑→ HDL-C ↑ (and LDL-C ↓*)

Clinical, intervention

Haffner et al. 1983 Conway et al. 1988 Marin et al. 1992 Tenover 1992, Morley et al. 1993, Zgliczynski et al. 1996, Ly et al. 2001 Bagatell et al. 1992 Snyder et al. 2001

S-T ↑→ HDL-C ↓ TRT (arom.) T → HDL-C ↔ TRT (nonarom.) T → HDL-C ↓ TRT TRT TRT TRT

→ → → →

HDL-C Total C Total C Total C

↓ ↓/Total C ↔ ↓, HDL-C ↔ ↓, LDL-C ↓, and HDL-C ↔

TRT → Total C ↑, HDL-C ↓, and LDL-C ↔ TRT → Total C ↔, and LDL-C ↔

HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; Total C, total cholesterol; arom., aromatisable; nonarom., nonaromatisable. Symbols as in Table 1.

Fig. 2. It shows the time (in seconds) to 1 mm of exercise-induced ST depression in middle-aged men with stable angina pectoris treated with either testosterone patch (5 mg/day) (left panel) or placebo patch (right panel), at baseline (left bars), after 6 weeks (center bars), and 14 weeks (right bars) of treatment. ANCOVA P = 0.02 between groups after adjustment for baseline differences. Printed with permission from the author and the copyright owner, Lippincott Williams & Wilkins [97].

in vitro and in vivo have not yielded consistent results. For instance, some experimental studies thus have indicated that androgens inhibit proliferation and migration of VSMCs and afford vasodilation [100–103], whereas others have shown that androgens (and especially testosterone) cause vasoconstriction enhancing the risk of an atherothrombotic event [104]. These data are supported by further experimental studies showing effects of testosterone what may be potentially detrimental in terms of CHD [99,105–109], in direct contrast to other studies of testosterone on rabbit vascular rings [100]. These data are further supported by experimental studies clearly demonstrating a dilatory (i.e. beneficial) effect of physiological and supraphysiological (pharmacological) doses of testosterone on canine coronary arteries in vivo [101]. Whether differences in study design, methodology, and species can account for these apparently discrepancies and the fact that indeed some studies are done in both males and females [109] whereas others are done exclusively in male animals [101] remain unclear. As far as

DHEA is concerned, this hormone on the other hand seems to have properties that are favorable (i.e. antiatherogenic) on the male arterial system and cardiovascular risk factors [102,103,110,111]. Experimental studies in cholesterol-fed male rabbits treated with testosterone support a favorable, or at least a neutral, effect of androgens on the accumulation of cholesterol and plaque formation [92,112,113] and similar marked antiatherogenic influences are observed for DHEA [92,114–117]. In addition, with regard to stroke, few experimental data in male animals have suggested a neutral effect of testosterone [118] and cross-sectional data have indicated that compared to healthy men levels of serum total testosterone in male patients with ischemic stroke was significantly and inversely associated with infarction size (r = −0.32, P = 0.01) and severity (r = 0.34, P = 0.0001) and even with mortality 6 months later (P = 0.004) [119]. In conclusion, the effect of androgens on the arterial wall seems to be complex and probably depends on whether the endothelium is intact or whether the atherogenic pro-

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Table 6 Studies on androgens and direct vascular effects and experimental atherosclerosis studies, expressed in terms of presumed CHD risk Studies

Author and year

Findings

Experimental

Nakao et al. 1981, Masuda et al. 1991, Weyrich et al. 1992, Fujimoto et al. 1994, Schror et al. 1994, Farhat et al. 1995, Hutchington et al. 1997 Larsen et al. 1993 Gordon et al. 1988, Arad et al. 1989, Eich et al. 1993, Chou et al. 1996, Tanigushi et al. 1996, Bruck et al. 1997, Mohan and Beghuzzi 1997, Alexandersen et al. 1999, Yue et al. 1998, Furutama et al. 1998, Hayashi et al. 2000, Williams et al. 2002 Jaffe et al. 1977, Webb et al. 1999a and b, Rosano et al. 1999, English et al. 2000

TRT → CVD risk ↑

Clinical, intervention

TRT → CVD risk ↔ TRT and/or DHEA RT → CVD risk ↓

TRT → CVD risk ↓

CVD, cardiovascular disease. Symbols as in Table 1.

cess is already advanced when the androgen is administered. Data on the direct effect are not consistent for testosterone although to a greater extent for DHEA. Studies of androgen administration (by oral or non oral route) in male cholesterol-fed animals mostly suggest a neutral or even significant reduction in the amount of cholesterol accumulated in the arterial wall compared to controls, but mechanistic data on arterial rings, VSMCs, and risk factors (such as thromboxane A2, lipoproteins, etc.) have yielded contrasting results. Long-term randomized, placebo-controlled, double blind studies on middle-aged men at risk of CHD and stroke are greatly needed to clarify this matter of great interest to the population at large. Table 6 summarizes the studies on androgens and direct vascular effects and experimental atherosclerosis studies, expressed in terms of presumed CHD risk.

