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Published on 16 September 2009

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Is there a need for testosterone replacement therapy in older men?

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Low levels of testosterone are a factor in the aetiology of common ailments of elderly men such as the metabolic syndrome and osteoporosis, and the central role of testosterone in erectile dysfunction is increasingly recognised

Aksam A Yassin
MD PhD EdD FEBU
Chairman
Institute of Urology &
Andrology
Segeberger Kliniken
Norderstedt-Hamburg
Germany

Ageing can be viewed as a time-related functional decline of health into the frailty of old age, with an ever-increasing vulnerability to disease and eventually to death. Among the many processes of ageing, endocrine changes are relatively easy to identify and quantify. The first reports on an age-related decline of testosterone were by Werner (1939)[1] and by Heller & Myers (1944),[2] and about 10 years later McGavack[3] drew a close parallel with the female menopause. The male climacteric ‘strikes at the core of what it is to be a man … his youthful sexual drive and performance and includes such symptoms as hot flashes, depression, insomnia, mood swings, irritability, impotence, decreased libido, weakness, lethargy and loss of bone mass.’ Terms like male menopause and male climacterium, or andropause, were used. It has, however, become clear that levels of testosterone do, indeed, show an age-related decline but that the characteristics of this age-related decline of testosterone are so fundamentally different from the menopause that drawing parallels generates more confusion than clarity. In men, testosterone production is affected in a slowly progressive way as part of the normal ageing process. It starts after the fourth decade of life, but it will rarely manifest in men under the age of 50 years and becomes usually only quantitatively significant in men over 60 years of age.[4] Disease is a strong predictor of the age-related decline of plasma testosterone.[5-7] It has been argued that lifestyle changes (reduction/prevention of obesity) may decelerate the age-related decline of plasma testosterone.[8]

Low testosterone induces disease
So, while it is clear that disease, and in particular features of the metabolic syndrome, suppress circulating testosterone levels, it has also been documented that low testosterone induces the metabolic syndrome,[9,10] dramatically demonstrated by findings in men with prostate cancer who undergo androgen ablation therapy.[11-13] A recent study showed convincingly that acute androgen deprivation reduces insulin sensitivity in young men.[14] Very well documented is that androgen deprivation leads to osteoporosis and increases bone fractures.[15] So, it is evident that low levels of testosterone are a factor in the aetiology of common ailments of elderly men such as the metabolic syndrome and osteoporosis.

Triad of cardiovascular disease, visceral obesity and erectile dysfunction
Cardiovascular disease, (visceral) obesity, erectile dysfunction and hypogonadism occur frequently in ageing men. Until recently they were viewed as more or less independent entities of the ageing male, usually treated by various medical specialties. With a more integrative approach to the health situation of the ageing male, these conditions appear closely interrelated in their aetiology, diagnostic strategy and treatment.[16] Treatment of one of the components will positively impact on the others. Most ageing men are inclined to view the above conditions as inevitable occurrences at advancing age and do not readily seek medical consultation. The complaint that may motivate them to seek medical advice is erectile dysfunction. Appropriate treatment of sexual dysfunction in elderly men will imply treatment of the other conditions mentioned above, which are aetiologically closely interrelated to the complaint. Low testosterone levels predict the development of the metabolic syndrome. Testosterone administration to men with lower-than-normal plasma testosterone levels will positively influence both erectile function and the metabolic syndrome.

Testosterone and erectile (dys)function
Over the last few years there has been a renewed interest in the role of testosterone in male (patho)physiology and, more particularly, in a better definition of the place of testosterone in erectile dysfunction (ED).[17] Recent studies provide convincing evidence that there is a powerful effect of testosterone on the anatomical and physiological substrate of penile erection. Furthermore, it has become clear that testosterone is not simply one of the many factors playing a role in erectile (dys)function. Indeed, circulating levels of testosterone are closely related to manifestations of other aetiological factors in ED, such as atherosclerotic disease and diabetes. Conversely, the latter are correlated with lower than-normal testosterone levels.[18] Therefore, the central role of testosterone in erectile (dys)function is increasingly recognised.

Erectile potency is physiologically a complex interaction of vascular, neural, metabolic, endocrine and, last but not least, psychological factors. Erectile difficulties often provide a window into the presence of pathology in these areas. Rather than a disease in itself, ED is, particularly in elderly men who have enjoyed normal sexual functions earlier in life, a manifestation of pathologies of the biological systems involved in erectile function.[18] But the advent of successful treatment modalities of erectile difficulties, such as the phosphodiesterase type 5 (PDE5) inhibitors, has led to a concept of erectile failure as an entity in itself rather than an expression of underlying pathology of its constituents. In other words, it has opened the door to viewing diagnosis and treatment of underlying pathology of erectile failure as redundant. But many men discontinue PDE5 inhibitors, which leads to a better definition of their ED and renewed interest in the role of testosterone. Testosterone appears to have profound effects on tissues of the penis involved in the mechanism of erection, and testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity. It has been shown that the full therapeutic potential of PDE5 inhibitors will only become manifest in a eugonadal state.[20]

