Bening Prostate Hyperplasia

BENIGN PROSTATIC HYPERPLASIA
Benign prostatic hyperplasia (BPH) is among the most common health problems in aging men. This disease is well known in all countries and continents. BPH affects approximately 50% of men at the age of 51-60 yo and over 80% of men at 81-90 (Guess 1990; Roehrborn 2005).

Due to its increasing prevalence with age, BPH is a significant burden for the US healthcare system. It led to approximately 4.5 million physician visits and 1.1 billion US dollars in direct healthcare costs (Kok Bin Lim 2017).

BPH presents with prostate volume enlargement and characteristic lower urinary tract symptoms (Kellogg 2010):  

  • Urinary bladder output obstruction
  • Incomplete bladder evacuation
  • Acute or chronic urinary retention
  • Urinary tract infections
  • Formation of urinary stones in the bladder
  • Hematuria and urosepsis. 

Lower urinary tract symptoms (LUTS) can be caused by either obstruction of the urethra, or by urinary bladder dysfunction (Harvard Health 2012).

RISK FACTORS FOR BENIGN PROSTATIC HYPERPLASIA
Despite the significant health impact of benign prostatic hyperplasia (BPH) the causes of the disease are not well defined. Several risk factors have been identified that contribute to disease development and progression (Kok Bin Lim 2017).

  1. Age

    Aging was establishes as the most significant demography factor for the prevalence and severity of the disease (Taylor 2006). The percentage of men with BPH increases with age, (The Baltimore Longitudinal Study of Aging) taking into account both the size of the prostate and the severity of LUTS (Bosch 2007). It has been reported that the average weight of the prostate increases from approximately 20 g at the age of 40 to 38.8 g in men over 80 (Berry 1984).

    In addition to aging, other factors have also been studied and established as risk factors for developing BPH: Non-modifiable ( geography and genetics) and modifiable (sex steroid hormones, the metabolic syndrome, obesity, diabetes, physical activity, diet, and inflammation) ( Patel 2014).

  2. Genetics

    A study conducted in Olmsted County, Minnesota, as well studies with twins indicate that heredity is the most important determinant of LUTS, as compared to aging and prostate total volume (Sanda 1994).
    The potential of the genetic factors was studied in men below 64 years of age, who underwent prostatectomy for BPH. The first-degree relatives of these men had a 4-fold increase of the risk for developing BPH compared to the relatives of healthy individuals (Kok Bin Lim 2017).

    Hereditary BPH is revealed in more than 50% of patients under 60 years (Sanda 1994; Kok Bin Lim 2017). Men with three and more members of their families affected, have larger prostates, abnormally high serum androgen concentrations and good response to treatment with 5-alpha-reductase inhibitors (Kok Bin Lim 2017).

  3. Overweight / obesity

    Research shows that obesity has a positive correlation with prostate volume – the greater the amount of adiposity, the greater the prostate volume. Body weight, body mass index (BMI) and waist circumference are also positively associated with prostate volume in various patient populations in different studies (Joseph 2002; Parsons 2009; Parsons 2011).

    A study in 5,667 patients demonstrated that each 0.05 increase in waist-to-hip ratio (a measure of abdominal obesity) was associated with a 10% increased risk of total and severe benign prostatic hyperplasia. Epidemiological evidence also show that obesity increases the risk of surgical intervention, progression of urinary symptoms and initiation of medical treatment for BPH (Kristal 2007; Parsons 2007).

  4. Diabetes
    A study conducted in 2009 revealed that elevated insulin levels stimulate prostate growth. In another study in 307 men with BPH, the effect of fasting insulin levels in plasma on the annualized enlargement of the prostate was evaluated. Greater prostate size was revealed in patients with higher plasma insulin (Sarma 2009; Gupta 2006; Parsons 2008).   

  5. Lipids
    There is little evidence for the potential association between lipids and BPH. Some studies show positive, while other do not find any associations (Sarma 2009; Kristal 2008).

  6. Lifestyle
    It is already well recognized that modifiable lifestyle factors significantly impact the natural history of BPH (Parsons 2010; Kok Bin Lim 2017).

  7. Diet
    There are data showing that increased consumption of red meat, fats, milk and dairy products, cereals, bread, poultry and starch potentially increase the risks of developing BPH, while vegetables, fruit, polyunsaturated fatty acids, linoleic acid, and vitamin D potentially decrease the risks of BPH (Gupta 2006) . For micronutrients, higher circulating concentrations of vitamin E, lycopene, selenium, and carotene have been inversely associated with BPH (Parsons 2007; Kok Bin Lim 2017).

  8. Physical activity
    Increased physical activity and exercise are associated with decreased risks of surgical intervention for BPH, clinical BPH, histological BPH and lower urinary tract symptoms (Sarma 2009; Parsons 2008; Kok Bin Lim 2017). A meta-analysis of 11 published trials  (n=43,083) shows, that moderate to vigorous physical activity reduced the risk of BPH by as much as 25% as compared to sedentary lifestyle (Parsons 2009; Kok Bin Lim 2017).


