Uro Flash
Uro Flash 2015 › Uro Flash Vol-2, No-4, 2015

Urological considerations in diabetics

Introduction

Diabetes, once considered the ‘rich man’s metabolic construct’, has now traduced into one of the biggest public health challenges of the 21st century given the rapidly rising prevalence worldwide that too in epidemic proportions.1   An increase in aging population, changing eating habits and obesity are identified as major contributors in the widening global enormity of this disease, particularly in the developing nations.2-4    Herein, as the aging population is also at risk of multiple other pathophysiological aberrations, it seems imperative to appraise how diabetes impacts the functioning of other organ systems. This short review aims to identify this association, in part, by evaluating the urological consequences of diabetes; those in fact have been recognized since 1930s.5   Pertinent data generated through multiple studies in this context have clearly associated the chronic hyperglycemia of diabetes with long-term damage, dysfunction and failure of multiple organ systems, including the urological system. Diabetes is associated with multiple urological consequences because of its impact on the function and structure of the lower urinary tract, in most cases relating to the bladder and/or prostate pathology.6,7   The impact seems significant since as many as 80% of individuals diagnosed with diabetes mellitus may exhibit lower urinary tract complications.8  

Effect of diabetes on bladder

Bladder dysfunction

Although not so detrimental as other co-morbidities, diabetic uropathy necessitates consideration as it contributes to a significantly reduced quality-of-life in those affected. Diabetes mellitus causes bladder remodelling leading to uropathy in a multifactorial way; however, clinical data extrapolating this association have revealed that detrusor overactivity, both neurogenic and myogenic, and changes in transmitter regulation leading to detrusor hyperexcitability, are major findings in the individuals with diabetic neuropathic bladders. It thus identifies bladder dysfunction as a progressive condition encompassing a broad spectrum of lower urinary tract symptoms (LUTS), including urinary urgency, frequency, nocturia, and incontinence.9   The observation might however vary depending on the stage of diabetes. While these findings seem to be related to an earlier stage of diabetes, later stages of this metabolic abnormality could be related to detrusor underactivity,2,10   and characterized by a large, flaccid, underactive bladder.11   It therefore postulates that LUTS would trend more towards early stage of diabetes. Regardless, for the mechanisms, hyperglycemia seems to have a direct modulatory effect on the detrusor smooth muscle cells; and data per se supports the theory that hyperglycemia-induced oxidative stress in detrusor smooth muscle and both micro and macrovascular events are responsible for the urological complications of diabetes. The characteristics may also differ based on gender as bladder dysfunction in women can be manifested as hypersensitivity (in 39-61% of the diabetic women) or neurogenic bladder, whereas in males, LUTS can be the major manifestations.12  

Bladder dysfunction in women

There exist numerous evidences reporting that bladder instability or hypersensitivity is a frequent finding in both men and women with diabetes, ranging from 39-61% of the patients.12   Though urinary incontinence is already a well-known clinical finding affecting almost 50% of middle aged and older women,9   diabetes – as an important independent risk factor for incontinence – accentuates this risk even further. Different aspects of diabetes severity, including glycemic control and microvascular complications resulting in damage to bladder innervation, have been suggested as possible mechanisms for increasing the incontinence.

Bladder dysfunction in men

In men, LUTS are common, age-related complaints often attributable to benign prostatic hyperplasia (BPH). These patients frequently present with complaints like straining, intermittency, postvoid dribbling, and weak stream that may signify urethral obstruction from BPH. However, it is important to consider that similar symptoms among men with diabetes may also result from bladder dysfunction due to denervation and poor detrusor contractility.9   An estimated 25% to nearly two-fold increased risk of LUTS has been identified in men with diabetes.12   Thus, while a clinical overlap exists between presence of BPH and LUTS, they can be manifestations of different pathophysiological pathways mediated though genetic, environmental, hormonal, neuropathic, and (micro)vascular influences, particularly in the diabetics.

