Effects of exogenous testosterone on cardiovascular risk factors Lipoproteins

In the majority of studies, substitution of testosterone in hypogonadal men had no impact on total cholesterol, LDL cholesterol and triglycerides but decreased HDL-C and Lp(a) levels.

Treatment with supraphysiological doses of testosterone or androgen-like anabolic steroids in normal men decreased HDL-C by about 20% and more.

Conversely, castration as well as biochemical suppression of endogenous testosterone by GnRH antagonists increased HDL-C (reviewed in Wu and von Eckardstein 2003). In one study, exogenous testosterone only produced a fall in HDL-C in the presence of aromatase inhibitors. These observations and the finding of low HDL-C in men with aromatase deficiency or estrogen resistancy suggest that physiological tissue levels of estradiol play a role in maintaining physiological levels of HDL-C in men.

Since low HDL-C is an important coronary artery disease risk factor and since HDL exerts several potentially anti-atherogenic actions, lowering of HDL-C by testosterone is considered to increase cardiovascular risks (Hersberger and von Eckardstein 2003). However, the epidemiological association of low HDL-C with coronary artery disease has not been proven to be causal. Instead, low HDL-C frequently coincides with other components of the metabolic syndrome and markers of chronic inflammation, and may therefore merely be a surrogate marker for a separate but linked pro-atherogenic condition. Moreover, in transgenic animal models, only increases of HDL-C induced by apoA-I overproduction but not by inhibition of HDL catabolism were consistently found to prevent atherosclerosis (von Eckardstein et al. 2001, Hersberger and von Eckardstein 2003). Therefore, the mechanism of HDL modification rather than changes in levels of HDL-C per se appear to determine the (anti)-atherogenicity of HDL modification. Two genes involved in the catabolism of HDL are up-regulated by testosterone, namely scavenger receptor B1 and hepatic lipase. Scavenger receptor B1 mediates the selective uptake of HDL lipids into hepatocytes and steroidogenic cells including Sertoli and Leydig cells of the testes as well as cholesterol efflux from peripheral cells including macrophages. Testosterone up-regulates scavenger receptor B1 in the human hepatocyte cell line HepG2 and in macrophages thereby stimulating selective cholesterol uptake and cholesterol efflux, respectively (Langer et al. 2002). Hepatic lipase hydrolyses phospholipids on the surface of HDL thereby facilitating the selective uptake of HDL lipids by SR-B1. The activity of HL in postheparin plasma is increased after administration of exogenous testosterone (Tan etal. 1999) and slightly decreased by suppression of testosterone after GnRH antagonist treatment (Buchter etal. 1999). Increasing both scavenger receptor B1 and hepatic lipase activities are therefore consistent with the HDL lowering effect of testosterone. Interestingly, overexpression of SR-BI or HL in transgenic mice is associated with a dramatic fall in HDL-C which inhibited rather than enhanced atherosclerosis (von Eckardstein etal. 2001). This again demonstrates that the HDL lowering effect of testosterone may not increase and could even decrease cardiovascular risk.

Results of many case-control studies and most prospective population studies demonstrated that lipoprotein(a) (Lp(a)) levels higher than 30 mg/dl are an independent risk factor for coronary, cerebrovascular, and peripheral atherosclerotic vessel diseases especially if they coexist with other cardiovascular risk factors (Danesh et al. 2000). Although Lp(a) levels are predominantly genetically determined, administration of testosterone to men decreased serum levels of Lp(a) significantly by 25% to 59%. Conversely Lp(a) levels were increased by 40% to 60% in controls and patients in whom endogenous testosterone was suppressed by treatment with the GnRH antagonist cetrorelix or the GnRH agonist buserelin (Angelin 1997; Wu and von Eckardstein 2003; von Eckardstein etal. 1997). The Lp(a) lowering effect of testosterone is independent of estradiol, which also reduces Lp(a) levels. Itis not knownhow testosterone regulates Lp(a). Itis also not known whether changes in Lp(a) induced by testosterone will affect cardiovascular risk. The hemostatic system

In agreement with an important role of thrombus formation in the pathogenesis of acute coronary events and stroke, prospective studies have identified various hemostatic variables as cardiovascular risk factors, among them fibrinogen and the fibrinolysis inhibitor PAI-1 or tissue plasminogen activator antigen. Administration of supraphysiological dosages testosterone to 32 healthy men participating in a trial of male contraception, led to a sustained decrease of fibrinogen by 15 to 20% over 52 weeks of treatment (Anderson etal. 1995). In this study the doubling of testosterone levels initially also led to significant decreases of PAI-1, protein S, and protein C as well as to increases of antithrombin and (p-thromboglobulin. Likewise PAI-1 was decreased in men who received the anabolic androgen stanozolol. Suppression of testosterone in patients with prostate cancer or benign prostate hypertrophy, however, by treatment with the nonsteroidal anti-androgen casodex or the GnRH agonist leuprolide exerted no significant effects on plasma fibrinogen levels (Eri et al. 1995). In agreement with the lowering effects of testosterone on PAI-1, testosterone inhibited the secretion of PAI-1 from bovine aortic endothelial cells in vitro. Taken together the current data indicate that testosterone lowers fibrinogen and PAI-1. However, these anti-coagulatory and pro-fibrinolytic effects maybe opposed by pro-aggregatory effects on platelets since high dosages of androgens were found to decrease cyclooxygenase activity and thereby increase platelet aggregability. Inflammation