8. Effect on behavior, cognitive function and mood The subject of androgens in relation to brain function and disease, i.e. cognitive function, memory, and dementia, has become a matter of increasing interest during the last decade. There is not much evidence of what effect(s) androgens have on the brain in terms of cognition and mood. And the data available are conflicting. Early studies in healthy older men indicated that treatment with methyltestosterone significantly improved their ability to perceive flickers [120]. Others have reported an improvement of verbal fluency and concentration abilities in hypogonadal men by testosterone replacement [121,122]. Similar beneficial data of testosterone treatment have been confirmed by other groups [123,124]. However, in a recent three months study by Ly et al. no effect on cognitive function was demonstrated [37]. Gender differences in cognitive function tests are well known, with men typically more spatially cognitive than women, but women more verbally fluent than men [125]. Although sex hormones probably are important for the development and maintenance of acquired cognitive abilities, various other external factors are crucial in early stages of development, e.g. cultural, educational, and social conditions [126]. Androgens, and especially testosterone, are often associated with

aggression. For instance, high testosterone has been reported among young criminal male offenders as compared with nonviolent offenders [127,128]. However, since aggressive behavior per se may stimulate testosterone secretion, this may result in selection bias with regard to offenders. However, factors such as education, cultural background, social status, combined with a significant inter-individual variation in testosterone secretion patterns most likely are also important in predisposing a person for violent and aggressive behavior, and therefore caution should be made as to draw simplistic theories of pure androgen causality (both intrinsic and exogenous androgens) in relation to aggressive behavior [129]. O’Connor et al. found no change in aggression or mood compared to placebo in eugonadal men and even less anger in hypogonadal men after testosterone replacement for 8 weeks [130]. These observations are in line with other clinical studies of testosterone replacement [131,132]. Some studies have even found that testosterone therapy inproves the mood in hypogonadal men and makes them less aggressive [36,133]. In a recent and currently up-dated review on the subject of DHEA supplementation by the Cochrane Library, the authors concluded that having reviewed the only three published studies on cognition in normal older men, even the most optimistic results showed no significant improvement in men after few weeks of DHEA supplementation [134]. Nevertheless, DHEA has been found to increase neuronal excitability and to possess certain neuroprotective properties in rodents, but whether this applies for (hu)man life remains unknown. Ravaglia and coworkers measured crude serum concentrations of DHEA or its sulfate (DHEAS) in elderly men with cognitive impairment and reported no association between these concentrations and cognitive testing scores [135]. Others have reported a similar lack of effect of DHEA supplementation in middle-aged and elderly men [136]. But a positive effect on anxiety and feeling of well-being seems to be obtained by DHEA substitution in women with adrenal insufficiency [137], but whether this is also true in male counterparts is presently not known. Interestingly, when DHEA or DHEAS concentrations are expressed relative to simultaneously obtained serum cortisol concentrations (as the cortisol/DHEAS ratio) another picture seems to emerge. In a prospective study in elderly people

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165

Table 7 Studies on androgens and cognition/mood Studies

Author and year

Findings

Clinical

Klaiber et al. 1971, Stenn et al. 1972, Janowsky et al. 1994, Alexander et al. 1998 Bagatell et al. 1994; Tricker et al. 1996, Huppert and Van Niekert 2001, Ly et al. 2001, O’Connor et al. 2002 Wang et al. 1996b and 2000

TRT → mental concentration↑ TRT or DHEA RT → cognition/mood ↔ TRT → mood ↑

Symbols as in Table 1.

it was found that a high ratio was significantly associated with cognitive impairment (OR = 1.8; 95% confidence interval, 1.0–3.2). [138]. Accumulating evidence suggest that low DHEA(S)/cortisol ratios are correlated to a large variety of other diseases (especially cardiovascular and immunological/inflammatory illness) and since these low ratios seem to predict disease it could be hypothesized that a ‘DHEA deficiency’ could be indicative of a pathologic immune system [139]. Table 7 summarizes the studies on androgens and cognition/mood.

9. Effects on the prostate In the aging male both benign prostatic hyperplasia (BPH) and prostate cancer are very frequent and the incidence of both conditions increases with increasing age [140]. Androgens, as well intrinsic as exogenous, can stimulate growth of ade nocarcinoma of the prostate, although a quantitative relation between the degree of androgen stimulation and the growth rate is difficult to assess in men with prostate cancer [141]. Androgen deprivation (e.g. through castration) and antiandrogen treatment, on the other hand, lead to measurable decrease in metastatic and biochemic disease (as determined by prostate specific antigen (PSA) and acid phosphatase (AP)), and thus these treatments have been used to inhibit BPH and prostate cancer [142]. Aromatization of androgens to estrogens could, at least theoretically, play a role in the development of prostate cancer, since aromatase protein and mRNA have both been identified in the human prostate, suggesting that local aromatization of androgens could provide an estrogen source to the gland [143]. The role of this local production of estrogens in terms of prostate health has however not been established. As correctly pointed out recently by Tenover [142], at present the real problem in terms of androgens replacement in the aging male is whether replacement with testosterone increases the risk of developing clinically significant prostate malignancy from pre-existing (but subclincal) disease. For the physician, it is particularly the effect of androgens on the prostate that prevents him from prescribing androgens to patients with testosterone deficiency. Cancer of the prostate and BPH are conditions with a long natural history, and at the present time available clinical data on testosterone replacement in older

