Author: Gianpiero Pescarmona
Enantone or Leuprorelina
As reported in the side effects of ADT there are many evidence of a strong association between testosterone deficiency and general risk factors for atherosclerosis such as obesity, lipid alterations, metabolic syndrome and type 2 diabetes. (The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process, 2009)
Evidence suggests that pro-inflammatory cytokines are involved in the early stages of atherosclerotic plaque formation. Under normal conditions, the endothelial cell layer is permeable to a number of molecules which readily pass between the circulating plasma and the sub-endothelial space. LDL-cholesterol is one such macromolecule, but on binding to proteoglycan molecules, is retained in the sub-endothelial space, a process exacerbated by increased circulating concentrations of LDL-cholesterol. The captured LDL-cholesterol becomes prone to oxidization, which triggers the expression of adhesion molecules on the endothelial cell surface. Monocytes are attracted to the adhesion molecules and pass into the sub-endothelial space where they differentiate into macrophages and produce inflammatory cytokines such as IL-6, IL-1β and TNF-α. This propagates the local inflammatory response, eventually resulting in the formation of a mature plaque, comprised of a lipid core retaining within a fibrous cap.
Continued expression of pro-inflammatory mediators such as IL- 6, IL-1β and TNF-α increases the instability of the plaque, making it prone to rupture. Evidence also suggests that TNF-α also plays a pathological role other vascular diseases suppressing nitric oxide synthase expression and contributing to the impaired endothelial function inherent to the condition. In vitro studies indicate that testosterone has immuno-modulatory capabilities, suppressing the expression of IL-6, IL-1β and TNF-α in human cell lines (Testosterone inhibits tumor necrosis factor-induced vascular cell adhesion molecule-1 expression in human aortic endothelial cells, 2002; Sex hormones modulate inflammatory mediators produced by macrophages, 1999; Androgens modulate interleukin-6 production by gingival fibroblasts in vitro,1999) and stimulating the production of anti-inflammatory IL-10. (Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production, 2001)
Evidence from several clinical studies investigating the association between testosterone levels and inflammatory cytokines highlights the potential benefits of testosterone therapy. In a detailed study of the relationship between serum testosterone and inflammatory cytokines in testosterone-deficient men with stable coronary artery disease, levels of IL-1β increased as serum testosterone decreased, and both IL-1β and IL-10 were implicated in disease pathogenesis. (Inverse relationship between serum levels of interleukin-1beta and testosterone in men with stable coronary artery disease, 2007)
C-reactive protein (CRP)
CRP is an acute phase protein produced primarily by hepatocytes in response to IL-6. The presence of CRP in plasma is indicative of acute inflammation and elevated levels of CRP bring an increased risk of metabolic syndrome, type 2 diabetes and CHD. (C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus, 2007) However, it has been suggested that it can be the amount of LDL-cholesterol that determines CRP levels in CHD, rather than the presence of inflammatory mediators. CRP is used as a predictive indicator of myocardial infarction, ischaemic stroke and vascular death.
There appears to be an inverse correlation between CRP and testosterone levels in some reports (Study of androgen and atherosclerosis in old age male, 2005; The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes, 2007), but not others. (Differential contribution of testosterone and estradiol in the determination of cholesterol and lipoprotein profile in healthy middle-aged men, 2003) However, androgen deprivation treatment was found to cause an undesirable increase in CRP levels over time in a retrospective study of diabetic prostate cancer patients. (Effects of androgen deprivation on glycaemic control and on cardiovascular biochemical risk factors in men with advanced prostate cancer with diabetes, 2007)
The thrombotic process involves many factors, including tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI), which act as anti-coagulant factors, and the pro-thrombotic plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Testosterone levels correlate negatively with fibrinogen and PAI-1 and positively with tPA. (Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidemic men,1993)
Testosterone can also be locally converted to the 5-reduced dihydro-metabolites (5α and 5β reductions), which include 5α-DHT via the enzyme 5α-reductase type 1 and 2 and 5β-DHT via the enzyme 5β-reductase, a member of AKR superfamily. It is also important to recognize that the levels of 5α- and 5β-DHT in androgen target tissues that express 5-reductase are likely to be much higher than circulating plasma concentrations, which suggests that these metabolites act mainly as intracrine mediators in the androgen target tissues in which they are formed. For example, in the prostate gland, tissue 5α-DHT concentrations are 10-fold higher than in plasma. Thus the same may be true in the vascular wall. 5-reduced dihydro-metabolites, especially the 5β, could be more potent than testosterone in non-genomic vasodilatation. (Do androgens play a beneficial role in the regulation of vascular tone? Nongenomic vascular effects of testosterone metabolites, 2010)
Endothelial cells senescence
In S. cerevisiae, the Sir2 (silent information regulator-2) family of genes governs budding exhaustion and replicative life span (Sir2 links chromatin silencing, metabolism, and aging, 2000). Sir2 has been identified as an NAD+ -dependent histone deacetylase and is responsible for maintenance of chromatin silencing and genome stability. Mammalian sirtuin 1 (Sirt1), the closest homolog of Sir2, regulates the cell cycle, senescence, apoptosis and metabolism, by interacting with a number of molecules such as p53. Senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis, and SIRT1 has been recognized as a key regulator of vascular endothelial homeostasis, controlling angiogenesis, endothelial senescence, and dysfunction. SIRT1 plays an important role in prevention of endothelial senescence induced by oxidative stress. (Sirt1 modulates premature senescence-like phenotype in human endothelial cells, 2007; MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1, 2009)
Testosterone might improve parameters relating to CVD through mediation of endothelial progenitor cell activity.
Foresta et al. (Reduced number of circulating edothelial progenitor cells in hypogonadal men, 2006) investigated the effects of testosterone on the role that endothelial progenitor cells play in endothelial repair in 10 young idiopathic patients with hypogonadotrophic hypogonadism. They observed that the number of endothelial progenitor cells in hypogonadal men was fewer than the number in healthy control subjects. The authors further found that treating idiopathic hypogonadotropic hypogonadism with testosterone gel therapy, at 50 mg/d for 6 months, increased the number of circulating endothelial progenitor cells in these men. These findings point toward a decreased number of circulating endothelial progenitor cells as being apotential risk factor for CVD seen in patients with hypogonadism. Interestingly clinical data demonstrates that androgens can stimulate endothelial progenitor cells. Because all of the effects were abolished after flutamide (androgen receptor blocker) pretreatment, it was concluded that the effects were mediated via the androgen receptor. The levels of testosterone used in these studies were calculated to be in the normal physiological range. (Androgens stimulate endothelial progenitor cells through an androgen receptor-mediated pathway, 2008)