Complex urinary associations among diabetic men therefore mostly include symptoms of urgency, frequency, and nocturia that may occur from detrusor overactivity, resulting from BPH and/or microvascular complications associated with diabetes, which increase detrusor hyperactivity. Overall, combination of different factors with differing time courses lead to these LUTS and known urodynamic findings; with biology of diabetes-associated bladder complications encompassing alternation in the detrusor smooth muscle, neuronal dysfunction, and urothelial dysfunction. Accordingly, the pathology often represents a combination of both storage and voiding abnormalities, and symptoms may vary from urge incontinence (risk of 40% to 80%) to the most severe expression of overflow incontinence (80% increased risk).12,13  

Flavoxate in patients with overactive bladder

Anticholinergic drugs could be considered in the treatment of overactive bladder, but have concerns related to side-effects associated with them.14   In contrast, flavoxate hydrochloride is a smooth muscle relaxant that is free from such concerns; and found major application in the treatment of urgency/urge incontinence; alleviating symptoms of LUTS and overactive bladder with minimal side-effects and high tolerability.15,16   Per se, it enjoys the status of being the first antispasmodic agent approved by the Food and Drug Administration (FDA) to treat symptoms of overactive bladder.17   The therapeutic rationale possibly stays with the presence of phosphodiesterase enzymes in the prostate and the detrusor muscle of the bladder, and the phosphodiesterase inhibitory property of flavoxate; while it also possesses moderate calcium antagonistic activity and local anesthetic properties.18,19     Research based on experimental models has suggested possible involvement of pertussis toxin-sensitive G-proteins in brain in the flavoxate induced suppression of the micturition reflex; abolishing isovolumetric rhythmic bladder contractions.20   The clinical effects of flavoxate in patients with detrusor overactivity and frequency, urgency and incontinence have been studied in multiple studies of patients with urgency/incontinence of various types; with reported improvement rates of up to 83%.21,22     In hyperactive neurogenic bladders, it was found to significantly increase the bladder capacity, without increasing the residual urine in them.23  

uroflash-volume

Bladder cancer

There exists ample evidence to indicate that individuals with diabetes have increased risk of several malignancies, including cancers of the colon and rectum. The same relationship for carcinogenic potential of diabetes has also been intensively evaluated in uro-oncology, and it seems that the incidence of bladder cancer, a common genitourinary malignancy, is higher in those with diabetes.24-28     Interestingly, further analysis has indicated a gender disparity, with risk being more in men, but this needs to be validated further.29  

Effect of diabetes on prostate

BPH

BPH and associated LUTS are highly prevalent in older men, representing a substantial challenge to the public health. The disease seems to have a multifactorial pathogenesis, though recent findings highlight the key role of metabolic disturbances, such as obesity and disturbances of glucose homeostasis, in its development. These findings are consonant with that derived from rising epidemiological evidences, which suggest that diabetes significantly increases the risks of BPH and LUTS.30   It therefore seems to establish that the risk of LUTS and BPH would be higher in a diabetic elderly as compared to an elderly subject without diabetes; and these symptoms will hence occur more frequently among men with diabetes compared to nondiabetic men.9   Although the exact relationship of BPH with diabetes remains unclear,31   a number of pathophysiological mechanisms have been proposed to potentially explain these associations; mediated through not only prostate pathology but dynamic components of the lower urinary tract function as well (Figure 1).32   Relating to the factors underlying this pathophysiology, one potential explanation of BPH in diabetic patients involves the insulin-like growth factor (IGF) – insulin may cause growth of prostate during type 2 diabetes by activating the IGF receptor.12   Incidentally, a recent study investigating the association between intraprostatic levels of IGF-1, IGF-2, as well as to evaluate the role of locally expressed IGF binding protein-3 (IGFBP-3) in BPH development in pre-diabetes, showed intraprostatic levels of IGFBP-3, prostate-specific antigen (PSA) and waist circumference to be positively associated with the prostate volume.33  

Tamsulosin in patients with BPH

The approach to patients with BPH has dramatically changed over the last few decades, with pharmacotherapy gaining wide significance over invasive methods for this common problem of aging men.34   The trend is that medical therapy is now the first used treatment for BPH; and in many cases resection of prostate may no longer be required.35,36       Within this therapeutic armamentarium, receptor-specific alpha-blockers, such as tamsulosin, comprise the first line of therapy because of their efficacy and rapid response seen upon initiation. These agents reduce bladder outlet obstruction by decreasing the alpha-adrenergic tone of the smooth muscle within the prostate, lessening the symptoms related to urinary storage, including frequency, nocturia, urgency, and incontinence.

