madman
Super Moderator
Abstract
Testosterone levels in men begin declining in the early years of adulthood, with a 1-2% reduction/year. Low testosterone levels in men are associated with obesity, metabolic syndrome, diabetes mellitus, dyslipidemia, hypertension and increased cardiovascular mortality. However, observational studies of testosterone levels in males and their relationship with peripheral arterial disease (PAD) have yielded mixed results; only some cohorts show a clear association with low free testosterone levels. This discrepancy may, in part, be due to methodological issues with estimating free testosterone but also to different effects of testosterone on the vessel wall and metabolism. While testosterone improves glycemic control, has anti-obesity effects and induces vasodilation, it also stimulates platelet aggregation and increases the hematocrit. Androgen deprivation treatment for advanced prostate cancer may be associated with elevated cardiovascular risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.
2. TESTOSTERONE AND VASCULAR FUNCTION
Androgen receptors are widely distributed in several tissues, including vascular endothelial and smooth muscle cells 2. 51. In experimental animals, testosterone induces relaxation of many vascular beds, including coronary. mesenteric. iliac, renal, and femoral arteries — largely by mechanisms such as potassium channel opening and calcium channel antagonistic effects but also by modulating nitric oxide (NO) release [2, 6, 7). Although aging itself progressively impairs vascular function and accelerates atherosclerosis, there is evidence that androgen deficiency in males plays an independent role.
A meta-analysis of prospective and cross-sectional studies of testosterone replacement suggested that acute testosterone replacement was associated with an improvement of endothelial function measured by flow-mediated dilation of the brachial artery, while chronic treatment was associated with deterioration of endothelial function, but statistical significance was not reached for either effect [13)
Testosterone up-regulates the expression of thromboxane A2 receptors, which stimulates platelet aggregation [14], and increases hemoglobin and hematocrit [15], which may exert prothrombogenic effects 15, 16]. The main effects of testosterone on metabolism and vascular function are shown in Fig. (1).
3. EPIDEMIOLOGICAL DATA ON LEVELS OF TESTOSTERONE AND PAD
Overall, the association between low free testosterone and PAD remains equivocal since two large observational studies found an association [29, 30], while three other observational studies failed to do so [28, 31, 32]. The reasons for the discrepancies may go beyond differences in baseline characteristics of the studied cohorts and may involve methodological issues [27].
4. METHODOLOGICAL ISSUES REGARDING DETERMINING FREE AND BOUND TESTOSTERONE IN THE CIRCULATION
Only 1-2% of total testosterone circulates in blood free, while the vast majority is bound to carrier proteins: approximately 60% to SHBG, approximately 40% to albumin, and a small portion to cortisol-binding globulin and orosomucoid [27. 36]. Free testosterone is directly bioavailable to exert its hormonal effects [27, 36]. Testosterone bound to albumin is also considered bioavailable because of its low binding affinity [27. 37]. The properties of testosterone binding to proteins are incompletely understood. Some widely used assumptions are oversimplified and contribute to inaccurate linear models for calculating free testosterone [27]. Methods for direct measurement of free testosterone are currently plagued by numerous problems; more reliable assays for measuring free testosterone are needed [38].
5. TESTOSTERONE TREATMENT OF MALE HYPOGONADISM
Currently, the United States Food and Drug Administration (US FDA) recommends that men on testosterone treatment be advised of the potential CV risks [43]. Still, the European Medicines Agency has concluded that there is insufficient evidence to link testosterone treatment with increased CV risk [44]. Based on the available evidence, concerns about CV safety should not discourage the initiation of testosterone treatment in men with low CV risk, whereas men with high CV risk should be counseled that the CV safety of testosterone therapy is uncertain. The US FDA-mandated trial Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) will provide robust evidence on this topic [45].
Novel and possibly safer ways of testosterone replacement for hypogonadal males are being developed, including nasal and oral medications, that together with gels and patches - avoid long-term supraphysiological testosterone levels, characteristic of injectable preparations which strongly suppress the hypothalamic-pituitary-gonadal axis [46].