Table 8 Studies on androgens and the prostate Clinical

Tenover 1996 and 1999, Basaria 1999

TRT → prostate cancer ? Probably not TRT → growth of existing prostate cancer↑

Symbols as in Table 1.

men cover but some 800 patient year [142]. Therefore, the issue is of concern, although there are no data directly to suggest that androgen replacement in the aging male should increase his risk of neoplastic prostatic disease [144,145]. At present, cancer of the prostate is regarded as a multifactorial disease, where inheritance, diet, and endocrine factors probably are believed to be key factors in its pathogenesis [141]. Recently, polymorphisms of the androgen receptor (AR) [140,146,147] and the PSA gene [148] have been identified and seem to play a pivotal role in the development of prostate cancer [149]. Table 8 summarizes the studies on androgens and prostate cancer.

10. Conclusions Our knowledge of androgen replacement therapy in the aging male has greatly improved over the last 15–20 years, although data on most aspects remain controversial. Good randomized, double-blind, placebo-controlled clinical studies in the aging male are clearly lacking. We need studies that can help us better understand the effect of long-term (i.e. more than 3 years) androgen replacement therapy (both with testosterone and DHEA) on important aspects of men’s health: cardiovascular disease, body composition, cognition and dementia, osteoporosis, and the prostate. Until such data will become available (probably not for the next decade to come), we recommend an individual and careful evaluation of present health problems combined with assessment of prostatic health (palpation, transrectal ultrasound, and PSA determination), cardiovascular health and cerebral status (including overall quality of life) be undertaken before androgen replacement is initiated and treatment monitored. The future probably will show development of ‘designer androgens’ with (ideally) beneficial effects on the cardiovascular system, bone, muscle, and fat tissues, and the brain, and simultaneous neutral or even inhibitory effects on the

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prostate. Hopefully, we will also see clinical studies on the potentials of soy phytoestrogens and soy protein in relation to men’s health in the future. References [1] Morales A, Heaton JP, Carson III CC. Andropause: a misnomer for a true clinical entity. J Urol 2000;163:705–12. [2] Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis 1996;125:1–13. [3] Hak AE, Witteman JC, de Jong FH, Geerlings MI, Hofman A, Pols HA. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 2002;87:3632–9. [4] Holmäng A, Björntorp P. The effects of testosterone on insulin sensitivity in male rats. Acta Physiol Scand 1992;146:505–10. [5] Mukasa K, Kanesiro M, Aoki K, Okamura J, Saito T, Satoh S, Sekihara H. Dehydroepiandrosterone (DHEA) ameliorates the insulin sensitivity in older rats. J Steroid Biochem Mol Biol 1998;67:355–8. [6] Friedl KE, Jones RE, Hannan Jr CJ, Plymate SR. The administration of pharmacological doses of testosterone or 19-nortestosterone to normal men is not associated with increased insulin secretion or impaired glucose tolerance. J Clin Endocrinol Metab 1989;68:871– 5. [7] Marin P, Oden B, Bjorntorp P. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab 1995;80:239–43. [8] Marin P, Lonn L, Andersson B, Oden B, Olbe L, Bengtsson BA, Bjorntorp P. Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone. J Clin Endocrinol Metab 1996;81:1018–22. [9] Godsland IF, Gangar KF, Walton C, Cust MP, Whitehead MI, et al. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism 1993;42:846–53. [10] Seidell JC, Bjöntorp P, Kvist H, Sannerstedt R, Sjöström L. Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism 1990;39:897–901. [11] Pasquali R, Casimirri F, Cantobelli S, Melchionda N, Morselli Labate AM, Fabbri R, Capelli M, Bortoluzzi L. Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism 1991;40:101–4. [12] Simon D, Preziosi P, Barrett-Connor E, Roger M, Saint-Paul M, Nahoul K, Papoz L. Interrelation between plasma testosterone and plasma insulin in healthy adult men: the Telecom Study. Diabetologia 1992;35:173–7. [13] Phillips G. Relationship between sex hormones and the glucose insulin lipid defect in men with obesity. Metabolism 1993;42:116–20. [14] Haffner SM, Valdez RA, Mykkänen L, Stern MP, Katz MS. Decreased testosterone and dehydroepiandrosterone sulfate concentrations are associated with increased glucose and insulin concentrations in nondiabetic men. Metabolism 1994;43:599–603. [15] Birkeland KI, Hanssen KF, Torjesen PA. Vaaler S, Level of sex hormone-binding globulin is positively correlated with insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 1993;76:275–8. [16] Nestler JE. Sex hormone binding globulin: a marker for hyperinsulinemia and/or insulin resistance (Editorial). J Clin Endocrinol Metab 1993;76:273–4. [17] Haffner SM, Shaten JS, Stern MP, Smith GD, Kuller L. Low levels of sex hormone binding globulin and testosterone predict the

