51. Testosterone Metabolism

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51. Testosterone Metabolism




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Abstract and resume XV
Preface XXIII
Lis of abbreviations XXVII
Thesis structure XXXI
Chapter 1: General introduction 1
1.1. General aspects of doping 2
1.2. Anabolic androgenic steroids 12
1.3. EAAS and doping 23
1.4. Analytical strategies for the detection of
1.5. Metabolic studies by MS based methods 38
1.6. References 44
Chapter 2: Justification and objectives 63
2.1. Justification 65
2.2. Objectives 66
Part I: Re-exploring testosterone metabolism 69
Chapter 3: Testosterone metabolism revisited 75
3.1. Introduction 77
3.2. Experimental 78
3.3. Results and discussion 85
3.4. Conclusion 96
3.5. Reference 98

Chapter 4: Steroid metabolites conjugated with
cysteine 103

4.1. Introduction 105
4.2. Experimental 107
4.3. Results and discussion 119
4.4. Conclusions 136
4.5. References 137
Chapter 5: Hepatocyte studies 143
5.1. Introduction 145
5.2. Experimental 148
5.3. Results and discussion 152
5.4. Conclusion 159
5.5. References 160

Part II: Studies on cysteinyl metabolites 165
Chapter 6: Quantification of cysteinyl metabolites 171
6.1. Introduction 173
6.2. Experimental 176
6.3. Method validation 179
6.5. Results and discussion 182
6.6. Conclusions 190
6.7. References 191

Chapter 7: Population studies 195
7.1. Introduction 197
7.2. Experimental 199
7.3. Results 203
7.4. Discussion 207
7.5. Conclusions 208
7.6. References 208
Chapter 8: Factors affecting urinary excretion of
cysteinyl metabolites 211
8.1. Introduction 213
8.2. Experimental 215
8.3. Sample preservation 220
8.4. Endogenous factors 226
8.5. Exogenous factors 235
8.6. General Conclusions 242
8.7. References 244
Part III: New insights for doping control 253
Chapter 9: New insights for the detection of
testosterone oral misuse 257

9.1. Introduction 259
9.2. Experimental 261
9.3. Results 266
9.4. Discussion 272

9.5. Conclusions 276
9.6. References 277
Chapter 10: New insights for the detection of
testosterone gel and other EEAS 281

10.1. Introduction 283
10.2. Experimental 286
10.3. Results 291
10.4. Discussion 300
10.5. Conclusions 303
10.6. References 304
Chapter 11: Discussion and future works 309
11.1. Discussion 311
11.2. Suggestion for future works 313
Chapter 12: Conclusions 315
Annexes I 321
Annexes II 333
Annexes III 337

Testosterone Metabolism

Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials. This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement.

There has been an alarming increase, of epidemic proportions, in both obesity and diabetes in the general population with increased cardiovascular risk associated with type 2 diabetes mellitus (T2DM) and/or metabolic syndrome (MetS). MetS is defined as the presence of at least three of the following components: central obesity, hyperglycaemia (including T2DM), hypertension, hypertriglyceridaemia and low HDL-cholesterol (HDL-C). The MetS, a condition recognised by the World Health Organization, is associated with an increased risk of myocardial infarction, stroke and cardiovascular death. Reduced insulin sensitivity (known as insulin resistance) is the central biochemical defect associated with MetS and T2DM. Central obesity, hepatic steatosis and intracellular fat in muscle cells as well as lack of exercise and genetic factors precipitate the development of insulin resistance. Insulin resistance in turn promotes the development of glucose intolerance, hypertriglyceridaemia, low HDL-C, hypertension, endothelial dysfunction and a proinflammatory milieu, which combine to promote atherogenesis.

Men develop coronary artery disease and experience premature coronary events earlier than women, increasing the risk of cardiovascular mortality by more than twofold. This led to the belief that testosterone per se exerts a detrimental influence upon the cardiovascular system; however, evidence has emerged over recent years to suggest that a number of the cellular mechanisms intimate to the atherosclerotic process are beneficially modulated by testosterone. Indeed, it is well established that total and biologically available testosterone in men decreases with age and the age-associated decline may be related to the increased prevalence of cardiovascular disease (CVD) and comorbidities. In fact, testosterone deficiency has been reported in population studies to be associated with an increase in all-cause mortality, and this has been shown to be accounted for mainly by CVD (Khaw et al. 2007, Vikan et al. 2009, Araujo et al. 2011). Moreover, accumulating evidence suggests that testosterone deficiency is an independent cardiovascular risk factor and many recent reviews have focussed on the link between hypogonadism, MetS, T2DM and CVD (Makhsida et al. 2005, Shabsigh etal. 2008, Yassin et al. 2008, Corona et al. 2009, Diaz-Arjonilla et al. 2009, Jones & Saad 2009, Stanworth & Jones 2009, Traish et al. 2009, Zitzmann 2009a, Grossmann et al. 2010, Jones 2010a,b, Muraleedharan & Jones 2010, Moulana et al. 2011, Wang et al. 2011, Saad etal. 2012, Salam et al. 2012).