Frailty
The vulnerable health status usually preceding theonset of overt disability is often referred to as frailty. Many elements of frailty are related to the neurological system, metabolism, joints, bones and muscles. Central to frailty is the dramatic decline in muscle mass and strength with ageing. Therefore, sarcopenia seems to be the major determinant of frailty. Several components of the frailty syndrome are related to the physiological actions of testosterone. Testosterone has effects on psychological functioning. Testosterone (or its aromatisation product, oestradiol) is required for maintenance of bone mineral density. Testosterone stimulates red blood cell formation. Testosterone has a profound effect on body composition. A significant characteristic of ageing and a factor in frailty is the loss of muscle mass and the increase in fat mass. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, thus reversing the development of a downward spiral of loss of muscle mass and increase of fat mass. Skeletal muscles of older men are as responsive to the anabolic effects of testosterone as those of younger men, indicating that age as such should not be an impediment to elderly men benefiting from the anabolic effects of testosterone.[21] So, while frailty is obviously a complex syndrome, some elements are androgen-associated and these may improve in men with subnormal testosterone levels.

Decrease of bone mineral density
With an increasing longevity, maintenance of good health is pivotal for independent living of older people. Osteoporotic fractures are a crippling occurrence in their lives and are an obvious impediment for most of the activities of daily living. Osteoporotic fractures have long been regarded as a female ailment, but with increasing longevity of men it appears that incidence and prevalence of osteoporotic fractures is not very different from the female rate, be it approximately 10 years later in the lives of men when their general health is deteriorating. A multitude of factors determine bone strength: genetic, nutritional (calcium), vitamin D (both nutritional or exposure to sunlight), physical activity and hormonal factors. Hormonal factors are significant throughout life from puberty onwards. In adolescence they are indispensable for the formation of peak bone mass. Throughout life sex steroids maintain bone formation. Surprisingly, in men oestrogens appear more significant for development of peak bone mass and maintenance of bone mineral density than androgens. In men oestrogens are derived from androgens and levels of oestrogens and androgens are strongly interrelated. Adequate androgen levels imply adequate oestrogen levels.

Guidelines
Professional organisations recognise that androgen deficiency in the ageing male should receive due interest and debate, not least because the demographics clearly demonstrate the increasing percentage of the population in the older age groups.[22,23] Whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention can only be resolved by sufficiently powered studies. In the views of a number of professional bodies, these studies are timely since studies in the past decade have produced evidence of the benefit of androgen treatment on multiple target organs of hypogonadal men, and recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men.[21] Long-term data on the effects of testosterone treatment in the older population are limited, and specifically data on the risks of prostate and cardiovascular disease are needed. A diagnosis of androgen deficiency should be based on consistent symptoms and signs and unequivocally low serum testosterone levels.

References
1. Werner A. The male climacteric. JAMA 1939;112:1441-3.
2. Heller C, Myers GB. The male climacteric, its symptomatology, diagnosis and treatment. JAMA 1944;126:472-7.
3. McGavack T. The male climacterium. J Am Geriatric Soc 1955;3:639-55.
4. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005;26:833-76.
5. Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991;73:1016-25.
6. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002;87:589-98.
7. Svartberg J, Midtby M, Bonaa KH, Sundsfjord J, Joakimsen RM, Jorde R. The associations of age, lifestyle factors and chronic disease with testosterone in men: the Tromso Study. Eur J Endocrinol 2003;149:145-52.
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9. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000;23:490-4.
10. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27:1036-41.
11. Smith RM LH, Nathan DM. Insulin sensitivity durin combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 2006;91:1305-8.
12. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 2006;106:581-8.
13. Haidar A, Yassin A, Saad F, Shabsigh R. Effects of androgen deprivation on glycaemic control and on cardiovascular biochemical risk factors in men with advanced prostate cancer with diabetes. Aging Male 2007;10:189-96.
14. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2007;92:4254-9.
15. Ryan CW, Huo D, Bylow K, Demers LM, Stadler WM, Henderson TO, Vogelzang NJ. Suppression of bone density loss and bone turnover in patients with hormonesensitive prostate cancer and receiving zoledronic acid. BJU Int 2007;100:70-5.
16. Shabsigh R, Arver S, Channer KS, Eardley I, Fabbri A,
Gooren L, Heufelder A, Jones H, Meryn S, Zitzmann M. The triad of erectile dysfunction, hypogonadism and the metabolic syndrome. Int J Clin Pract 2008;62:791-8.
17. Gooren LJ, Saad F. Recent insights into androgen action on the anatomical and physiological substrate of penile erection. Asian J Androl 2006;8:3-9.
18. Shabsigh R, Perelman MA, Lockhart DC, Lue TF, Broderick GA. Health issues of men: prevalence and correlates of erectile dysfunction. J Urol 2005;174:662-7.
19. Traish AM, Guay AT. Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence. J Sex Med 2006;3:382-407.
20. Saad F, Grahl AS, Aversa A, Yassin AA, Kadioglu A, Moncada I, Eardley I. Effects of testosterone on erectile function: implications for the therapy of erectile dysfunction. BJU Int 2007;99:988-92.
21. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, Magliano L, Storer TW. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005;90:678-88.
22. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91:1995-2010.
23.
Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morley JE, Schulman C, Wang C, Weidner W, Wu FC. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur Urol 2005;48:1-4.



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