[18]

[19]

[20] [21] [22]

[23]

[24] [25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

development of non-insulin dependent diabetes mellitus in men. Am J Epidemiol 1996;143:889–97. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care 2002;25:55–60. Yamaguchi Y, Tanaka S, Yamakawa T, Kimura M, Ukawa K, Yamada Y, Ishihara M, Sekihara H. Reduced serum dehydroepiandrosterone levels in diabetic patients with hyperinsulinaemia. Clin Endocrinol (Oxf) 1998;49:377–83. Khaw KT, Barrett-Connor E. Lower endogenous androgens predict central adiposity in men. Ann Epidemiol 1992;2:675–82. Haffner SM, Valdez RA, Stern MP, Katz MS. Obesity, body fat distribution and sex hormones in men. Int J Obesity 1993;17:643–9. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol 1997;146:609–17. Tsai EC, Boyko EJ, Leonetti DL, Fujimoto WY. Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int J Obes Relat Metab Disord 2000;24:485–91. Rebuffe-Scrive M, Marin P, Bjorntorp P. Effect of testosterone on abdominal adipose tissue in men. Int J Obes 1991;15:791–5. Young NR, Baker HW, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab 1993;77:1028–32. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes 1992;16:991–7. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996;81:4358–65. Vogiatzi MG, Boeck MA, Vlachopapadopoulou E, el-Rashid R, New MI. Dehydroepiandrosterone in morbidly obese adolescents: effects on weight, body composition, lipids, and insulin resistance. Metabolism 1996;45:1011–5. Flynn MA, Weaver-Osterholtz D, Sharpe-Timms KL, Allen S, Krause G. Dehydroepiandrosterone replacement in aging humans. J Clin Endocrinol Metab 1999;84:1527–33. Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids. Clin Endocrinol (Oxf) 1998;49:421–32. Alexandersen P, Hassager C, Christiansen C. Influence of female and male sex steroids on body composition of rabbits. Climacteric 2001;4:219–27. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996;335:1–7. Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J, Lee WP, Bunnell TJ, Casaburi R. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 1997;82:407–13. Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men—a clinical research center study. J Clin Endocrinol Metab 1996;81:3469–75. Wang C, Eyre DR, Clark R, Kleinberg D, Newman C, Iranmanesh A, Veldhuis J, Dudley RE, Berman N, Davidson T, Barstow TJ, Sinow R, Alexander G, Swerdloff RS. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and

P. Alexandersen, C. Christiansen / Atherosclerosis 173 (2004) 157–169

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46] [47]

[48] [49] [50] [51]

[52]

[53]

[54]

increases bone formation markers in hypogonadal men—a clinical research center study. J Clin Endocrinol Metab 1996;81:3654–62. Wang C, Swedloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N. Transdermal testosterone gel improves sexual function, mood, muscle strength. J Clin Endocrinol Metab 2000;85:2839–53. Ly LP, Jimenez M, Zhuang TN, Celermajer DS, Conway AJ, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. J Clin Endocrinol Metab 2001;86:4078–88. Hyyppa S, Karvonen U, Rasanen LA, Persson SG, Poso AR. Androgen receptors and skeletal muscle composition in trotters treated with nandrolone laureate. Zentralbl Veterinarmed A 1997;44:481–91. Bricout VA, Serrurier BD, Bigard AX, Guezennec CY. Effects of hindlimb suspension and androgen treatment on testosterone receptors in rat skeletal muscles. Eur J Appl Physiol 1999;79:443–8. Yarnell JWG, Baker IA, Sweetnam PM, Bainton D, O’Brien JR, Whitehead PJ, Elwood PC. Fribrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease: the Caerphilly and Speedwell Collaborative Heart Disease Studies. Circulation 1991;83:836–84. Caron P, Bennet A, Camare R, Louvet JP, Boneu B, Sie P. Plasminogen activator inhibitor in plasma is related to testosterone in men. Metabolism 1989;38:1010–5. Rosenblum WI, el-Sabban F, Nelson GH, Allison TB. Effects in mice of testosterone and dihydrotestosterone on platelet aggregation in injured arterioles and ex vivo. Thromb Res 1987;45:719–28. Yang XC, Jing TY, Resnick LM, Phillips GB. Relation of hemostatic risk factors to other risk factors for coronary heart disease and to sex hormones in men. Arterioscler Thromb 1993;13:467–71. Glueck CJ, Glueck HI, Stroop D, Speirs J, Hamer T, Tracy T. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidemic men. J Lab Clin Med 1993;122:412–20. De Pergola G, De Mitrio V, Sciaraffia M, Pannacciulli N, Minenna A, Giorgino F, Petronelli M, Laudadio E, Giorgino R. Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men. Metabolism 1997;46:1287–93. Winkler UH. Effects of androgens on hemostasis. Maturitas 1996;24:147–55. Anderson RA, Ludlam CA, Wu FC. Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost 1995;74:693–7. Fearnley GR, Chakrabarti R. Increase of blood fibrinolytic activity by testosterone. Lancet 1962;2:128–32. Shapiro J, Christiana J, Frishman WH. Testosterone and other anabolic steroids as cardiovascular drugs. Am J Ther 1999;6:167–74. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–26. Keller ET, Chang C, Ershler WB. Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem 1996;271:26267–75. McCrohon JA, Jessup W, Handelsman DJ, Celermajer DS. Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1. Circulation 1999;99:2317–22. McCrohon JA, Death AK, Nakhla S, Jessup W, Handelsman DJ, Stanley KK, Celermajer DS. Androgen receptor expression is greater in macrophages from male than from female donors. A sex difference with implications for atherogenesis. Circulation 2000;101:224–6. Mukherjee TK, Dinh H, Chaudhuri G, Nathan L. Testosterone attenuates expression of vascular cell adhesion molecule-1 by con-

