Background

Male lower urinary tract symptoms (LUTS) that include urinary urgency, frequency, nocturia, straining, post-micturition dribbling and a feeling of incomplete bladder emptying can cause significant bother and morbidity.1 Up to 31% of men aged 50 years and more suffer from moderate-to-severe LUTS.1 In the United States, 70% of men between 60 and 69 years of age have LUTS, while 90% of men aged over 90 years are similarly affected.2,3 Thought previously to be symptoms suffered by the elderly, a recent, large population-based international survey found that 51.3% of men aged 39 years and under also complained of at least one LUTS.4 As a result of its high frequency, there is considerable cost associated with the management of LUTS worldwide.3,5 Historically attributed to bladder outlet obstruction as a result of benign prostate hyperplasia (BPH), it is becoming increasingly recognized that the etiology of LUTS is multi-factorial and are influenced by disease processes not traditionally associated with the urological tract.5 While urological disease processes such as BPH, overactive bladder, detrusor underactivity, neurogenic bladder dysfunction, infections, malignancy and some medications can cause LUTS,5 systemic lifestyle diseases such as obesity, type 2 diabetes mellitus, obstructive sleep apnea and biochemical states such as low testosterone, high cholesterol and low-density lipoprotein levels have also been associated with the development and progression of LUTS.6-8

Lower urinary tract symptoms are not a diagnosis but rather a constellation of symptoms. Academic work on LUTS has been plagued by the heterogeneity of definitions for this constellation of symptoms. Benign prostate hyperplasia is a histological diagnosis; however, this term has been used synonymously to describe the symptoms it causes, which leads to confusion. Lower urinary tract symptoms is now the preferred term as it describes the symptomatology without description of the potential underlying disease process.9

Lower urinary tract symptoms can be categorized into symptoms predominantly associated with the storage of urine termed "storage symptoms"; these include urgency (a sudden compelling urge to urinate), frequency (characterized by urination at short intervals) and nocturia (frequent episodes of urination during the night). Symptoms predominantly associated with voiding, termed "voiding symptoms" include straining, weak stream and post-void dribbling. Commonly, an individual will have a mixed symptomatology that is termed "mixed LUTS". The 2017 International Classification of Diseases, 10th Revision, Clinical Modification groups LUTS within Diagnostic Related Group(s) (MS-DRG v34.0); 695 (kidney and urinary tract signs and symptoms with MCC).10

The underlying cause or causes of LUTS can be investigated by conducting a thorough history and examination, urine and blood analysis, urological tract ultrasound and bladder diary.11 In many cases, more invasive investigations such as flexible cystoscopy or urodynamic studies are required to reach a diagnosis or to rule out sinister pathology such as transitional cell carcinoma.

It can be difficult for the patient to describe the individual symptoms, the severity of their symptoms as well as the temporal changes following treatment. To aid the clinician and to standardize reporting within the scientific community, validated, objective and reproducible tools by which LUTS severity can be scored have been developed.12,13 Since 1991, numerous symptom severity scores have been developed that include the American Urological Association Symptom Index (AUA-SI), International-Prostate Symptom Score (I-PSS) and the Danish Prostate Symptom Score (DAN-PSS). These scoring systems are short, self-administered questionnaires aimed to assess the severity of storage and voiding LUTS as well as the level of bother they cause for the patient. Repeating the same tool after treatment implementation can help the patient and clinician assess the patient's response. The I-PSS (a revision of the AUA-SI that includes an extra question on the global impact of LUTS on the patient's quality of life) is an eight-part questionnaire (seven symptom questions and one quality of life question) that asks the patient to describe the frequency with which they suffer a symptom. These are graded on a 0-3 score with a maximum total score of 35. Symptoms are classified as mild (0-7), moderate (8-19) and severe (20-35). While there is no standardized definition of LUTS progression or improvement based on the I-PSS, the American Urological Association considers a three-point improvement in scores meaningful,13 while numerous other studies have used a change in score of 4 or more to be clinically significant.14-17 The DAN-PSS is a 12-part questionnaire that assesses the presence and severity of LUTS. While the I-PSS has a single question relating to "bother", the DAN-PSS individually assesses the level of "bother" related to each individual symptom. Both the severity score and the bother score are scored from 0 to 3, and a subsequent score is obtained by multiplying both of these together, giving a score from 0 to 9. A final score out of 108 is obtained by adding all symptom scores together.12 There is no standard measure of progression or symptom improvement attributed to the DAN-PSS.