Concurrently, innovations in drug-delivery systems have also been made to make the treatment even more acceptable, particularly considering the target population. Tamsulosin with Advanced Delivery System (ADS) is one such innovative technology that has been developed to ensure continuous and consistent release of tamsulosin throughout the entire gastrointestinal tract (GIT), including colon where water is poorly available. This is in contrast to conventional tamsulosin formulations that depend on the presence of water in the GIT to release the active ingredient. Thus, the advantage with ADS technology is that it provides a more constant drug exposure over 24 hours, with a smaller peak-to-trough fluctuation than the conventional formulations. Also, the dependency on food is reduced/eliminated. As such, the innovation appears superior to conventional modified release formulations of tamsulosin that have a variable absorption profile dependent on food intake and gastrointestinal transit time. In real practice, such independence to food intake might considerably improve the tolerability of tamsulosin considering that not all patients completely comply with the dosing recommendations in the patient leaflet.37   Accordingly, the ADS advantage thus equates with less adverse effects on physiological parameters and a more feasible application (Box 1).

uroflash-volume

Prostate cancer

While diabetes is a common metabolic disease, prostate cancer is a common malignancy, and the incidence of both is increasing worldwide.38   As many older patients may have both conditions concurrently, the link between diabetes and prostate cancer has been evaluated multiple times; but it is complex and not exactly clear yet.24,39     This is in contrast to many other cancers, like cancers of the breast, colon, and pancreas, with which diabetes has been clearly associated many times.40   Whilst prostate cancer and thus androgen deprivation therapy (ADT) are involved in diabetes relating as diabetes-associated carcinogenesis and ADT-related metabolic disorder, respectively; studies have also reported that diabetes mellitus might reduce the overall risk of prostate cancer.41   This apparent paradox may be due to the fact that while early diabetes is associated with increased insulin (accounting for increased risk of prostate cancer), longstanding diabetes is associated with insulin depletion and decreased IGF-1 signaling (accounting for decreased risk of prostate cancer).42   A recent meta-analysis of nine studies also appeared corroborating such positive association, and suggested a possible inverse relationship between diabetes mellitus and prostate cancer of different stage or grade.43   However, the evidence appears contrasting in general. For instance, many population-based studies have shown that unlike other malignancies, type 2 diabetes is associated with a lower incidence of prostate cancer; but, at the same time, large cohort studies have reported an association of diabetes with advanced high-grade prostate cancer. These evidences show that the relationship between diabetes, insulin resistance, testosterone milieu, PSA, and prostate cancer and its malignant potential is subtle, and needs to be interpreted with caution. While at one end, reason for lower prevalence of prostate cancer among diabetic men is not exactly clear; low serum testosterone environment and PSA levels in them could account for increased risk of advanced disease at diagnosis where their PSA level reaches a certain cut-off/threshold. Treatment of prostate cancer using ADT (the therapeutic mainstay for men with metastasis or recurrent disease following definitive local therapy44  ) exerts similarly contrasting effect. It has been observed that insulin resistance appears in 25%-60% of the patients three months after introduction of ADT; and long-term ADT leads to a higher incidence of diabetes, the mechanism of which remains unclear.41   Nevertheless, it may finally be conceived that pre-existing diabetes invariably affects the risk and outcomes of prostate cancer.45  