ETIOLOGY OF BPH
Etiology of BPH is still not well understood, despite the persistent research over many years. The hormonal hypothesis, or the role of dihydrotestosterone, is among the dominating hypotheses. It is now clear that male gender (with functional testes) and aging are of prominent significance for the development of BPH (Parsons 2006).
 The contemporary understanding of BPH etiology is that it is a multifactorial process (Parsons 2006).

Hormonal changes
BPH is observed in approximately 70% of men over the age of 70 and it develops when plasma testosterone levels decrease and estrogens increase, thus increasing the estrogen-androgen ratio (Smith 2002). Although androgen does not cause BPH, the presence of testicular androgen is required for the development of the disease. Studies of the intraprostatic levels of steroid sex hormones revealed that bioavailability of testosterone in the prostate gland decreases with age. Secretory cells in the prostate lumen require androgens, particularly the intracellular metabolite of testosterone – dihydrotestosterone (DHT), for their secretory function and differentiation. DHT is synthetized primarily in the fibroblasts in the stroma and in the basal epithelial cells via the enzyme 5α-reductase. The disrupted balance between androgens and estrogens induces a feedback mechanism, in which 5α-reductase converts more testosterone into DHT. As a result, production of 3α-androstanediol increases. The combination of high estrogen levels and 3α-androstanediol stimulates cell proliferation and enlargement of the prostate gland (Briganti 2009).
The significance of DHT for the development of BPH is supported by the fact that in prostate cells from BPH patients DHT is 5-fold higher than DHT level in cells from normal prostate. This age-related change in the hormonal balance is suspected to be involved in the etiology of BPH. (Smith 2002; Prins 2008).

Chronic inflammation
Chronic inflammation is considered to be one of the prominent factors, contributing to the fibromuscular growth in BPH. Inflammatory infiltrates are frequently seen in prostate glands of BPH patients ‒ Kohnen et al report inflammatory infiltrates on 98% of 162 prostate specimens analyzed. Chronic inflammation induces increased production of growth factors and angiogenesis in prostate tissue (Kramer 2007; Djavan 2009).


SYMPTOMS OF BPH
The anatomic location of the prostate is the main reason for symptoms of LUTS in BPH. Since the prostate envelops the beginning of the urethra in its entire circumference, prostate enlargement leads to compression and narrowing and to impaired bladder evacuation – obstructive symptoms (EAU guidelines 2013).

Obstructive symptoms include (EAU guidelines 2013):

  • Delayed initiation of voiding; 
  • Splitting of stream during voiding; 
  • Slow stream; 
  • Prolonged voiding; 
  • Slow stream with frequent interruptions and terminal dribble; 
  • Post-void urine; 
  • Retention of urine. 

Constant irritation and compression on the bladder muscle, in combination with increasing intra-bladder pressure and resistance lead to development of another major group of symptoms of BPH – irritation symptoms (EAU guidelines 2013).

Irritation symptoms include (EAU guidelines 2013):

  • Dysuria; 
  • Increased daytime frequency in intervals shorter than 2 hours; 
  • Increased frequency of night-time voiding (nocturia); 
  • Imperative voiding calls (urgency); 
  • A feeling of residual urine; 
  • Painful voiding; 
  • Incontinence. 


DIAGNOSIS OF BPH
Although bordersome LUTS are usually the only factor leading to the diagnosis of BPH in clinical practice, there are simple and effective assessments for diagnosing LUTS caused by BPH (EAU guidelines 2013).

The European Association of Urology (EAU) Guidelines provide recommendation for initial assessment of males with LUTS predisposed to obstruction of the urinary bladder output. It includes collection of medical history using a validated symptoms questionnaire (International Prostate Symptom Score, IPSS), physical examination, measurement of creatinine, urinalysis, assessment of strength of urinary stream, post-void volume, and serum prostate specific antigen (PSA). Very high or rapidly increasing PSA may be a sign of prostate cancer, which may influence further therapeutic decisions (EAU 2004 guidelines). 

Initial diagnostic workup recommended by the American Urological Association AUA includes clinical history, use of a validated symptoms questionnaire, physical examination, urinalysis and serum PSA (American Urological Association. Guideline on the Management of Benign Prostatic Hyperplasia,  2008). A recent study revealed a strong association between the parameters PSA, digital rectal examination (DRE) and IPSS. This comes to show that the simple diagnostic tools available in the primary health care can serve as the initial step for establishing a diagnosis in patients with suspected BPH, as well as to provide a valid strategy for minimizing the delays in the treatment of the disease and facilitating the appropriate referral to specialized medical care (Rodríguez 2006).


CONSERVATIVE TREATMENT OF BPH
BPH significantly affects patients’ quality of life, because it is linked to sleep disturbances due to the nocturia, limitations of everyday activity caused by polakyuria, and anxiety because of the potential surgical treatment. Despite the high prevalence of BPH in the contemporary aging society, many patients are left untreated (Cheng-Ling Lee 2017).

There are a number of therapeutic options for males suffering from LUTS, BPH or urinary bladder obstruction. The decision which is the best therapeutic choice is strictly individual and is based on the patient’s symptoms and personal characteristics – severity of complaints, general health and concurrent illnesses, prostate volume, etc. (Tanguay 2009).

