Abstract
Late onset hypogonadism was originally perceived as an academic topic. In the course of two decades it has become an issue impacting on everyday urology. For long time clinical conditions, such as cardiovascular disease, diabetes mellitus type 2, sexual dysfunction and urological complaints affecting the aging male, were regarded as independent clinical entities, treated by a number of medical specialists. Over the last decade their close interrelationship could be convincingly demonstrated. Declining testosterone levels in elderly appear to be central to the above pathologies. Epidemiological studies show that prostate disease occurs at an age when serum testosterone levels decline. It is now clear that erectile dysfunction is a local expression of endothelial dysfunction of the cardiovascular system. Testosterone deficiency is associated with an increased incidence of cardiovascular disease and diabetes mellitus, sequels of the metabolic syndrome. There is a relationship between the metabolic syndrome and lower urinary tract symptoms (LUTS). The pathophysiology of LUTS has much in common with the pathological substrate of erectile dysfunction with regard to vascular factors and the role of nitric oxide, explaining why phosphodiesterase type 5 inhibitors have often a beneficial effect on LUTS. It must be regarded an omission not to include testosterone measurements in the work-up of the LUTS, erectile dysfunction, cardiovascular disease and diabetes mellitus type 2. These conditions hinge on testosterone deficiency, and if testosterone deficiency can be proven, testosterone treatment can improve these conditions. There are many sites in the lower urinary tract where testosterone exerts effects.
REFERENCES
1). Vermeulen A, Rubens R, Verdonck L. Testosterone secretion and metabolism in old age. Acta Endocrinol Suppl (Copenh). 1971; 152:23.
2). Liu PY, Beilin J, Meier C, Nguyen TV, Center JR, Leedman PJ, et al. Age-related changes in serum testosterone and sex hormone binding globulin in Australian men: longitudinal analyses of two geographically separate regional cohorts. J Clin Endocrinol Metab. 2007; 92:3599–603.
3). Yassin AA, Saad F, Gooren LJ. Metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone. Andrologia. 2008; 40:259–64.
4). Saad F, Gooren L. The role of testosterone in the metabolic syndrome: a review. J Steroid Biochem Mol Biol. 2009; 114:40–3.
5). Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol. 2007; 52:54–70.
6). McVary K. Lower urinary tract symptoms and sexual dysfunction: epidemiology and pathophysiology. BJU Int. 2006; 97(Suppl 2):23–8. discussion 44-5.
7). Haider A, Gooren LJ, Padungtod P, Saad F. Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia. 2009; 41:7–13.
8). Amano T, Imao T, Takemae K, Iwamoto T, Nakanome M. Testosterone replacement therapy by testosterone ointment relieves lower urinary tract symptoms in late onset hypogonadism patients. Aging Male. 2010; 13:242–6.
9). Shigehara K, Sugimoto K, Konaka H, Iijima M, Fukushima M, Maeda Y, et al. Androgen replacement therapy contributes to improving lower urinary tract symptoms in patients with hypogonadism and benign prostate hypertrophy: a randomised controlled study. Aging Male. 2011; 14:53–8.
10). Verhamme KM, Dieleman JP, Bleumink GS, van der Lei J, Sturkenboom MC, Artibani W, et al. Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care–the Triumph project. Eur Urol. 2002; 42:323–8.
11). Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, Guess HA, et al. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status. J Urol. 1999; 162:1301–6.
12). Trifiro MD, Parsons JK, Palazzi-Churas K, Bergstrom J, Lakin C, Barrett-Connor E. Serum sex hormones and the 20-year risk of lower urinary tract symptoms in community-dwelling older men. BJU Int. 2010; 105:1554–9.
13). Rohrmann S, Nelson WG, Rifai N, Kanarek N, Basaria S, Tsilidis KK, et al. Serum sex steroid hormones and lower urinary tract symptoms in Third National Health and Nutrition Examination Survey (NHANES III). Urology. 2007; 69:708–13.