Prostatitis

uroflash-volume

Prostatitis is a common and clinically important genitourinary disorder, the risk of which is especially high among those with diabetes, and immunocompromised.46,47     Clinical presentation of the disease is variable and can range from mild LUTS to emphysematous prostatic abscess and full sepsis;48   Box 2 shows the consensus classification of prostatitis syndromes as provided by the National Institutes of Health (NIH).49   Nonetheless, within this classification, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an important variant, being one of the most common diagnoses arising out of urologic office visits.50   While antimicrobials are used as a first-line agent in these patients, second-line pharmacotherapy includes alpha-blockers, 5-alpha reductase inhibitors and anti-inflammatories for providing symptomatic relief especially in those with more severe symptoms.51  

Urinary infections and asymptomatic bacteriuria

Diabetic patients have a generally increased risk of infections, with urinary tract being the most frequent site of involvement. As such, while bacterial cystitis is frequently suffered by diabetic patients; hospitalization due to pyelonephritis also occurs more frequently in the diabetics. Several factors specific to diabetes, such as glucosuria, adherence of bacteria to the uroepithelium, and immune dysfunction, possibly account for such predilection to urinary infections in this population.52   Nevertheless, the causative pathogen (Escherichia coli is mostly the same as in non-diabetics.9,12   Furthermore, the difference in predisposition seems more pronounced in women, both in symptomatic infections and asymptomatic bacteriuria (presence of bacteria in bladder urine in an asymptomatic individual).53-55  

Many urinary tract infections (UTIs) are asymptomatic, but whether asymptomatic bacteriuria precedes symptomatic infections in general is not exactly clear. Regardless, this entity has clearly been identified as a risk factor for symptomatic UTIs in women with diabetes, and they are at risk for developing more recurrent and more serious consequences.56   Generally, asymptomatic bacteriuria is found in 2%-5% of healthy adult women, is quite unusual in healthy men, and has been claimed to be 2 to 4 times more common in women with diabetes than in healthy women. A study evaluating the prevalence of and risk factors for asymptomatic bacteriuria in women 18-75 years with and without diabetes showed that more than one-fourth (26%) of women with diabetes had asymptomatic bacteriuria compared to 6% of the control subjects (women without diabetes).57   A more recent meta-analysis however shows that the prevalence of asymptomatic bacteriuria is higher among men, children and adolescents with diabetes as well, as compared with healthy control subjects, and all patients with asymptomatic bacteriuria more often have albuminuria and symptomatic UTIs.58  

Nitrofurantoin in patients with urinary infections

Antimicrobial agents are probably the most reflective advance in the management of UTIs. Numerous antibiotics are available for this application, but the choice depends on many factors, such as subtype of infection, patient subgroup, resistance patterns, and characteristics of different agents. Nevertheless, amidst the concerns of rising resistance for most antimicrobials, demonstration of efficacy with minimal drug resistance makes nitrofurantoin an attractive agent to treat and prevent UTIs59  ; with effectiveness shown in diabetics and those with asymptomatic bacteriuria as well.60-64    Analysis of antimicrobial susceptibility patterns of urinary isolates has shown high bactericidal rate of nitrofurantoin (bactericidal to a mean of 95% of E. coli   UTIs) compared to the increasing resistance rates of ciprofloxacin, levofloxacin and co-trimoxazole.65   Thus, the broad range of bactericidal action of nitrofurantoin could possibly explain the relative lack of accumulated resistance to the drug over the past many years, making it a drug of choice for this indication. A sustained release formulation of nitrofurantoin has also been tested,66   which may further improve compliance by offering an advantage of fewer fluctuations in plasma drug concentration, and better tolerability.

