Introduction
Most common causes of lower urinary tract symptoms [LUTS] in males are benign prostatic hyperplasia (BPH) and overactive bladder (OAB).In aging males along with the other geriatric health problems there is a gradual rise in the incidence of BPH from the 6th to 9th decades of life and reaches to 80% by 80 years of age. Approximately three-fourths of men with symptoms of LUTS aged more than 50 years require medical management for BPH.1, 2
The metabolic syndrome (MetS, syndrome X, insulin resistance syndrome) is highly prevalent in adult population. Metabolic syndrome as a comorbidity increases with age and varies from 7.9% to 39% among developing countries in the World 3 and 9.2% to 43.2 (India).4, 5 MeS consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease (CVD) and diabetes mellitus (DM). The Adult Treatment Panel III Criteria is the one used commonly today because it incorporates the key concepts of MetS and relies on routinely available clinical parameters. 6
Currently, research works on MetS and the chronic prostatic inflammation are providing new insights on the pathophysiology of LUTS symptoms suggestive of BPH. A number of evidences have pointed towards a direct and significant relationship between MetS and BPH/LUTS.7, 8, 9 The severity of lower urinary tract symptoms in patients with BPH and the likelihood of having diabetes are significantly associated. 10 Presence of MetS had a significantly negative impact on the responsiveness to α1-blocker in men with BPH/LUTS. 11, 12, 13 Moreover, Finasteride is an efficient 5-α reductase inhibitor shows mild differences in metabolic profile with slight amelioration of glucose metabolism regulation. 14, 15
Currently BPH a condition where treatment approach has transformed from exclusively surgical to an effective and primarily medical management with surgical treatment reserved for cases in which initial management has failed. 16 Evidences show that less than 5% of men on medical management had complications with subsequent surgical intervention at the 4-year follow-up. 17 Currently approved drugs for management of moderate to severe LUTS associated with BPH include Alfuzosin, Doxazosin, Silodosin, Tamsulosin and Terazosin [α1blockers], Dutasteride, Finasteride [5-α reductase inhibitors], Oxybutynin, Darifenacin [Anticholinergics] Tadalafil, sildenafil [Phospodiesterase type 5 inhibitors] and mirabegron [selective β3–adrenergic agonist]. 18 The conventional medications used to treat LUTS secondary to BPH fall into two classes of agents: α1blockers and 5-α reductase inhibitors. 19 These agents are used either alone or in combination (larger prostate volumes). LUTS due to BPH are caused by factors like dynamic (factor regulating tone of the prostatic smooth muscle and bladder neck), static (i.e, factor causing enlarged prostatic adenoma followed by mechanical obstruction), and compensatory (hypertrophy and irritability of the detrusor muscle). 20, 21, 22, 23
There have been a number of studies in different countries and population showing the correlations of metabolic syndrome (MeS) and BPH /prostate volume. However, there is paucity of data with regard to MeS as a risk factor for BPH and comparison of effectiveness of BPH medications among those with and /or without underlying MeS in the population where the present study was conducted. Therefore, findings of the present study would give an important insight in managing the public health burden of BPH with underlying MeS. In this context the present study aims, to find the outcome of medical treatment of BPH in patients having metabolic syndrome as a comorbidity.
Materials and Methods
This was a prospective, open labeled, observational study conducted in the Outpatient Department of Urology and Department of Pharmacology of a tertiary care hospital for a duration of 2 years (Jan.2017 to Jan.2019). Institutional Ethics Committee approval was obtained before initiation of the study. Written informed consent in local language from the study subjects was collected prior to their enrolment. 894 adult males diagnosed to be suffering from LUTS secondary to BPH based on their inclusion exclusion criteria [Table 1 ] were enrolled for the study. According to the NCEP ATP III definition, 24 metabolic syndrome is present if three or more of the following five criteria are met: waist circumference over 40 inches (men) or 35 inches (women), blood pressure over 130/85 mmHg, fasting triglyceride (TG) level over 150 mg/dl, fasting high-density lipoprotein (HDL) cholesterol level less than 40 mg/dl (men) or 50 mg/dl (women) and fasting blood sugar over 100 mg/dl. The enrolled study participants were further stratified into two groups: a group having MeS and a group not having MeS based on NCEP ATP III Guidelines. All the patients irrespective of their metabolic syndrome status were advised either α1- Blockers or 5 α- Reductase inhibitors or a combination of both basing on their presenting symptoms. Patients with IPSS >8, prostate size <30 g were prescribed α1- Blockers [Tamsulosin 0.4 mg or Alfuzosin 10 mg). Those having IPSS >8, prostate size >30 g were treated with combination therapy [Tamsulosin 0.4 mg or Alfuzosin10 mg+Dutasteride 0.5 mg].
