Recent studies have investigated a correlation between lower urinary tract symptoms (LUTS) and endogenous testosterone levels and the effect of exogenous testosterone therapy on LUTS. Please briefly describe these studies and review the potential clinical implications of this research.



Response by Culley C. Carson III, MD
Numerous studies have reported a strong association between LUTS and erectile dysfunction (ED) that is independent of age and other comorbidities.^1,2 Also well-recognized is the relationship between ED and hypogonadism, and evidence suggests that testosterone levels inversely correlate with ED severity.^3,4

Two recent studies explored the relationship between LUTS and hypogonadism. Favilla et al investigated the relationship between LUTS severity and serum sex hormone levels in men with symptomatic benign prostatic hyperplasia (BPH) who required surgery for severe benign prostatic obstruction (n=122; mean age, 71 y; age range, 39-86 y).⁵ Prior to surgery, serum hormone levels (total testosterone [TT], free testosterone [FT], estradiol [E₂], prolactin, luteinizing hormone, and follicle-stimulating hormone) were measured, and BPH was assessed by digital rectal examination, transrectal ultrasonography, prostate-specific antigen (PSA) level, maximum urinary flow rate (Q_max), and International Prostate Symptom Score (IPSS).

The association between IPSS and serum sex hormone levels was evaluated: Total IPSS was significantly associated with TT (r=0.298, P=.020) and age (r=0.405, P<.001) but not with other serum sex hormones or FT.⁵ Though IPSS did not show a relationship with prostate volume or Q_max, PSA level (r=0.394, P<.001) and age (r=0.374, P<.001) correlated with prostate volume. Median TT levels were ascertained for the two cohorts: Eighty-two men had an IPSS of >19 (median TT, 425.7 ng/mL), and 40 men had an IPSS of <19 (median TT, 346.8 ng/mL). Men with a higher serum concentration of TT were significantly at increased risk for LUTS (P=.042). Concluding that age is the predominant predictor of LUTS and that LUTS severity is associated with serum TT level, the authors noted that the potential impact of testosterone on LUTS may be indirect.

In an analysis of data from the landmark prospective, community-based Rancho Bernardo study, logistic regression was used to examine whether baseline hormone concentrations correlated with the American Urological Association symptom index (AUASI).⁶ Baseline serum sex hormone concentrations measured between 1984 and 1987 were compared with results of an AUASI mailed to surviving participants in 2006. Men with complete data and no prostate cancer history (N=158) were included in the study. Mean (SD) age for serum sex steroid assessment was 58 (6.6) years, with mean (SD) follow-up period and LUTS assessment occurring at 20.3 (0.6) years. Age-adjusted logistic regression showed a significant inverse association between LUTS and the testosterone:dihydrotestosterone (DHT) ratio (P=.05). Men in the highest testosterone:DHT quartile had a 66% lower risk of LUTS compared with those in the lowest quartile. No significant association was found between LUTS and TT, DHT, E₂, testosterone:E₂ ratio, or dehydroepiandrosterone. Furthermore, men with higher bioavailable testosterone levels were at decreased risk for LUTS, but this nonstatistically significant association was not found evenly across quartiles.

These data support the results of other studies showing inverse associations between serum testosterone and LUTS and reinforce the need to clarify whether altered androgen serum concentrations are associated with increased risk of LUTS or clinical BPH.⁶ The implications of this research may be of great interest because it remains to be seen whether testosterone therapy exacerbates or improves LUTS in older men. Therefore, including LUTS and clinical BPH in testosterone therapy clinical trials may present outcomes that point to optimal treatment paradigms.

Response by Jason Hedges, MD, PhD, and Kevin T. McVary, MD
Testosterone plays an important role in physiologic, biochemical, and structural aspects of erectile function.³ Particularly in patients with BPH, testosterone therapy should be initiated after careful consideration and monitored closely, both because the prostate is androgen-dependent and because LUTS may be exacerbated by testosterone therapy. Studies investigating the effects of normalizing testosterone levels in older men suggest that reestablishing eugonadal testosterone levels may positively affect IPSS; this warrants further investigation in sufficiently powered, randomized, placebo-controlled trials.⁷