Conclusion

Both diabetes and urological diseases are very common clinical problems, and appear to be closely related. Diabetes is a clear risk factor for multiple urological complications owing to its effect on the urinary tract pathophysiology, and is therefore associated with an earlier onset and increased severity of urological consequences. Since many of these urological complaints might be an initial presentation of earlier undiagnosed diabetes, it is important to promptly recognize this association in order to diagnose and manage diabetes early, and thus avoid more serious complications in the future. For domain outcomes, the implications seem widely relevant for the urologists who should be aware of the potential effects of diabetes on the urological systems. While effective control of blood glucose is imperative for optimal outcome in all diabetics, treatment needs to be tailored for individual urological manifestations. For most common problems, like BPH, overactive balder and urinary infections, effective treatments are available – such as tamsulosin, flavoxate and nitrofurantoin – which would help in alleviating both the disease burden and bother.

References

  1. Jankun J, Al-Senaidy A, Skrzypczak-Jankun E. Can inactivators of plasminogen activator inhibitor alleviate the burden of obesity and diabetes? (Review).Int J Mol Med. 2012 Jan;29(1):3-11.
  2. Kirschner-Hermanns R, Daneshgari F, Vahabi B, Birder L, Oelke M, Chacko S. Does diabetes mellitus-induced bladder remodeling affect lower urinary tract function? ICI-RS 2011.Neurourol Urodyn. 2012 Mar;31(3):359-64.
  3. Chu KF, Rotker K, Ellsworth P. The impact of obesity on benign and malignant urologic conditions.Postgrad Med. 2013 Jul;125(4):53-69.
  4. Chaturvedi N. The burden of diabetes and its complications: trends and implications for intervention.Diabetes Res Clin Pract. 2007 May;76 Suppl 1:S3-12.
  5. Hill SR, Fayyad AM, Jones GR. Diabetes mellitus and female lower urinary tract symptoms: a review.Neurourol Urodyn. 2008;27(5):362-7.
  6. Goldstraw MA, Kirby MG, Bhardwa J, Kirby RS. Diabetes and the urologist: a growing problem.BJU Int. 2007 Mar;99(3):513-7.
  7. Fleshner NE, Bhindi B. Metabolic syndrome and diabetes for the urologist.Can Urol Assoc J 2014;8(7-8):S159-61.
  8. Daneshgari F, Moore C. Diabetic uropathy.Semin Nephrol. 2006 Mar;26(2):182-5.
  9. Brown JS, Wessells H, Chancellor MB, Howards SS, Stamm WE, Stapleton AE, Steers WD, Van den Eeden SK, Mcvary KT. Urologic complications of diabetes.Diabetes care 2005;28(1):177-185.
  10. Fedele D. Therapy Insight: sexual and bladder dysfunction associated with diabetes mellitus.Nat Clin Pract Urol. 2005;2(6):282-90; quiz 309.
  11. Chartier-Kastler E, Robain G, Mozer P, Ruffion A. Lower urinary tract dysfunction and diabetes mellitus.Prog Urol. 2007 May;17(3):371-8.
  12. Arrellano-Valdez F, Urrutia-Osorio M, Arroyo C, Soto-Vega E. A comprehensive review of urologic complications in patients with diabetes.SpringerPlus 2014;3:549.
  13. Golbidi S, Laher I. Bladder dysfunction in diabetes mellitus.Frontiers in Pharmacology 2010;1:Article 136.
  14. Roxburgh C, Cook J, Dublin N. Anticholinergic drugs versus other medications for overactive bladder syndrome in adults.Cochrane Database Syst Rev. 2007 Jul 18;(3):CD003190.