6. ANDROGEN DEPRIVATION THERAPY (ADT)
Overall, most observational studies and randomized trials found an increased risk of CV events with ADT [47.50]. Some heterogeneity in the results might be due to different selections of patients in terms of age, preexisting CVD, CV risk factors, and comorbidities, as well as the duration of observation [47, 50]. It should also be emphasized that adverse CV effects associated with ADT may vary depending on the type of therapy.
7. ABUSE OF TESTOSTERONE AS A PERFORMANCE-ENHANCING DRUG
Abuse of androgenic anabolic steroids, among which testosterone is most widely available as a performance-enhancing drug, is associated with adverse CV effects [52]. Repetitive injection of supraphysiologic doses of androgenic anabolic steroids has been associated with increased low-density lipoprotein cholesterol (LDL-C), decreased HDL-C, hypercoagulability, leading to myocardial infarction and cerebrovascular disease, and myocardial hypertrophy with fibrosis, leading to cardiac arrhythmias and heart failure [52]. Long-term anabolic-androgen abuse in strength-trained men aged 29-37 years resulted in lower maximal exercise capacity than in control subjects. and 20% of abusers had signs of coronary artery disease on CT angiography [53].
8. TRANS-MEN
In older comparisons with cis-gender people, trans-people showed an increased risk for myocardial infarction and death due to CVD, but the risk was consistently higher in trans-women than in trans-men [54, 55]. Newer data, albeit limited by the relatively small sample sizes and imperfect control populations, do not show an increased risk of CVD in transgender males receiving testosterone, indicating that appropriate testosterone dosing in trans-men is probably safe regardless of consistently increasing systolic blood pressure and LDL-C and lowering HDL-C levels [56].
CONCLUSION
Testosterone improves glycemic control, has anti-obesity effects and induces vasodilation, but it also stimulates platelet aggregation and increases hematocrit. The association of low testosterone levels in men with PAD is not unequivocally proven.
Androgen deprivation treatment for advanced prostate cancer may he associated with elevated CV risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.
Testosterone levels in men begin declining in the early years of adulthood, with a 1-2% reduction/year. Low testosterone levels in men are associated with obesity, metabolic syndrome, diabetes mellitus, dyslipidemia, hypertension and increased cardiovascular mortality. However, observational studies of testosterone levels in males and their relationship with peripheral arterial disease (PAD) have yielded mixed results; only some cohorts show a clear association with low free testosterone levels. This discrepancy may, in part, be due to methodological issues with estimating free testosterone but also to different effects of testosterone on the vessel wall and metabolism. While testosterone improves glycemic control, has anti-obesity effects and induces vasodilation, it also stimulates platelet aggregation and increases the hematocrit. Androgen deprivation treatment for advanced prostate cancer may be associated with elevated cardiovascular risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.
2. TESTOSTERONE AND VASCULAR FUNCTION
Androgen receptors are widely distributed in several tissues, including vascular endothelial and smooth muscle cells 2. 51. In experimental animals, testosterone induces relaxation of many vascular beds, including coronary. mesenteric. iliac, renal, and femoral arteries — largely by mechanisms such as potassium channel opening and calcium channel antagonistic effects but also by modulating nitric oxide (NO) release [2, 6, 7). Although aging itself progressively impairs vascular function and accelerates atherosclerosis, there is evidence that androgen deficiency in males plays an independent role.
A meta-analysis of prospective and cross-sectional studies of testosterone replacement suggested that acute testosterone replacement was associated with an improvement of endothelial function measured by flow-mediated dilation of the brachial artery, while chronic treatment was associated with deterioration of endothelial function, but statistical significance was not reached for either effect [13)
Testosterone up-regulates the expression of thromboxane A2 receptors, which stimulates platelet aggregation [14], and increases hemoglobin and hematocrit [15], which may exert prothrombogenic effects 15, 16]. The main effects of testosterone on metabolism and vascular function are shown in Fig. (1).