Biochemical evaluation
Body weight, height, waist circumference (WC) of study participants was measured. The body mass index (BMI) was then calculated from the weight and height. Fasting glucose, lipid profile was measured using automated methods and commercially available assays. Insulin resistance was determined by the homeostasis model assessment (HOMA-IR) index, calculated as blood glucose (mmol/l−1) × insulin concentration (µIU/ml−1)/22.5. 25 HOMA-IR cut-off of 2.77 was used to recognize patients having insulin resistance. 26, 27 The lipid accumulation product (LAP), a useful marker of metabolic risk was calculated using the equation: LAP = (waist circumference in centimeters − 65) × triglycerides (nmol/l). 28, 29
Efficacy evaluation
Parameters like -Prostate Symptom Score (I-PSS) 30, Quality of Life Score (QOL) 30 and prostatic volume using Ultrasound abdomen and pelvis (USG) were measured at baseline, 4th, 12th, and 24th week. Efficacy of the treatment received was evaluated by improvement in LUTS at 24th week of treatment basing on the changes observed in the above mentioned parameters. During the study period patients were regularly assessed for clinical, biochemical, USG and IPSS changes treatment modified accordingly.
Statistical analysis
Data were analyzed using Graph-Pad Prism version 6.0. Continuous variables like IPSS, QOL Score, and USG findings were expressed as mean ± SD. Differences among groups were analyzed by an independent t-test or nonparametric Mann–Whitney U-test for continuous variables. Discrete variables were expressed as absolute numbers and percentage, and were compared by Chi-square test/Fisher’s exact test.
Results
This study was conducted between January 2017 and January 2019. Total 894 patients were enrolled during this period. All the study participants were screened for metabolic syndrome initially and further divided into MeS +ve and MeS-ve groups. But at the end of the study, 49 patients were lost to follow-up [LFU]. Therefore of rest 845 patients [MeS +ve (370) and MeS-ve (475)] comprised the study population. Majority (84%) of patients belonged to the age group of 51-75 years with 5% in the age of 40-50 years and 11% in the age of 76-85 years. Anthropometric characteristics like BMI and waist circumference differed significantly among MetS+ and MetS- groups. [Table 2 ] Similarly both the groups differed significantly with respect to FBG (Fasting blood glucose) and HDL Cholesterol on evaluation of the biochemical variables. [Table 3] Risk factor analysis revealed that, waist circumference >102cm, BMI >25kg/m2, FBS >110mg/dl, Total Cholesterol >200mg/dl, HDL cholesterol <40md/dl, LDL cholesterol >100mg/dl & HOMA-IR >2.77 were the associated in the MetS +ve patients.[Table 5 ]
Table 1
Table 2
Anthropometric characteristics of the Study population
|
Variable |
MetS +ve |
MetS -ve |
p value |
|
Age |
65.05±8.65 |
64.60±9.4 |
0.1488 |
|
BMI (kg/m2) |
30.37±2.76 |
24.22±1.93 |
<0.001** |
|
Waist circumference (cm) |
104.01±2.13 |
89.27±2.27 |
<0.001** |
Table 3
Biochemical Profile of the Study population
Table 4
Analysis of LAP Score and Insulin resistance of the study population
Table 5
Risk factors associated with BPH and MetS (MetS +ve vs. MetS –ve)
Discussion
There are increasing evidence from clinical studies suggesting associations between lower urinary tract symptoms(LUTS) and major chronic illnesses such as heart diseases, diabetes, and Metabolic Syndrome (MetS) 31 The presence of metabolic syndrome was associated with higher IPSS total scores (21.86) compared to the subjects with no MetS (15.91). Our study found that improvement in IPSS score was better in the MetS –ve subjects (0.78) compared to the other group (1.44) [Table-6].This study showed that MetS had a negative impact on the overall response to medical treatment of BPH similar to the results obtained with Kupelian et al 32 & Lee YC et al 33 who showed that MetS had a significantly negative impact on the responsiveness to α1-blocker in men with BPH/LUTS. Prostate volume differed significantly between patients with and without MetS (54.20cc vs. 28.06 cc) [Table-6] which corroborates with another study by Koo et al 34 and Hammarsten et al.35 Lower HDL cholesterol, increased triglycerides above 1.7 mmol/l and higher LAP Score (67.29 vs. 35.74) [Table-3&4] was seen among those with MetS than in those without MetS. Significantly higher insulin levels and HOMA-IR(5.49 vs. cut-off of 2.77) in MetS +ve as compared to MetS-ve subjects(2.34) as supported by Kasturi et al, 2006 [Table-4]. HOMA-IR is an insulin like growth factor, a known prostatic mitogen. Several recent studies have provided convincing evidence of a possible role of MetS, and/or its individual components, in the development of BPH, prostate growth, and worsening of LUTS. 36
Conclusion
Our study confirmed the frequent coexistence of MetS and BPH. This association seems to be a consequence of the MetS-related changes in the clinical symptoms and metabolic derangements. MetS negatively affects the response to medical treatment of BPH. Therefore, it is necessary to consider MetS as a potential risk factor in treating pts with BPH. Further long term studies with larger sample size are needed to substantiate the above findings. Our study emphasizes that MetS evaluation should be an integral part of the standard assessment of male patients with LUTS as well as a new domain in clinical and basic research. Treating physicians need to be cognizant of the impact that MetS has on urologic diseases as well as on overall patient health.