Testosterone levels themselves are considered to be lowered by chronic disease, making the designation of a causal relationship difficult to delineate (Morris & Channer 2012). Androgen deprivation therapy (ADT) as treatment for prostate cancer is a unique situation where the direct effects of lowering testosterone can be observed. While ADT reduces tumour growth and survival, it also increases the risk of coronary heart disease, diabetes and cardiovascular death (Levine et al. 2010, Jones 2011). This supports a key role of testosterone in atheroprotection, noted by a science advisory from the American Heart Association (Levine et al. 2010). Testosterone replacement therapy (TRT) in androgen-deficient men is now slowly being recognised for its therapeutic potential in the management of MetS and T2DM as well as its known benefit on quality of life and sexual health. Remarkably, physiologically replacing testosterone in men with T2DM and low testosterone levels has been demonstrated to significantly improve survival (Muraleedharan et al. 2011, Shores et al. 2012). However, with some confounding results, a lack of long-term placebo-controlled trials and an uncertainty regarding the underlying mechanisms of action, TRT remains controversial and its use as a protective metabolic hormone in CVD is at the centre of great debate. This review focuses on some of the clinical, experimental and mechanistic evidence implicating a role for testosterone in cardio-metabolic disorders.

Testosterone deficiency and metabolic risk
Testosterone deficiency has a high prevalence in men with T2DM (Dhindsa et al. 2004, Corona et al. 2006, Ding et al. 2006, Kapoor et al. 2007a, Corona et al. 2009). Furthermore, low testosterone is associated with impaired insulin sensitivity, increased percentage of body fat, truncal obesity, dyslipidaemia, hypertension and CVD (see Wang et al. (2011)). Epidemiological studies have consistently reported that up to 40% of men with T2DM have testosterone deficiency (Dhindsa et al. 2004, Corona et al. 2006, 2009, Ding et al. 2006, Kapoor et al. 2007a). Two recent systematic reviews and meta-analyses support that endogenous total and free testosterone was lower in subjects with MetS compared with those without (Brand et al. 2010, Corona et al. 2011). Several longitudinal studies demonstrate a similar association with a low testosterone concentration independently predicting the future development of insulin resistance, MetS and T2DM (Haffner et al. 1996, Stellato et al. 2000, Oh et al. 2002, Laaksonen et al. 2004, Kupelian et al. 2006, Rodriguez et al. 2007, Selvin et al. 2007, Haring et al. 2009).

The causality of this relationship between low testosterone and metabolic disease is unclear with obesity-induced androgen deficiency and hypogonadism-induced obesity both likely contributing to a bidirectional effect on disease pathology. Indeed, increased body fat is a well-known clinical feature of hypogonadism, and men with MetS at baseline are at an increased risk of developing hypogonadism based on an 11-year follow-up (Laaksonen et al. 2005). The finding that obesity impairs testosterone levels while low testosterone levels promote increased fat deposition was initially proposed as the hypogonadal–obesity cycle hypothesis by Cohen (1999). Testosterone is converted to 17βoestradiol (E2) by the enzymatic activity of aromatase in adipose tissue. Thus, with higher adipocyte expression of aromatase comes a subsequent reduction of circulating testosterone. Falling testosterone promotes increasing adipocyte number and fat deposition, which gradually leads to a further lowering effect on testosterone levels. In addition, the majority of the normal negative feedback of testosterone on the hypothalamo–pituitary axis occurs via its aromatisation (either in peripheral adipose tissue or centrally) to E2 (Hayes et al. 2000, 2001). Therefore, the excess aromatase activity from increased adipocyte numbers in obese men results in the suppression of gonadotrophin-mediated testosterone secretion leading to progressive hypogonadism.

The hypogonadal–obesity–adipocytokine hypothesis (Fig. 1) extends Cohen’s theory and explains why the body cannot respond to low testosterone levels by the normal homoeostatic compensatory production of androgens via increased gonadotrophin secretion to stimulate the testis (Jones 2007). E2 and the inflammatory adipocytokines tumour necrosis factor α (TNFα) and interleukin 6 (IL6) inhibit hypothalamic production of GNRH and subsequent release of LH and FSH from the pituitary. This, in turn, reduces gonadal stimulation and inhibits testosterone release, thus causing a state of hypogonadotrophic hypogonadism. Leptin, an adipose-derived hormone with a well-known role in regulation of body weight and food intake, also induces LH release under normal conditions via stimulation of hypothalamic GNRH neurons. GNRH neurons, however, exhibit little or no mRNA for leptin receptors (Finn et al. 1998). Kisspeptins are peptides secreted by specific neurons in the hypothalamus and may provide the functional link between leptin and downstream gonadal regulation as they play a central role in the modulation of GNRH secretion and subsequent LH release. Indeed, GNRH neurons in the hypothalamus possess the kisspeptin receptor and kisspeptin neurons express the leptin receptor (Roseweir & Millar 2009). In human obesity, whereby adipocytes are producing elevated amounts of leptin, the hypothalamic–pituitary axis becomes leptin resistant (Isidori et al. 1999, Mantzoros 1999). In addition, oestrogen receptors (ERs) are demonstrated on kisspeptin neurons and there is evidence from animal studies that leptin resistance, inflammation and oestrogens inhibit neuronal release of kisspeptin (see George et al. (2010)). Beyond hypothalamic action, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells of the testis to decrease testosterone production; therefore, elevated leptin levels in obesity may further diminish androgen status (Isidori et al. 1999). Moreover, increasing insulin resistance assessed by glucose tolerence test and hypoglycemic clamp was shown to be associated with a decrease in Leydig cell testosterone secretion in men



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