14). Litman HJ, Bhasin S, O'Leary MP, Link CL, McKinlay JB. BACH Survey Investigators. An investigation of the relationship between sex-steroid levels and urological symptoms: results from the Boston Area Community Health survey. BJU Int. 2007; 100:321–6.
15). Koritsiadis G, Stravodimos K, Mitropoulos D, Doumanis G, Fokitis I, Koritsiadis S, et al. Androgens and bladder outlet obstruction: a correlation with pressure-flow variables in a preliminary study. BJU Int. 2008; 101:1542–6.
16). Celayir S. Effects of different sex hormones on male rabbit urodynamics: an experimental study. Horm Res. 2003; 60:215–20.
17). Kasturi S, Russell S, McVary KT. Metabolic syndrome and lower urinary tract symptoms secondary to benign prostatic hyperplasia. Curr Urol Rep. 2006; 7:288–92.
18). Rohrmann S, De Marzo AM, Smit E, Giovannucci E, Platz EA. Serum C-reactive protein concentration and lower urinary tract symptoms in older men in the Third National Health and Nutrition Examination Survey (NHANES III). Prostate. 2005; 62:27–33.
19). Teoh H, Verma S. C-reactive protein, metabolic syndrome, and end organ damage. Metabolism. 2007; 56:1620–2.
20). Kupelian V, McVary KT, Barry MJ, Link CL, Rosen RC, Aiyer LP, et al. Association of C-reactive protein and lower urinary tract symptoms in men and women: results from Boston Area Community Health survey. Urology. 2009; 73:950–7.
21). Han JH, Lee YT, Kwak KW, Ahn SH, Chang IH, Myung SC, et al. Relationship between insulin resistance, obesity and serum prostate-specific antigen levels in healthy men. Asian J Androl. 2010; 12:400–4.
22). Demir O, Akgul K, Akar Z, Cakmak O, Ozdemir I, Bolukbasi A, et al. Association between severity of lower urinary tract symptoms, erectile dysfunction and metabolic syndrome. Aging Male. 2009; 12:29–34.
23). Hammarsten J, Högstedt B. Hyperinsulinaemia as a risk factor for developing benign prostatic hyperplasia. Eur Urol. 2001; 39:151–8.
24). Rosen RC. Update on the relationship between sexual dysfunction and lower urinary tract symptoms/benign prostatic hyperplasia. Curr Opin Urol. 2006; 16:11–9.
25). Yassin A, Saad F, Hoesl CE, Traish AM, Hammadeh M, Shabsigh R. Alpha-adrenoceptors are a common denominator in the pathophysiology of erectile function and BPH/LUTS–implications for clinical practice. Andrologia. 2006; 38:1–12.
26). El-Sakka AI. Lower urinary tract symptoms in patients with erectile dysfunction: is there a vascular association? Eur Urol. 2005; 48:319–25.
27). Khoo J, Piantadosi C, Worthley S, Wittert GA. Effects of a low-energy diet on sexual function and lower urinary tract symptoms in obese men. Int J Obes (Lond). 2010; 34:1396–403.
28). Moul S, McVary KT. Lower urinary tract symptoms, obesity and the metabolic syndrome. Curr Opin Urol. 2010; 20:7–12.
29). Rosenzweig BA, Bolina PS, Birch L, Moran C, Marcovici I, Prins GS. Location and concentration of estrogen, progesterone, and androgen receptors in the bladder and urethra of the rabbit. Neurourol Urodyn. 1995; 14:87–96.
30). Tek M, Balli E, Cimen B, Efesoy O, Oğuz I, Cayan S. The effect of testosterone replacement therapy on bladder functions and histology in orchiectomized mature male rats. Urology. 2010; 75:886–90.
31). Chavalmane AK, Comeglio P, Morelli A, Filippi S, Fibbi B, Vignozzi L, et al. Sex Steroid Receptors in Male Human Bladder: Expression and Biological Function. J Sex Med. 2010; 7:2698–713.