The first-line treatment for men with LUTS often involves behavioral education and observation; this is termed watchful waiting. Watchful waiting provides a period of observation to assess the progression of a man's symptoms, and patients should be reviewed regularly to assess progression or improvement.11 Depending on the predominant feature of the symptoms (voiding or storage), and the severity, age and comorbidities of the man, treatment may include [alpha]1-adrenergic-blockers, 5[alpha]-reductase inhibitors, muscarinic receptor antagonists and, in rare cases, desmopressin.11 Surgical treatment is typically reserved for men who have refractory symptoms despite the use of optimal medical management or men with clear surgical indications such as recurrent urinary tract infections, acute or chronic urinary retention, bladder calculi or upper urinary tract dilation with or without associated renal insufficiency as a result of benign bladder outlet obstruction.5

The natural history of LUTS suggests that although they are common, many symptoms will fluctuate in their presence and severity. Parsons et al.17 found that 45% of untreated men with severe LUTS at baseline reported an improvement in their symptoms, while 17% reported change consistent with progression. Other studies have described similar fluctuating symptomatology in the natural history of LUTS over time.16,18

Given this fluctuation, it is reasonable to suggest that a single snapshot of a man's LUTS severity may not be enough to dictate management decisions. Severe consequences of LUTS progression such as acute urinary retention and the need for BPH-related surgery are strongly related to baseline variables such as severe LUTS, old age, low peak flow rate, increased post-void residual urine, prostamegaly and a high serum prostate-specific antigen (PSA).19 It remains unclear, however, which of the baseline personal characteristics predict progression and improvement of LUTS. A number of studies have identified potential risk factors for the development of LUTS;8,20 however, most do not assess the severity of the individual's symptoms at two or more points in time; subsequently, while they provide details on the development of symptoms, they do not provide details on possible influences of change in the untreated individual. Martin et al.7 looked at risk factors for progression or improvement in LUTS in a prospective cohort of men and found that storage and voiding LUTS improved or remained stable in 60.1% and 67.4% of men, respectively, over a five-year period. Progression of voiding LUTS was predicted by lower serum testosterone and higher estradiol levels, depression, BPH and erectile dysfunction, while high levels of physical activity, high serum high-density lipoprotein levels, low triglyceride levels and absence of obstructive sleep apnea conferred a benefit for voiding LUTS.7 Marshall et al.21 found that men with progressing symptoms were more likely to have mobility limitations, poor mental health, body mass index of >25 kg/m², hypertension and back pain compared with those men with symptoms that remained stagnant.

Identifying predictors of symptom change would provide clinicians with several useful tools. First, it may be possible to identify which men are likely to respond well to lifestyle interventions such as weight loss, exercise and improvement in comorbidities. For those men who have a poor chance of symptom improvement, it may be appropriate to initiate medical or surgical management early. For those with a high chance of symptom improvement, appropriate lifestyle interventions may be initiated. Second, if it is found that improvement in cardiovascular health, metabolic profile, weight and other comorbidities will improve symptomatology, bothersome LUTS could be used as an incentive for men to get healthier without the use of additional medications or operative risks.

Understanding the mediating factors predictive of LUTS progression, stagnation and improvement will inform practitioners in order to educate men on secondary prevention measures. Modifiable risk factors are likely to be contributory, and management of these may have the potential to reduce the need for LUTS medication and surgery in the future as well as improve the man's overall wellbeing.

A preliminary search of the Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports and MEDLINE was performed in March 2015 to establish that no previous systematic reviews had been published on this topic. None were found specific to the criteria in this systematic review.

Inclusion criteria

Types of participants

Studies that include human males aged >18 years in a non-hospital setting with untreated LUTS will be considered for this review.

The definition of "untreated" LUTS in this review is as follows: subjects who are yet to receive any pharmacological or surgical intervention directed to improve their LUTS.

Exclusion criteria

A baseline history of prostate cancer, BPH surgery or medication use for LUTS or BPH.

Exposure of interest

Risk factors/prognostic factors are attributes, characteristics or exposures that increase the likelihood of a person developing a disease or health disorder. Prognostic factors can be negatively (hazardous factor) and positively (protective factor) associated with the progression in the severity of LUTS. Prognostic factors will be categorized into three distinct groups and include, but are not limited to, the following:

* Modifiable prognostic factors:-Environmental (e.g. medications not taken for LUTS, smoking status and alcohol intake)-Social (e.g. employment, marriage status and socio-economic status)-Biological (e.g. co-morbidities)

* Non-modifiable prognostic factors:-Genetic (e.g. age and race)

* Disease factors (e.g. type of LUTS and severity of LUTS at time of inclusion into study).