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67] [68]

[69]

[70]

[71]

[72]

[73]

167

version to estradiol by aromatase in endothelial cells: implications in atherosclerosis. Proc Natl Acad Sci USA 2002;99:4055–60. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 2000;51:245–70. Nussdorfer GG, Mazzocchi G. Immune-endocrine interactions in the mammalian adrenal gland: facts and hypotheses. Int Rev Cytol 1998;143:143–84. Szalai AJ, Agrawal A, Greenhough TJ, Volanakis JE. C-reactive protein: structural biology, gene expression, and host defense function. Immunol Res 1997;16:127–36. Ng MK, Liu PY, Williams AJ, Nakhla S, Ly LP, Handelsman DJ, Celermajer DS. Prospective study of effect of androgens on serum inflammatory markers in men. Arterioscler Thromb Vasc Biol 2002;22:1136–41. Giltay EJ, Fonk JC, von Blomberg BM, Drexhage HA, Schalkwijk C, Gooren LJ. In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. J Clin Endocrinol Metab 2000;85:1648–57. Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich J, Falk W, Lang B. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6). J Clin Endocrinol Metab 1998;83:2012–7. Gutai JP, LaPorte RE, Kuller LH, Dai W, Falvo-Gerard L, Caggiula A. Plasma testosterone, high density lipoprotein cholesterol and other lipoprotein fractions. Am J Cardiol 1981;48:897–902. Dai W, Gutai JP, Kuller LH, LaPorte RE, Falvo-Gerard L, Caggiula A. Relation between plasma high density lipoprotein cholesterol and sex hormone concentrations in men. Am J Cardiol 1984;53:1259–63. Duell PB, Bierman EI. The relationship between sex hormones and high density lipoprotein cholesterol levels in healthy adult men. Arch Intern Med 1990;150:2317–20. Khaw KT, Barett-Connor E. Endogenous sex hormones, high density lipoprotein cholesterol, and other lipoprotein fractions in men. Arterioscler Thromb 1991;11:489–94. Haffner SM, Mykkänen L, Valdez RA, Stern MP, Katz MS. Relationship of sex hormones to lipids and lipoproteins in non-diabetic men. J Clin Endocrinol Metab 1993;77:1610–5. Ooi LS, Panesar NS, Masarei JR. Urinary excretion of testosterone and estradiol in Chinese men and relationships with serum lipoprotein concentrations. Metabolism 1996;45:279–84. Semmens J, Rouse J, Beilin LJ, Masarei JR. Relationship of plasma HDL cholesterol to testosterone. Metabolism 1983;32:428–32. Stefanik ML, Williams PT, Krauss RM, Terry RB, VranizanWood KMWoodPD. Relationships of plasma estradiol, testosterone and sex hormone binding globulin with lipoproteins, apolipoproteins, and high density lipoprotein subfractions in men. J Clin Endocrinol Metab 1987;64:723–9. Applebaum DM, Goldberg AP, Pykalisto OJ, Brunzell JD, Hazzard WR. Effect of estrogen on post-heparin lipolytic activity. Selective decline in hepatic hepatic triglyceride lipase. J Clin Invest 1977;59:601–8. Friedl KE, Hannan CR, Jones RE, Plymate SR. High density lipoprotein cholesterol is not decreased if aromaizable androgen is administered. Metabolism 1990;39:69–74. Bagatell CJ, Knopp RH, Rivier JE, Bremner WJ. Physiological levels of estradiol stimulate plasma high density lipoprotein2 cholesterol levels in normal men. J Clin Endocrinol Metab 1994;78:855–61. Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res 1982;23:97–104. Snyder PJ, Peachey H, Berlin JA, Rader D, Usher D, Loh L, Hannoush P, Dlewati A, Holmes JH, Santanna J, Strom BL. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med 2001;111:255–60.

