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Chapter 5 In 2003, two review papers concluded that endogenous androgens do not show any consistent association with cardiovascular disease (CVD) risk 1,2. Apparently, androgens can exert both beneficial and deleterious actions on a multitude of factors implicated in the pathogenesis of atherosclerosis and CVD. Current evidence does not permit a meaningful assessment of the net effects of testosterone or DHEAS on CVD risks in men or women 3,2. There is agreement that total, free, and bioavailable testosterone levels decline progressively with age 4 and that many of the physiological changes that occur with advancing age, such as loss of bone and muscle mass, increased fat mass, and impairment of physical, sexual, and cognitive function, are similar to those associated with androgen deficiency in young men. However, the true relations between testosterone and health-related outcomes in older men have yet to be demonstrated and thus the possible benefits of testosterone supplementation. Besides beneficial effects, testosterone could also have health risks, particularly the risk of prostate cancer 5. Despite the paucity of safety data, the use of testosterone and other androgenic products is on the increase, as are media attention and public interest. The increased testosterone use by older men, without a clear understanding of its benefits or long-term risks, is a matter of concern. In this thesis we have concentrated on the question whether testosterone has beneficial effects on the cardiovascular system. In subsequent chapters of this thesis we examined whether endogenous androgen concentrations are associated with circulating homocysteine concentration, and high-sensitivity C- reactive protein (hs-crp) levels as a marker of chronic low-grade inflammation independent of other cardiovascular risk; and whether endogenous androgens related to aortic artery stiffness as an important marker of and/or intermediate outcome for future cardiovascular events. To these aims, cross sectional data were used. Furthermore, we conducted a randomized placebo-controlled study with testosterone capsules for six months, and examined the impact on blood pressure, chronic lowgrade inflammation as measured by hs-crp, and large artery stiffness. The shortcomings and merits of the individual studies presented in this thesis have been discussed in the previous chapters. Here I discuss certain aspects of the methods we used and the validity of our findings and provide some recommendations for future research. Main findings and implications Do we need bigger studies? We did not find independent relations between endogenous androgen levels and circulating homocysteine or hs-crp. Moreover, we showed that endogenous androgens concentrations within the physiologic range are not likely to be related to aortic stiffening. We also found that testosterone supplementation for a 6-month period had no clinical significant effect on blood pressure measurements (systolic blood pressure, diastolic blood pressure, pulse pressure), chronic low-grade inflammation measured by hs-crp levels and large artery stiffening in elderly men. Overall, these findings do not support the presence of a direct cardiovascular protective effect of testosterone in the short term. It should be noted that the size of the trial we conducted was 128
General discussion large compared to previous studies, but may still have been too small to detect small effects of testosterone. However, the confidence limits around the estimates leave little room for large effects, and if small effects have been missed the clinical relevance of these may be questioned. Should we use a higher dosage? It is possible that the testosterone dosage that we used was too low to exert a beneficial effect, at least on the cardiovascular risk factors under the investigation. However, the dose of testosterone we used is the same or higher than the dose that is used in clinical practice to treat hypogonadal men. For similar or even lower dosages significant beneficial effects have previously been shown with respect to quality of life 6, sexual interest and behavior 7, prostate symptoms and sexual function 8, and lean body mass and fat mass 9. At the time of the design of our trial, given the state of knowledge, we believe to have selected the appropriate dose if only in view of the possible hazards associated with testosterone supplementation. However, in future studies higher dosages may be considered, particularly since we did not find any material adverse response to the dose used in our trial. Should supplementation be tested over a longer period of time? The optimal time period for a study clearly depends on the type of outcome one aims to address. To definitively determine effects of testosterone supplementation of cancer risk or cognition, longer trials than the six month we studied are likely to be needed. It may, however, be questioned whether six months intervention is also too short to fully disclose effects on the