3. EPIDEMIOLOGICAL DATA ON LEVELS OF TESTOSTERONE AND PAD
Overall, the association between low free testosterone and PAD remains equivocal since two large observational studies found an association [29, 30], while three other observational studies failed to do so [28, 31, 32]. The reasons for the discrepancies may go beyond differences in baseline characteristics of the studied cohorts and may involve methodological issues [27].
4. METHODOLOGICAL ISSUES REGARDING DETERMINING FREE AND BOUND TESTOSTERONE IN THE CIRCULATION
Only 1-2% of total testosterone circulates in blood free, while the vast majority is bound to carrier proteins: approximately 60% to SHBG, approximately 40% to albumin, and a small portion to cortisol-binding globulin and orosomucoid [27. 36]. Free testosterone is directly bioavailable to exert its hormonal effects [27, 36]. Testosterone bound to albumin is also considered bioavailable because of its low binding affinity [27. 37]. The properties of testosterone binding to proteins are incompletely understood. Some widely used assumptions are oversimplified and contribute to inaccurate linear models for calculating free testosterone [27]. Methods for direct measurement of free testosterone are currently plagued by numerous problems; more reliable assays for measuring free testosterone are needed [38].
5. TESTOSTERONE TREATMENT OF MALE HYPOGONADISM
Currently, the United States Food and Drug Administration (US FDA) recommends that men on testosterone treatment be advised of the potential CV risks [43]. Still, the European Medicines Agency has concluded that there is insufficient evidence to link testosterone treatment with increased CV risk [44]. Based on the available evidence, concerns about CV safety should not discourage the initiation of testosterone treatment in men with low CV risk, whereas men with high CV risk should be counseled that the CV safety of testosterone therapy is uncertain. The US FDA-mandated trial Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) will provide robust evidence on this topic [45].
Novel and possibly safer ways of testosterone replacement for hypogonadal males are being developed, including nasal and oral medications, that together with gels and patches - avoid long-term supraphysiological testosterone levels, characteristic of injectable preparations which strongly suppress the hypothalamic-pituitary-gonadal axis [46].
6. ANDROGEN DEPRIVATION THERAPY (ADT)
Overall, most observational studies and randomized trials found an increased risk of CV events with ADT [47.50]. Some heterogeneity in the results might be due to different selections of patients in terms of age, preexisting CVD, CV risk factors, and comorbidities, as well as the duration of observation [47, 50]. It should also be emphasized that adverse CV effects associated with ADT may vary depending on the type of therapy.
7. ABUSE OF TESTOSTERONE AS A PERFORMANCE-ENHANCING DRUG
Abuse of androgenic anabolic steroids, among which testosterone is most widely available as a performance-enhancing drug, is associated with adverse CV effects [52]. Repetitive injection of supraphysiologic doses of androgenic anabolic steroids has been associated with increased low-density lipoprotein cholesterol (LDL-C), decreased HDL-C, hypercoagulability, leading to myocardial infarction and cerebrovascular disease, and myocardial hypertrophy with fibrosis, leading to cardiac arrhythmias and heart failure [52]. Long-term anabolic-androgen abuse in strength-trained men aged 29-37 years resulted in lower maximal exercise capacity than in control subjects. and 20% of abusers had signs of coronary artery disease on CT angiography [53].
8. TRANS-MEN
In older comparisons with cis-gender people, trans-people showed an increased risk for myocardial infarction and death due to CVD, but the risk was consistently higher in trans-women than in trans-men [54, 55]. Newer data, albeit limited by the relatively small sample sizes and imperfect control populations, do not show an increased risk of CVD in transgender males receiving testosterone, indicating that appropriate testosterone dosing in trans-men is probably safe regardless of consistently increasing systolic blood pressure and LDL-C and lowering HDL-C levels [56].
CONCLUSION
Testosterone improves glycemic control, has anti-obesity effects and induces vasodilation, but it also stimulates platelet aggregation and increases hematocrit. The association of low testosterone levels in men with PAD is not unequivocally proven.
Androgen deprivation treatment for advanced prostate cancer may he associated with elevated CV risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.