  15. Ruffmann R, Sartani A. Flavoxate, a drug with smooth muscle relaxing activity.Drugs Exp Clin Res. 1987;13(1):57-62.
  16. Zor M, Aydur E, Dmochowski RR. Flavoxate in urogynecology: an old drug revisited.Int Urogynecol J. 2014 Dec 6. [Epub ahead of print].
  17. Hesch K. Agents for treatment of overactive bladder: a therapeutic class review.Proc (Bayl Univ Med Cent). 2007 Jul;20(3):307-14.
  18. Sarma AV, Wei JT. Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms.N Engl J Med 2012;367:248-57.
  19. Giuliano F, Ückert S, Maggi M, Birder L, Kissel J, Viktrup L. The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia.Eur Urol. 2013;63(3):506-16.
  20. Oka M, Kimura Y, Itoh Y, Sasaki Y, Taniguchi N, Ukai Y, Yoshikuni Y, Kimura K. Brain pertussis toxin-sensitive G proteins are involved in the flavoxate hydrochloride-induced suppression of the micturition reflex in rats.Brain Res. 1996 Jul 15;727(1-2):91-8.
  21. Gu FL, Reng ZY, Shang GZ, Shao HX, Wang B, Cheng ZD, Jiang Y, Zhao WP, Zheng JF, Qu CT, et al. Treatment of urgency and urge incontinence with flavoxate in the People’s Republic of China.J Int Med Res. 1987 Sep-Oct;15(5):312-8.
  22. Andersson KE, Chapple CR, Cardozo L, Cruz F, Hashim H, Michel MC, Tannenbaum C, Wein AJ.. Committee 8. Pharmacological Treatment of Urinary Incontinence. Available at: http://www.ics.org/Publications/ICI_4/files-book/Comite-8.pdf [Accessed on 12/9/2014].
  23. Pedersen E. Studies on the effect and mode of action of flavoxate in human urinary bladder and sphincter.Urol Int. 1977;32(2-3):202-8.
  24. Brod’ak M, Romzova M, Kosina J. Urologic surgery in diabetes.Vnitr Lek. 2008 May;54(5):457-63.
  25. Cantiello F, Cicione A, Salonia A, Autorino R, De Nunzio C, Briganti A, Gandaglia G, Dell’Oglio P, Capogrosso P, Damiano R. Association between metabolic syndrome, obesity, diabetes mellitus and oncological outcomes of bladder cancer: A systematic review.Int J Urol. 2014 Oct 23. doi: 10.1111/iju.12644
  26. Fang H, Yao B, Yan Y, Xu H, Liu Y, Tang H, Zhou J, Cao L, Wang W, Zhang J, Zhao L, Chen X, Zhang F, Zhao Y. Diabetes mellitus increases the risk of bladder cancer: an updated meta-analysis of observational studies.Diabetes Technol Ther. 2013 Nov;15(11):914-22.
  27. Yang XQ, Xu C, Sun Y, Han RF. Diabetes mellitus increases the risk of bladder cancer: an updated meta-analysis.Asian Pac J Cancer Prev. 2013;14(4):2583-9.
  28. Zhu Z, Zhang X, Shen Z, Zhong S, Wang X, Lu Y, Xu C. Diabetes mellitus and risk of bladder cancer: a meta-analysis of cohort studies.PLoS One. 2013;8(2):e56662.
  29. Zhu Z, Wang X, Shen Z, Lu Y, Zhong S, Xu C. Risk of bladder cancer in patients with diabetes mellitus: an updated meta-analysis of 36 observational studies.BMC Cancer 2013;13:310.
  30. Sarma AV, Kellogg Parsons J. Diabetes and benign prostatic hyperplasia: emerging clinical connections.Curr Urol Rep. 2009 Jul;10(4):267-75.
  31. Stamatiou K, Lardas M, Kostakos E, Koutsonasios V, Michail E. The Impact of Diabetes Type 2 in the Pathogenesis of Benign Prostatic Hyperplasia: A Review. Hindawi Publishing Corporation Advances in Urology Volume 2009, Article ID 818965, 3 pages. doi:10.1155/2009/818965.