endpoint measurement. In our view, given the existing evidence regarding the time course of the effect of various other types of treatment on blood pressure measurements, arterial stiffness and hs-crp levels, a 6-month intervention should be long enough to exert effects 10-13. Should alternative formulations be used? Testosterone has been in clinical use for over 60 years, yet the choice of preparations was very limited until recently. During the last several years a number of new injectable, transdermal and buccal preparations have become available, and as clinical experience accumulates the advantages and disadvantages of the various preparations become evident. The choice of what androgen preparation to use depends on practical aspects, such as feasibility of application, pharmacokinetic behavior and patient s needs and preferences. In recent years newer therapeutic modalities have been developed with the aim of producing testosterone levels that more closely approximate physiological levels, to avoid the potential adverse effects and improve patients acceptability. Also, capsules containing testosterone undecanoate are popular and the only preparation available for oral ingestion. However, oral testosterone undecanoate results in high inter-individual and intra-individual variability of serum testosterone values. 129
Chapter 5 In our trial, oral testosterone undecanoate was used, but the change in serum testosterone levels after six months of supplementation was lower than anticipated. This could reflect limited reliability of oral bioavailability, short half life and fluctuating serum levels 14.Our finding may imply that the efficacy of oral testosterone undecanoate for supplementation is limited. Yet, for example hematocrit showed a response consistent with a testosterone effect in spite of the lack of clear changes in serum testosterone. Newer testosterone preparations such as transdermal patches or gels which are applied once daily and can provide stable levels of serum testosterone within the normal range. These may therefore be preferable in future work 15,16. Furthermore, intramuscular injections of testosterone undecanoate leads to very stable serum testosterone levels within the normal range for about three months after a single dosage injection in hypogonadal subjects and may thus provide a better alternative for long term supplementation. However, the feasibility of this preparation as a preventive agent in healthy men still is not clear 17,18. References. 1. Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis 1996; 125:1-13. 2. Wu FCW, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev 2003; 24:183-217. 3. Muller M, van der Schouw YT, Thijssen JHH, Grobbee DE. Endogenous sex hormones and cardiovascular disease in men. J Clin Endocrinol Metab 2003; 88:5076-86. 4. Vermeulen A. Clinical review 24: androgens in the aging male. J Clin Endocrinol Metab 1991; 73:221-224. 5. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005; 60:1451-1457. 6. Park NC, Yan BQ, Chung JM., Lee KM. Oral testosterone undecanoate (Andriol) supplement therapy improves the quality of life for men with testosterone deficiency. Aging Male 2003; 6:86-93. 7. Skakkebaek N, Bancroft J, Davidson D, Warner P. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin Endocrinol (Oxf) 1981;14:49-61. 8. Hong J, Ahn T. Oral testosterone replacement in Korean patients with PADAM. Aging Male 2002; 5:52-56. 9. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003; 58:618-625. 10. Miura S, Tanaka E, Mori A, et al. Hormone replacement therapy improves arterial stiffness in normotensive postmenopausal women. Maturitas 2003; 45:293-298. 130
General discussion 11. Breithaupt-Grogler K, Leschinger M, Belz G, et al. Influence of antihypertensive therapy with cilazapril and hydrochlorothiazide on the stiffness of the aorta. Cardiovasc Drugs Ther 1996; 10:49-57. 12. Milionis HJ, Kakafika AI, Tsouli SG, et al. Effects of statin treatment on uric acid homeostasis in patients with primary hyperlipidemia. American Heart Journal 2004; 148:635-640. 13. Gol M, Akan P, Dogan E, Karas C, Saygili U, Posaci C. Effects of estrogen, raloxifene, and hormone replacement therapy on serum C-reactive protein and homocysteine levels. Maturitas 2006; 53:252-259. 14. Behre H, Wang C, Handelsman D, Nieschlag E. Testosterone: Action, Deficiency, Substitution. 3rd ed: Cambridge University Press. 2004;405-444. 15. Swerdloff R, Wang C. Transdermal androgens: pharmacology and applicability to hypogonadal elderly men. J Endocrinol Invest 2005; 28:112-116. 16. Kuhnert B, Byrne M, Simoni M, et al. Testosterone substitution with a new transdermal, hydroalcoholic gel applied to scrotal or non-scrotal skin: a multicentre trial. Eur J Endocrinol 2005; 153:317-326. 17. Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism. Expert Opinion on Pharmacotherapy 2005; 6:1751-1759. 18. Schubert M, Minnemann T, Hubler D, et al. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab 2004; 89:5429-5434. 131
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