168

P. Alexandersen, C. Christiansen / Atherosclerosis 173 (2004) 157–169

[74] Haffner SM, Mykkänen L, Grüber KK, Rainwater DL, Laasko M. Lack of association between sex hormones and Lp(a) concentrations in American and Finnish men. Arterioscler Thromb 1994;14: 19–24. [75] Marcovina SM, Lippi G, Bagatell CJ, Bremner WJ. Testosterone-induced suppression of lipoprotein(a) in normal men relation to basal lipoprotein(a) level. Atherosclerosis 1996;122:89–95. [76] Haffner SM, Ksuhwaha RS, Foster DM, Applebaum-Bowden D, Hazzard WR. Studies on the metabolic mechanism of reduced high density lipoprotein during anabolic steroid therapy. Metabolism 1983;32:413–7. [77] Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. Randomized clinical trial of testosterone replacement in hypogonadal men. Int J Androl 1988;11:247–64. [78] Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;75:1092–8. [79] Morley ME, Perry MM, Kaiser FE, Kraenzle D, Jensen E, Houston K, Mattammal M, Perry Jr HM. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993;41:149–52. [80] Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis 1996;121:35–43. [81] Bagatell CJ, Knopp RH, Vale WW, Rivier JE, Bremner WJ. Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels. Ann Intern Med 1992;116:967–73. [82] Enzi GB, Giada F, Zuliani G, Baroni L, Vitale E, Enzi G, Magnini P, Fellini R. Lipid and apoprotein modifications in body builders during and after self-administration of anabolic steroids. Metabolism 1990;39:203–8. [83] Gyllenborg J, Rasmussen SL, Borch-Johnsen K, Heitmann BL, Skakkebaek NE, Juul A. Cardiovascular risk factors in men: The role of gonadal steroids and sex hormone-binding globulin. Metabolism 2001;50:882–8. [84] Clarkson TB, Anthony MS, Klein KP. Effects of estrogen treatment on arterial wall structure and function. Drugs 1994;47:42–51. [85] Collins P, Rosano GM, Jiang C, Lindsay D, Sarrel PM, Poole-Wilson PA. Cardiovascular protection by oestrogen—a calcium antagonist effect? Lancet 1993;341:1264–5. [86] Webb CM, Adamson DL, de Ziegler D, Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol 1999;83:437–9. [87] Webb CM, McNeill JG, Hayward CS, de Ziegler D, Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 1999;100:1690–6. [88] Rosano GMC, Leonardo F, Pagnotta P, Pelliccia F, Panina G, Cerquetani E, Lilla della Monica P, Bonfigli B, Volpe M, Chierchia SL. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 1998;99:1666–70. [89] Diano S, Horvath TL, Mor G, Register T, Adams M, Harada N, Naftolin F. Aromatase and estrogen receptor immunoreactivity in the coronary arteries of monkeys and human subjects. Menopause 1999;6:21–8. [90] Nathan L, Shi W, Dinh H, Mukherjee TK, Wang X, Lusis AJ, Chaudhuri G. Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc Nat Acad Sci USA 2001;98:3589–93. [91] Holm P, Korsgaard N, Shalmi M, Andersen HL, Hougaard P, Skouby SO, Stender S. Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits. J Clin Invest 1997;100:821–8. [92] Alexandersen P, Haarbo J, Byrjalsen I, Lawaetz H, Christiansen C. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circ Res 1999;84:813–9.