  32. Sarma AV, St. Sauver JL, Hollingsworth JM, Jacobson DL, McGree ME, Dunn RL, Lieber MM, Jacobsen SJ, and the Urologic Diseases in America Project. Diabetes treatment and progression of benign prostatic hyperplasia in community dwelling black and white men.Urology 2012;79(1):102-108.
  33. Protopsaltis I, Ploumidis A, Sergentanis TN, Constantoulakis P, Tzirogiannis K, Kyprianidou C, Papazafiropoulou AK, Melidonis A, Delakas D. Linking Pre-Diabetes with Benign Prostate Hyperplasia. IGFBP-3: A Conductor of Benign Prostate Hyperplasia Development Orchestra?PLoS ONE 8(12): e81411.
  34. Sarma AV, Jacobson DJ, McGree ME, Roberts RO, Lieber MM, Jacobsen SJ. A population based study of incidence and treatment of benign prostatic hyperplasia among residents of Olmsted County, Minnesota: 1987 to 1997. J Urol. 2005 Jun;173(6):2048-53.
  35. Pinto F, Racioppi M, Sacco E, Totaro A, Brescia A, Volpe A, Gardi M, Bassi PF. Progression, risk factors and subsequent medical management of symptomatic benign prostatic hyperplasia.Arch Ital Urol Androl. 2009 Mar;81(1):1-8.
  36. Long R, Connolly S, Sweeney P. Impact of pharmacotherapy on the incidence of transurethral prostatectomy for benign prostatic hyperplasia and the implications for surgical training.Ir Med J. 2010 Oct;103(9):281-2.
  37. Speakman M. Efficacy and safety of tamsulosin OCAS.BJU international 2006;98(2): 13-17.
  38. Anwar MA, Kheir WA, Eid S, Fares J, Liu X, Eid AH, Eid AA. Colorectal and prostate cancer risk in diabetes: metformin, an actor behind the scene.Journal of Cancer 2014;5(9):736-744.
  39. Joost HG. Diabetes and cancer: Epidemiology and potential mechanisms.Diabetes & Vascular Disease Research 2014;11(6):390-394.
  40. Cannata D, Fierz Y, Vijayakumar A, LeRoith D. Type 2 diabetes and cancer: what is the connection?Mt Sinai J Med. 2010 Mar-Apr;77(2):197-213.
  41. Hara N. Prostate Carcinogenesis with Diabetes and Androgen- Deprivation-Therapy-Related Diabetes: An Update. Hindawi Publishing Corporation.Experimental Diabetes Research 2012;Article ID 801610:8 pages. doi:10.1155/2012/801610.
  42. Grossmann M, Wittert G. Androgens, diabetes and prostate cancer.Endocrine-Related Cancer 2012;19:F47-F62.
  43. Xu H, Jiang HW, Ding GX, Zhang H, Zhang LM, Mao SH, Ding Q. Diabetes mellitus and prostate cancer risk of different grade or stage: a systematic review and meta-analysis.Diabetes Res Clin Pract. 2013 Mar;99(3):241-9.
  44. Smith MR. Treatment-related diabetes and cardiovascular disease in prostate cancer survivors.Annals of Oncology 2008;19(Supplement 7):vii86-vii90.
  45. Snyder CF, Stein KB, Barone BB, Peairs KS, Yeh HC, Derr RL, Wolff AC, Carducci MA, Brancati FL. Does pre-existing diabetes affect prostate cancer prognosis? A systematic review.Prostate Cancer Prostatic Dis. 2010;13(1):58-64.
  46. Brede CM, Shoskes DA. The etiology and management of acute prostatitis.Nat Rev Urol. 2011 Apr;8(4):207-12.
  47. Bilo HJ. Susceptibility to infection in patients with diabetes mellitus.Ned Tijdschr Geneeskd. 2006 Mar 11;150(10):533-4.
  48. Wen SC, Juan YS, Wang CJ, Chang K, Shih MC, Shen JT, Wu WJ, Jang MY. Emphysematous prostatic abscess: case series study and review.Int J Infect Dis. 2012 May;16(5):e344-9.
  49. Tunuguntla HSGR, Evans CP. Management of prostatitis.Prostate Cancer and Prostatic Diseases 2002;5:172-179.