Outcomes

The primary outcome of interest is the change in severity of LUTS over time in men with untreated LUTS. Progression and improvement of symptoms will be examined by a change in the baseline score of validated LUTS tools. While there is no standardized definition of LUTS progression or improvement, we will define clinically relevant change in symptoms based on treatment guidelines and prior studies16,22 using the AUA-SI and I-PSS as:

* Improvement - >=4-point reduction in score from baseline

* Progression - >=4-point increase in score from baseline

* Stable - not fitting into above criteria.

Other validated symptoms scores will be assessed individually for means by which progression and improvement are defined.

Progression of symptoms will also be defined as:

* Receiving new medication prescribed for LUTS

* Undergoing LUTS-related surgery

* Requiring bladder catheterization for acute urinary retention.

Medication prescribed for the treatment of LUTS includes:

* Alpha-blockers

* Anticholinergics

* 5-alpha reductase inhibitors

* PDE-5 inhibitors

* Beta-3 agonist

* Desmopressin.

Lower urinary tract symptoms related surgery includes but is not limited to the following:

* Trans-urethral resection of prostate or similar procedure that establishes an opening within the prostatic fossa

* Sacral nerve modulator

* Percutaneous tibial nerve stimulation

* Intra-vesical botulinum toxin A injections.

Any validated LUTS severity tools will be eligible for inclusion, including but not limited to:

* AUA-SI

* I-PSS

* DAN-PSS

* International Consultation on Incontinence Questionnaire - Male MLUTS.

Types of studies

The current review will consider studies that identify independent predictors of change in the severity of LUTS. Studies will need to have been conducted over a period of at least one year. Examining LUTS over a period shorter than one year may not give substantial time for changes in severity to occur. This review will consider research papers utilizing the following study designs:

* Observational epidemiological design

* Cohort design

* Case-control studies.

These three study designs are the most suitable for studying risk factors associated with diseases. A large variety of subjects can be evaluated and observed over time to assess what baseline characteristics are associated with either progression, remission or stagnation of LUTS severity.

Exclusion criteria

The current study will not examine the predictive properties of investigational tools such as ultrasound, prostate volume, PSA level and urinary flow rates on disease course.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies as will the PubMed-related articles feature. Only studies published in English will be considered for this review. Studies published after January 1, 1991 will be considered for inclusion in this review. Articles published prior to this date are unlikely to include symptomatology scores such as the DAN-PSS, developed in 1991, and the I-PSS (1992).

The databases to be searched include the following: PubMed, Embase, Scopus and Web of Science.

Gray literature will be searched through the following databases: Grey Literature Report and DIVA Academic Archive Online.

Initial keywords to be used will be: lower urinary tract symptoms, men, hypertrophy (benign) of prostate and prognosis, disease progression, risk factors and epidemiology.

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using "Guidelines for Assessing Quality in Prognostic Studies on the Basis of Framework of Potential Biases", published by Hayden et al.23 Studies of acceptable quality for inclusion in the synthesis must at least "partly" satisfy each of the six biases. Any disagreement that arises between the reviewers will be resolved through discussion or with a third reviewer.

Data extraction

Data will be extracted from papers included in the review using a modified version of the standardized data extraction tool from JBI-MAStARI (Appendix I). The data extracted will include specific details about the populations, study methods and outcomes of significance to the review question and specific objectives. Predictors and their accompanying odds ratios will be identified by multivariate analysis. Where details are missing or unclear, efforts will be made to contact corresponding authors for clarification.

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis using Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. All results will be subject to double data entry. Effect sizes expressed as relative risk for cohort studies and odds ratio for case-control studies (for categorical data) and their 95% confidence intervals will be calculated for analysis. A random effects model will be used, and heterogeneity will be assessed statistically using the standard chi-square. Changes in symptom severity scores do not consistently reflect the same change in clinical symptomatology among all validated symptom indexes. Where data are not sufficiently homogenous to combine, a narrative summary of results will be provided including tables and figures to aid in data presentation, where appropriate. Subgroup analyses will be performed, where possible, assessing the influence of predictors and their influence on men at different stages of disease severity.

A sensitivity analysis will be performed, and where appropriate (10 or more papers included in meta-analysis for one outcome), publication bias will be assessed by Egger's test and funnel plot.

Appendix I: Data extraction instruments

References