[93] Hanke H, Lenz C, Hess B, Spindler KD, Weidemann W. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 2001;103:1382–5. [94] Wu SZ, Weng XZ. Therapeutic effects of an androgenic preparation on myocardial ischemia and cardiac function in 62 elderly male coronary heart disease patients. Chin Med J (Engl) 1993;106:415–8. [95] Levine SA, Likoff WB. The therapeutic value of testosterone propionate in angina pectoris. N Engl J Med 1943;229:770–2. [96] Lesser MA. Testosterone propionate therapy in one hundred cases of angina pectoris. J Clin Endocrinol 1946;6:549–57. [97] English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 2000;102:1906–11. [98] Jaffe MD. Effect of testosterone cypionate on postexercise ST segment depression. Br Heart J 1977;39:1217–22. [99] Hutchison SJ, Sudhir K, Chou TM, Sievers RE, Zhu BQ, Sun YP, Deedwania PC, Glantz SA, Parmley WW, Chatterjee K. Testosterone worsens endothelial dysfunction associated with hypercholesterolemia and environmental tobacco smoke exposure in male rabbit aorta. J Am Coll Cardiol 1997;29:800–7. [100] Yue P, Chatterjee K, Beale C, Poole-Wilson PA, Collins P. Testosterone relaxes rabbit coronary arteries and aorta. Circulation 1995;91:1154–60. [101] Chou TM, Sudhir K, Hutchison SJ, Ko E, Amidon TM, Collins P, Chatterjee K. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation 1996;94:2614–9. [102] Mohan PF, Benghuzzi H. Effect of dehydroepiandrosterone on endothelial cell proliferation. Biomed Sci Instrum 1997;33:550–5. [103] Furutama D, Fukui R, Amakawa M, Ohsawa N. Inhibition of migration and proliferation of vascular smooth muscle cells by dehydroepiandrosterone sulfate. Biochim Biophys Acta 1998;1406:107–14. [104] Schror K, Morinelli TA, Masuda A, Masuda K, Mathur RS, Halushka PV. Testosterone treatment enhances thromboxane A2 mimetic induced coronary artery vasoconstriction in guinea pigs. Eur J Clin Invest 1994;24:50–2. [105] Nakao J, Change WC, Murota SI, Orimo H. Testosterone inhibits prostacyclin production by rat aortic smooth muscle cells in culture. Atherosclerosis 1981;39:203–9. [106] Masuda A, Mathur R, Halushka PV. Testosterone increases thromboxane A2 receptors in cultured rat aortic smooth muscle cells. Circ Res 1991;69:638–43. [107] Weyrich AS, Rejeski WJ, Brubaker PH, Parks JS. The effects of testosterone on lipids and eicosanoids in cynomolgus monkeys. Med Sci Sports Exerc 1992;24:333–8. [108] Fujimoto R, Morimoto I, Morita E, Sugimoto H, Ito Y, Eto S. Androgen receptors. J Steroid Biochem Mol Biol 1994;50:169–74. [109] Farhat MY, Wolfe R, Vargas R, Foegh ML, Ramwell PW. Effect of testosterone treatment on vasoconstrictor response of left anterior descending artery in male and female pigs. J Cardiovasc Pharmacol 1995;25:495–500. [110] Taniguchi S, Yanase T, Kobayashi K, Takayanagi R, Nawata H. Dehydroepiandrosterone markedly inhibits the accumulation of cholesteryl ester in mouse macrophage J774-1 cells. Atherosclerosis 1996;126:143–54. [111] Williams MR, Ling S, Dawood T, Hashimura K, Dai A, Li H, Liu JP, Funder JW, Sudhir K, Komesaroff PA. Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and Ers. J Clin Endocrinol Metab 2002;87:176–81. [112] Larsen BA, Nordestgaard BG, Stender S, Kjeldsen K. Effect of testosterone on atherogenesis in cholesterol-fed rabbits with similar plasma cholesterol levels. Atherosclerosis 1993;99:79–86. [113] Bruck B, Brehme U, Gugel N, Hanke S, Finking G, Lutz C, Benda N, Schmahl FW, Haasis R, Hanke H. Gender-specific differences in the effects of testosterone and estrogen on the de-

P. Alexandersen, C. Christiansen / Atherosclerosis 173 (2004) 157–169

[114]

[115]

[116]

[117]

[118] [119]

[120]

[121]

[122]

[123]

[124] [125] [126]

[127] [128] [129]

[130]

[131]

velopment of atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 1997;17:2192–9. Gordon GB, Bush DE, Weisman HF. Reduction of atherosclerosis by administration of dehydroepiandrosterone. A study in the hypercholesterolemic New Zealand white rabbit with aortic intimal injury. J Clin Invest 1988;82:712–20. Arad Y, Badimon JJ, Badimon L, Hembree WC, Ginsberg HN. Dehydroepiandrosterone feeding prevents aortic fatty streak formation and cholesterol accumulation in cholesterol-fed rabbit. Arteriosclerosis 1989;9:159–66. Eich DM, Nestler JE, Johnson DE, Dworkin GH, Ko D, Wechsler AS, Hess ML. Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotropic rabbit model of cardiac transplantation. Circulation 1993;87:261–9. Hayashi T, Esaki T, Muto E, Kano H, Asai Y, Thakur NK, Sumi D, Jayachandran M, Iguchi A. Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: the possible role of nitric oxide. Arterioscler Thromb Vasc Biol 2000;20:782–92. Toung TJ, Traystman RJ, Hurn PD. Estrogen-mediated neuroprotection after experimental stroke in male rats. Stroke 1998;29:1666–70. Jeppesen LL, Jørgensen HS, Kakayama H, Raaschou HO, Olsen TS, Winther K. Decreased serum testosterone in men with acute ischemic stroke. Arterioscler Thromb Vasc Biol 1996;16:749–54. Simonsen E, Kearns WM, Enzer N. Effect of methyl testosterone treatment on muscular performance and the central nervous system of older men. J Clin Endocrinol Metab 1944;4:528–34. Stenn PO, Klaiber EL, Vogel W, Broverman DM. Testosterone effects on photic stimulation of the EEG and mental performances of humans. Percept Mot Skills 1972;34:371–8. Alexander GM, Swerdloff RS, Wang C, Davidson T, McDonald V, Steiner B, Hines M. Androgen-behavior correlations in hypogonadal men and eugonadal men. II. Cognitive abilities. Horm Behav 1998;33:85–94. Klaiber EL, Broverman DM, Vogel M, Abraham GE, Crone FL. Effects of infused testosterone on mental performances and serum LH. J Clin Endocrinol Metab 1971;32:341–9. Janowsky JS, Oviatt SK, Orwoll ES. Testosterone influences spatial cognition in older men. Behav Neurosci 1994;108:325–32. Hyde JS, Fennema E, Lammon SJ. Gender differences in mathematics performance: a meta-analysis. Psych Bull 1990;107:139–55. Hassler M, Gupta D, Wollmann H. Testosterone, estradiol, ACTH and musical, spatial and verbal performance. Int J Neurosci 1992;65:45–60. Brooks JH, Reddon JR. Serum testosterone in violent and nonviolent young offenders. J Clin Psych 1996;52:475–83. Aromaki AS, Lindman RE, Eriksson CJP. Testosterone aggressiveness and antisocial personality. Aggress Behav 1999;25:113–23. Zitzmann M, Nieschlag E. Testosterone levels in healthy men and the relation to behavioural and physical characteristics: facts and constructs. Eur J Endocrinol 2001;144:183–97. O’Connor DB, Archer J, Hair WM, Wu FC. Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men. Physiol Behav 2002;75:557–66. Bagatell CJ, Heiman JR, Rivier JE, Bremner WJ. Effects of endogenous testosterone and estradiol on sexual behavior in normal young men. J Clin Endocrinol Metab 1994;78:711–6.