32). Keast JR. The autonomic nerve supply of male sex organs–an important target of circulating androgens. Behav Brain Res. 1999; 105:81–92.
33). Watkins TW, Keast JR. Androgen-sensitive preganglionic neurons innervate the male rat pelvic ganglion. Neuroscience. 1999; 93:1147–57.
34). Hall R, Andrews PL, Hoyle CH. Effects of testosterone on neuromuscular transmission in rat isolated urinary bladder. Eur J Pharmacol. 2002; 449:301–9.
35). Juan YS, Onal B, Broadaway S, Cosgrove J, Leggett RE, Whitbeck C, et al. Effect of castration on male rabbit lower urinary tract tissue enzymes. Mol Cell Biochem. 2007; 301:227–33.
36). Filippi S, Morelli A, Sandner P, Fibbi B, Mancina R, Marini M, et al. Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology. 2007; 148:1019–29.
37). McVary KT. Unexpected insights into pelvic function following phosphodiesterase manipulation–what's next for urology? Eur Urol. 2006; 50:1153–6.
38). Ehrén I, Adolfsson J, Wiklund NP. Nitric oxide synthase activity in the human urogenital tract. Urol Res. 1994; 22:287–90.
39). Kedia GT, Uckert S, Jonas U, Kuczyk MA, Burchardt M. The nitric oxide pathway in the human prostate: clinical implications in men with lower urinary tract symptoms. World J Urol. 2008; 26:603–9.
40). Smet PJ, Jonavicius J, Marshall VR, de Vente J. Distribution of nitric oxide synthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. Neuroscience. 1996; 71:337–48.
41). Werkstrom V, Svensson A, Andersson KE, Hedlund P. Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects. BJU Int. 2006; 98:414–23.
42). Chamness SL, Ricker DD, Crone JK, Dembeck CL, Maguire MP, Burnett AL, et al. The effect of androgen on nitric oxide synthase in the male reproductive tract of the rat. Fertil Steril. 1995; 63:1101–7.
43). Köhler TS, McVary KT. The relationship between erectile dysfunction and lower urinary tract symptoms and the role of phosphodiesterase type 5 inhibitors. Eur Urol. 2009; 55:38–48.
44). Roumeguere T, Zouaoui Boudjeltia K, Hauzeur C, Schulman C, Vanhaeverbeek M, Wespes E. Is there a rationale for the chronic use of phosphodiesterase-5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia? BJU Int. 2009; 104:511–7.
45). Holmäng S, Mårin P, Lindstedt G, Hedelin H. Effect of longterm oral testosterone undecanoate treatment on prostate volume and serum prostate-specific antigen concentration in eugonadal middle-aged men. Prostate. 1993; 23:99–106.
46). Karazindiyanoğlu S, Cayan S. The effect of testosterone therapy on lower urinary tract symptoms/bladder and sexual functions in men with symptomatic late-onset hypogonadism. Aging Male. 2008; 11:146–9.
47). Saad F, Gooren L, Haider A, Yassin A. An exploratory study of the effects of 12 month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Arch Androl. 2007; 53:353–7.
48). Saad F, Gooren L, Haider A, Yassin A. Effects of testosterone gel followed by parenteral testosterone undecanoate on sexual dysfunction and on features of the metabolic syndrome. Andrologia. 2008; 40:44–8.
49). Kalinchenko S, Vishnevskiy EL, Koval AN, Mskhalaya GJ, Saad F. Beneficial effects of testosterone administration on symptoms of the lower urinary tract in men with late-onset hypogonadism: a pilot study. Aging Male. 2008; 11:57–61.
50). St Sauver JL, Sarma AV, Jacobson DJ, McGree ME, Lieber MM, Girman CJ, et al. Associations between C-reactive protein and benign prostatic hyperplasia/lower urinary tract symptom outcomes in a population-based cohort. Am J Epidemiol. 2009; 169:1281–90.