Recent thinking on the pathogenesis ofatherosclerosis has re-discovered the pathological observations from over 100 years ago that atherosclerosis is a chronic inflammatory disease (Libby 2002). This is supported by the epidemiological finding that serum levels of the acute phase reactant C-reactive protein (CRP) are positively associated with the risk of coronary events (Pepys and Hirschfield 2003). Of special importance is that postmenopausal hormone replacement with estrogens and progestins causes an increase in CRP levels (Pradhan et al. 2002). This effect has been taken as one argument to explain the unexpected neutral or even adverse effect of postmenopausal hormone replacement on coronary artery disease. In two studies of healthy eugonadal men treatment with either increasing dosages of testosterone enanthate or dihydrotestosterone or recombinant chorionic gonadotropin as well as suppression of endogenous testosterone with a gonadotropin releasing hormone agonist had no effect on CRP levels. Neither had dihydrotestosterone any effect on serum levels of soluble adhesion molecules (Ng etal. 2002; Singh etal. 2002). Obesity and insulin sensitivity

Numerous observations point to mutual relationships between androgens, body fat distribution, and insulin sensitivity, of which the latter two are also involved in the regulation of HDL and triglyceride metabolism (Bjorntorp 1996; Wu and von Eckardstein 2003). It is, however, not clear whether androgens regulate adipose tissue and insulin sensitivity or whether vice versa adipocytes and insulin regulate testosterone levels. Probably a bi-directional relationship exists.

Morbidly obese and insulin resistant men frequently have low serum levels of testosterone which increase upon weight loss (Leenen et al. 1994). Estradiol levels show the opposite changes to testosterone with obesity and weight loss. It has therefore been suggested that obesity causes hypotestosteronemia by increased aro-matisation of testosterone to estradiol in the adipose tissue. Supporting a role of insulin in the determination of testosterone levels in men, infusion of insulin during euglycemic clamp increased testosterone levels in obese men but not in lean men (Pasquali et al. 1997). On the other hand, hypogonadal men are frequently obese with increased levels of leptin and insulin (Couillard etal. 2000). Body weight, leptin levels and insulin levels decrease upon substitution of testosterone in hypogonadal men (Behre etal. 1997). Even treatment of eugonadal obese men with testosterone led to a decrease of visceral fat mass and, in parallel, improved insulin sensitivity and corrected dyslipidemia (Wang et al. 2000). In the opposite experiment, suppression of testosterone by the GnRH-antagonist cetrorelix increased serum levels of leptin and insulin (Buchter et al. 1999). Moreover, male carriers of the testosterone-hypersensitive androgen receptor gene alleles with a low number of CAG repeats have less body fat than carriers with a high number of CAG repeats (Zitzmann et al. 2003). These data indicate that, in men, the dominant action in the bi-directional relationship is that testosterone reduces fat mass, especially in the abdomen, and improves insulin action. In agreement with this androgens activate the expression of ^-adrenergic receptors, adenylate cyclase, protein kinase A and hormone sensitive lipase in adipocytes (Bjorntorp 1996). As a result, testosterone stimulates lipolysis and thereby reduces fat storage in adipocytes.

In women, mutual interrelationships have also been observed between testosterone, adipose tissue and insulin sensitivity, but in the opposite direction to those seen in men. On the one hand, insulin sensitivity contributes to the patho-genesis of hyperandrogenemia in polycystic ovary syndrome. Insulin stimulates androgen synthesis in the ovaries via its cognate receptor and the inositolglycan pathway (Nestler et al. 1998). Since the ovaries remain sensitive to insulin when other tissues such as fat and muscle are resistant, hyperinsulinemia can augment the LH-dependent hyperandrogenism in insulin resistant women with polycystic ovary syndrome (Dunaif and Thomas 2001). In support of this, treatment of insulin resistance in women with polycystic ovary syndrome with metformin or the insulin sensitizer troglitazone significantly decreased serum levels of insulin as well as testosterone, independently of body mass index or gonadotropin levels (Kolodziejczyk et al. 2000; Pasquali and Filicori 1998). Concomittantly, plasma levels of HDL-cholesterol increased and plasma levels of PAI-1 decreased. These data imply that hyperinsulinemia contributes to the functional ovarian hyperan-drogenism in polycystic ovary syndrome. Vice versa, lowering androgen levels with GnRH agonists and androgen receptor blockade in hyperandrogenic women were also found to improve insulin sensitivity and lipid profile (Dahlgren et al. 1998; Diamanti-Kandarakis etal. 1998). The magnitude of these changes however is less than that usually encountered in polycystic ovary syndrome. Since short-term lowering of ovarian androgens by laparoscopic ovarian cautery did not alter insulin or lipid levels (Lemieux et al. 1999), androgens probably only aggravate rather than account for the insulin resistance in women with polycystic ovary syndrome. This however, does not exclude the possibility that androgens have an etiological role in polycystic ovary syndrome. For example, experiments in rats and marmoset monkeys recently showed evidence for androgen imprinting. Transient intrauter-ine or perinatal exposure to testosterone predisposed female animals to central adiposity and insulin resistance in adult life (Eisner etal. 2000). Supraphysiological doses of exogenous testosterone or other androgens to women or female cynomol-gus monkeys increased body mass index and the mass of both visceral fat and muscle and decreased insulin sensitivity (Adams etal. 1995). There appears to be a vicious circle where early androgen excess contributes to insulin resistance in adult women. The resulting hyperinsulinism contributes to the pathogenesis of polycystic ovary syndrome and aggravates the hyperandrogenism and the associated clinical phenotype.

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