169

[132] Tricker R, Casaburi R, Storer TW, Clevenger B, Berman N, Shirazi A, Bhasin S. The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men—a clinical research center study. J Clin Endocrinol Metab 1996;81:3754–8. [133] Wang C, Alexander G, Berman N, Salehian B, Davidson T, McDonald V, Steiner B, Hull L, Callegari C, Swerdloff RS. Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study. J Clin Endocrinol Metab 1996;81:3578–83. [134] Huppert FA, Van Niekert JK. Dehydroepiandrosterone (DHEA) supplementation for cognitive function. (Cohcrane review). The Cochrane Library 2001;issue 2:ISSN 1464-780X. [135] Ravaglia G, Forti P, Maioli F, Boschi F, DeRonchi D, Bernardi M, Pratelli L, Pizzoferrato A, Cavalli G. Dehydroepiandrosterone sulphate and dementia. Arch Geront Geriatr 1998;S6:423–6. [136] Arlt W, Callies F, Koehler I, van Vlijmen JC, Fassnacht M, Strasburger CJ, Seibel MJ, Huebler D, Ernst M, Oettel M, Reincke M, Schulte HM, Allolio B. Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion. J Clin Endocrinol Metab 2001;86:4686–92. [137] Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, Huebler D, Oettel M, Ernst M, Schulte HM, Allolio B. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;341:1013–20. [138] Kalmijn S, Launer LJ, Stolk RP, de Jong FH, Pols HAP, Hofman A, Breteler MMB, Lamberts SWJ. A prospective study on cortisol. J Clin Endocrinol Metab 1998;83:3487–92. [139] Hinson JP, Raven PW. DHEA deficiency syndrome: a new term for old age? (commentary). J Endocrinol 1999;163:1–5. [140] Novelli G, Margiotti K, Sangiuolo F, Reichardt JK. Pharmacogenitics of human androgens and prostatic diseases. Pharmacogenomics 2001;2:65–72. [141] Schröder FH. The prostate and androgens: the risks of supplementation. In: Androgens and the aging male. Eds. Oddens B, Vermeulen A. Parthenon Publishing Group Inc., New York, 1996. pp. 223-232. [142] Tenover JL. Testosterone replacement therapy in older adult men. Int J Androl 1999;22:300–6. [143] Tsugaya M, Harada N, Tozawa K, et al. Aromatase mRNA levels in benign prostatic hyperplasia and prostate cancer. Int J Urol 1996;3:292–6. [144] Tenover J.L., Effects of androgen supplementation in the aging male. In: Androgens and the aging male. Eds. Oddens B, Vermeulen A. Parthenon Publishing Group Inc., New York, 1996. pp. 191-204. [145] Basaria S, Dobs AS. Risks versus benefits of testosterone therapy in elderly men. Drugs Aging 1999;15:131–42. [146] Csaszar A. Abel T Receptor polymorphisms and diseases Eur J Pharmacol 2001;414:9–22. [147] Hsing AW, Gao YT, Wu G, Wnag X, Deng J, Chen YL, Sesterhenn IA, Mostofi FK, Benichou J, Chang C. Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. Cancer Res 2000;60:5111–6. [148] Yang Q, Shan L, Segawa N, Nakamura M, Nakamura Y, Mori I, Sakurai T, Kakudo K. Novel polymorphisms in protate specific antigen gene and its association with prostate cancer. Anticancer Res 2001;21(1A):197–200. [149] Barrack ER. Androgen receptor mutations in prostate cancer. Mt Sinai J Med 1996;63:403–12.