Amano et al recently published results of a pilot study to evaluate patients with hypogonadism and concomitant LUTS (N=41) treated with testosterone therapy daily for 3 months.⁸ Serum FT and scores from the Aging Male Survey (AMS), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), International Index of Erectile Function (IIEF-5), and IPSS and its subscores (post-voiding, storage, voiding symptoms, and quality-of-life) were assessed pre- and post-treatment. Serum FT levels rose significantly (P=.0047; paired t-test), total AMS scores decreased, and scores for the 3 AMS domains (psychological, physiologic, and sexual disturbance) were significantly reduced. Six of the 8 SF-36 domains and erectile function (P=.0001; paired t-test), as measured by IIEF-5, improved significantly. Total IPSS and all IPSS domains improved significantly, with marked improvement in voiding function. The study would have been enhanced had it been conducted as a placebo-controlled trial, according to the authors, but this was not feasible under Japanese governmental restrictions.

In an open-label pilot study, Kalinchenko et al evaluated the effect of testosterone therapy in older men with symptomatic LUTS whose plasma testosterone levels were in the hypogonadal range.⁹ Patients were randomized to receive either testosterone gel 50 mg/d for 3 months (n=10) or testosterone undecanoate (TU) intramuscular injection 1000 mg for 26 weeks (n=20). Both groups attained eugonadal plasma testosterone levels, though levels were higher in the group receiving TU. AMS and IIEF-5 scores and LUTS, as assessed by IPSS, improved significantly; there was no increase in prostate volume; and, notably, PSA levels decreased. The authors suggested future larger studies with a more rigorous design be undertaken to help resolve this clinically important issue.

Karazindiyanoğlu and Çayan evaluated hypogonadal men (N=25; age range, 38 to 73 y) presenting with sexual dysfunction and treated for 1 year with testosterone gel 50 to 100 mg/d.¹⁰ Before and after treatment, patients were evaluated with urodynamic studies (pressure-flow analysis) and measurements of prostate volume, PSA, and free PSA. IPSS, AMS, and IIEF-5 scores were assessed. A paired t-test was performed to compare parameters at baseline and after treatment. Mean AMS score decreased significantly (P=.001), and mean IIEF-5 score increased significantly (P=.001). Of note, whereas prostate volume increased significantly, mean IPSS decreased significantly. Furthermore, mean maximal bladder capacity significantly increased from baseline (P=.007), bladder compliance increased significantly (P=.032), and mean detrusor pressure decreased significantly (P=.017). The authors proposed that, in men with hypogonadism, testosterone therapy may improve LUTS/bladder function by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow.

In a study of middle-aged to elderly hypogonadal men treated with TU (N=95), Haider et al evaluated the effect of therapy on components of metabolic syndrome and other parameters.¹¹ Decreasing waist circumference correlated slightly with residual volume of urine but not with IPSS or prostate size. Improvement in metabolic syndrome parameters, IPSS, residual bladder volume, and C-reactive protein level were significant.

Though the precise impact of testosterone on androgen-dependent tissue remains to be elucidated, the complex interrelationship between hypogonadism, LUTS, and metabolic syndrome components may be explained by microanatomical changes causing fibrosis and loss of tissue elasticity, which, in turn, may correspond with the effect of testosterone on penile tissue in men with hypogonadism.⁹ In the future, epidemiologic studies may clarify the relationship between endogenous testosterone levels and LUTS, and large-scale randomized, placebo-controlled trials may help determine whether testosterone therapy affects risk of LUTS. Considering the range of current and novel therapies for the closely interrelated conditions of ED, LUTS, and hypogonadism, management strategies should consider all 3 conditions to optimally treat this patient population.

α-Blockers, 5α-reductase inhibitors, and phosphodiesterase type 5 (PDE5) inhibitors have been shown to improve LUTS.¹² Treatment algorithms are needed that consider the concomitant management of LUTS and hypogonadism as well as associated conditions, such as sexual dysfunction, ED, and obesity.

Links between specific lifestyle behaviors and LUTS/BPH are being studied. Findings suggest that a low-fat diet, including fruits and vegetables, known to be protective against obesity development may be protective against LUTS/BPH. A study of 184 patients with BPH and 246 control participants in Greece showed that increased fruit consumption was related to lower risk of BPH, whereas increased butter and margarine intake correlated with higher risk.¹³ The Prostate Cancer Prevention Trial showed that a diet low in fat and red meat and high in protein and vegetables is associated with reduced risk of BPH.¹⁴ Investigators analyzing a Health Professionals Follow-up Study (HPFS) cohort concluded that a vegetable-rich diet may lower the incidence of BPH.¹⁵ Consuming fruit and vegetables rich in β-carotene (P<.004), lutein (P<.0004), or vitamin C (P<.05), specifically, was inversely associated with risk of BPH. Generally, vegetable—but not fruit—consumption was inversely associated with BPH (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.80-0.99; P<.03).