  50. Murphy AB, Nadler RB. Pharmacotherapy strategies in chronic prostatitis/chronic pelvic pain syndrome management.Expert Opin Pharmacother. 2010 Jun;11(8):1255-61.
  51. Nickel JC, et al. Treatment of chronic prostatitis/chronic pelvic pain syndrome with tamsulosin: a randomized double blind trial.J Urol (Baltimore) 2004; 171: 1594-7.
  52. Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014 Mar;103(3):373-81.
  53. Julka S. Genitourinary infection in diabetes.Indian J Endocrinol Metab. Oct 2013;17(Suppl1):S83-S87.
  54. Muller LMAJ, Gorter KJ, Hak E, Goudzwaard WL, Schellevis FG, Hoepelman AIM, Rutten GEHM. Increased Risk of Common Infections in Patients with Type 1 and Type 2 Diabetes Mellitus.Clinical Infectious Diseases 2005;41:281-8.
  55. Ludwig E. Urinary tract infections in diabetes mellitus.Orv Hetil. 2008 Mar 30;149(13):597-600.
  56. Geerlings SE, Stolk RP, Camps MJL, Netten PM, Collet TJ, Hoepelman AIM, on behalf of the diabetes women asymptomatic bacteriuria Utrecht study group. Risk Factors for Symptomatic Urinary Tract Infection in Women With Diabetes.Diabetes Care 2000;23:1737-1741.
  57. Geerlings SE, Stolk RP, Camps MJL, Netten PM, Hoekstra JBL, Bouter KP, Bravenboer B, Collet JT, Jansz AR, Hoepelman AIM, for the diabetes mellitus women asymptomatic bacteriuria UTRECHT study group. Asymptomatic Bacteriuria May Be Considered a Complication in Women With Diabetes.Diabetes Care 2000;23:744-749.
  58. Renko M, Tapanainen P, Tossavainen P, Pokka T, Uhari M. Meta-Analysis of the Significance of Asymptomatic Bacteriuria in Diabetes.Diabetes Care 2011;34:230-235.
  59. Karlowsky JA, Thornsberry C, Jones ME, Sahm DF. Susceptibility of antimicrobial-resistant urinary Escherichia coli isolates to fluoroquinolones and nitrofurantoin.Clin Infect Dis. 2003 Jan 15;36(2):183-7.
  60. Lopez-Carmona JM1, Salazar-Lopez MA, Rodriguez-Moctezuma JR, Lopez-Delgado ME, Manrique-Lizarraga JM. Acute cystitis in women with type 2 diabetes. Three antimicrobial schemes.Rev Med Inst Mex Seguro Soc. 2007 Sep-Oct;45(5):503-12.
  61. Ruxer J, Mozdzan M, Loba J, Markuszewski L. Fosfomycin, co-trimoxazole and nitrofurantoin in the treatment of recurrent uncomplicated urinary tract infections in type 2 diabetes mellitus.Wiad Lek. 2007;60(5-6):235-40.
  62. Mozdzan M, Ruxer J, Siejka A, Loba J, Markuszewski L. Efficacy of nitrofurantoin in the treatment of chronic urinary tract infections in patients with type 2 diabetes mellitus.Pol Merkur Lekarski. 2006 Nov;21(125):434-8.
  63. Jha BK, Singh YI, Khanal LK, Yadab VC, Sanjana RK. Prevalence of asymptomatic bacteriuria among elderly diabetic patients residing in Chitwan.Kathmandu Univ Med J (KUMJ). 2009 Apr-Jun;7(26):157-61.
  64. Odetoyin WB, Aboderin AO, Ikem RT, Kolawole BA, Oyelese AO. Asymptomatic bacteriuria in patients with diabetes mellitus in Ile-Ife, South-West, Nigeria.East Afr Med J. 2008 Jan;85(1):18-23.
  65. Kashanian J, Hakimian P, Blute M Jr, Wong J, Khanna H, Wise G, Shabsigh R. Nitrofurantoin: the return of an old friend in the wake of growing resistance.BJU Int. 2008 Dec;102(11):1634-7.
  66. Bhatt N, Goyal S. Int. J. Sustained-Release Matrix Tablets of Nitrofurantoin: Formulation and Evaluation.ChemTech Res. 2013;5(1):491-501.
Back to Uro Flash Vol-2, No-4, 2015