Weight management and regular exercise during the early elderly years are associated with extended lifespan and good health and function for men in later life.¹⁶ The HPFS found strong associations between physical activity and a reduced risk of BPH.¹⁷ Both low- to moderate-intensity activity (eg, walking [OR, 0.73; 95% CI, 0.63-0.84]) and high-intensity activity (eg, racquetball or squash [OR, 0.69; 95% CI, 0.49-0.98]) were linked to significantly lower risk of BPH. Overall, low- to moderate-intensity activity (OR, 0.90; 95% CI, 0.86-0.93) imparted a slightly greater positive impact on total BPH risk than did high-intensity activity (OR, 0.97; 95% CI, 0.95-1.00). In addition, both weight loss and testosterone therapy raise testosterone levels, decrease fat mass, and improve insulin resistance.¹⁸

No single therapy for BPH/LUTS is superior to another; physicians should consider individual patient factors, efficacy, tolerability, treatment-related adverse effects (eg, retrograde ejaculation, diminished libido, ED), cost, and patient preference.¹² As evidence accumulates, considering how daily PDE5-inhibitor therapy that improves erectile function and BPH/LUTS and how treatment of hypogonadism with testosterone therapy affects LUTS and ED^8,19,20 may open new research avenues and shift the current treatment paradigm.

References

1. Jung JH, Jae SU, Kam SC, Hyun JS. Correlation between lower urinary tract symptoms (LUTS) and sexual function in benign prostatic hyperplasia: impact of treatment of LUTS on sexual function. J Sex Med. 2009;6(8):2299-2304.
2. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol. 2003;44(6):637-649.
3. Hwang TI, Lin YC. The relationship between hypogonadism and erectile dysfunction. Int J Impot Res. 2008;20(3):231-235.
4. Blute M, Hakimian P, Kashanian J, Shteynshluyger A, Lee M, Shabsigh R. Erectile dysfunction and testosterone deficiency. Front Horm Res. 2009;37:108-122.
5. Favilla V, Cimino S, Castelli T, Madonia M, Barbagallo I, Morgia G. Relationship between lower urinary tract symptoms and serum levels of sex hormones in men with symptomatic benign prostatic hyperplasia. BJU Int. 2010;106(11):1700-1703.
6. 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(11):1554-1559.
7. Yassin AA, El-Sakka AI, Saad F, Gooren LJ. Lower urinary-tract symptoms and testosterone in elderly men [review]. World J Urol. 2008;26(4):359-364.
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(4):242-246.
9. 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(2):57-61.
10. Karazindiyanoğlu S, Çayan 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(3):146-149.
11. 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(1):7-13.
12. Laborde EE, McVary KT. Medical management of lower urinary tract symptoms. Rev Urol. 2009;11(suppl 1):S19-S25.
13. Lagiou P, Wuu J, Trichopoulou A, Hsieh CC, Adami HO, Trichopoulos D. Diet and benign prostatic hyperplasia: a study in Greece. Urology. 1999;54(2):284-290.
14. Kristal AR, Arnold KB, Schenk JM, et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol. 2008;167(8):925-934.
15. Rohrmann S, Giovannucci E, Willett WC, Platz EA. Fruit and vegetable consumption, intake of micronutrients, and benign prostatic hyperplasia in US men. Am J Clin Nutr. 2007;85(2):523-529.
16. Yates L, Djoussé L, Kurth T, Buring JE, Gaziano M. Exceptional longevity in men: modifiable factors associated with survival and function to age 90 years. Arch Intern Med. 2008;168(3):284-290.
17. Platz EA, Kawachi I, Rimm EB, et al. Physical activity and benign prostatic hyperplasia. Arch Intern Med. 1998;158(21):2349-2356.
18. Grossman M. Testosterone and type 2 diabetes [review]. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):247-256.
19. Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology. 2010;75(6):1452-1458.
20. Porst H, McVary KT, Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol. 2009;56(4):727-735.

 

To view archived responses, click here.

back to top