Among the pharmacological treatment options patients and physicians can choose from a variety of phytotherapeutics, α1 adrenergic receptor blockers, 5α-reductase inhibitors administered as single or combination therapies (Tanguay 2009).

Alpha1 adrenergic receptor blockers (α1-blockers). The main mechanism of action of these medications is relaxation of the smooth muscles in the blood vessels, prostate and urinary bladder cervix, thus allowing for easier urination (Michel 2006). Its advantage is the rapid effect. Within several days after initiation of therapy increase of the urine stream is observed and urinary frequency is decreased. Relaxation of smooth muscles of the urinary bladder cervix and in the prostate tissue releases the obstruction of the urethra (Barendrecht  2008). Some of the common side effects of the α1-blockers are: hypotension (Chapple  2011), fatigue, and diminished to absent semen during ejaculation (Gacci 2012).

5α-reductase inhibitors. These compounds inhibit the enzyme 5α-reductase, which converts testosterone into dihydrotestosterone (Andriole 2004). They stop prostate growth and even decrease its volume as a result of blocking the hormonal processes, responsible for its enlargement. Their effect occurs slowly, sometimes weeks or months after initiation of treatment (Rittmaster 1996). Side effects are uncommon, however they can cause erectile dysfunction, decrease of the libido, and abnormal ejaculation (McConnell  2003). Approximately 1-2% of patients develop gynecomasty. Patients treated with 5α-reductase inhibitors should regularly monitor PSA levels (Hsieh 2015), although causal relationship with higher incidence in prostate cancer has not been established (Thompson 2003). A confirmed increase of PSA during treatment with 5α-reductase inhibitors requires re-assessment of therapy (Thompson 2003; Tanguay 2009).

Muscarinic receptor antagonists. Muscarinic receptor antagonists decrease the urinary bladder contractility (Chess-Williams 2001) Antimuscarinic effects ca also be induced by the bladder urothelium and/or the CNS (Matsui 2000). The administration of muscarinic antagonists is associated with the following side effects: dry mouth (16%), constipation (4%), difficulty in urination (2%), nasopharyngitis (3%) and dizziness (5%) (uroweb.org).

Phosphodiesterase 5 inhibitors (PDE5 inhibitors). PDE5 inhibitors decrease the tonus of smooth muscles of the detrusor, prostate and urethra. Majority of PDE5 inhibitors have been studied in LUTS (Giuliano 2013). They are used primarily to treat erectile dysfunction accompanying BPH. PDE5 inhibitors can cause headache, flushing, dizziness, dyspepsia, nasal congestion, myalgia, hypotension, sincope, tinnitus, conjunctivitis and altered vision (Gacci 2012). They are contraindicated in patients taking 1-blockers, those with myocardial ischemia, ischemic heart disease, stroke, and other diseases (Porst 2013).

Botulinum toxin. Botulinum toxin (BTX) is the most potent neurotoxin known to humans. Botulinum toxin type A (BoNT/A) directly or indirectly alleviates LUTS via inducing apoptosis of epithelial cells in in the prostate, which leads to tissue atrophy and decrease in prostate volume. In addition, it causes inhibition of the sensory neurons in the prostate and relaxation of the afferent signals to the CNS, as well as relaxation of the smooth muscles in the prostate parenchyma (Mangera 2014). The efficacy of intraprostatic injection of botulinum toxin type A in BPH has been studied in 20 randomized double-blind controlled trials. All of them observed improvement of symptoms as evident by IPSS and increase in Qmax (the maximum urinary current). A statistically significant decrease of the prostate volume was observed in 18 trials. The duration of the response to treatment varied between 3 and 30 months (Mangera 2014).

Pygeum africanum. A report of Cochrane Review Group summarized results from 18 randomized placebo-controlled trials of Pygeum africanum extract (given as single or combination compound). The meta-analysis included 1562 male, and patients treated with Pygeum africanum showed 2 times greater improvement of symptoms, as compared to placebo. A statistically significant improvement in urinary current Qmax and in the post-void residual was also observed (Wilt 2011).

Graminex G63. A report of Cochrane Review Group summarized results from 2 placebo-controlled and 2 active-controlled trials of 12 and 24 weeks of duration, respectively. Men treated with pollen extract report 2-fold greater improvement of symptoms as compared to those treated with placebo or active control (Chambliss 2003; Aoki 2002).

Serenoa repens/Sabal serrulata. A recently updated report of Cochrane Review Group summarized results from 30 clinical randomized trials, which included 5222 males. Serenoa repens was compared to placebo, various herbal extracts (Pygeum africanum, Urtica Dioica), finasteride (5α-reductase inhibitor) or tamsulosin. Mean duration of follow-up varied between 4 and 60 weeks. The Cochrane report concluded, that Serenoa repens was not superior to placebo, finasteride or tamsulosin in terms of improvement as evaluated with IPSS. Serenoa repens was superior to placebo in improving nocturia (Tacklind 2012).

Urtica dioica. Two trials compared the efficacy of Urtica dioica root extract versus placebo in 246 males with BPH-LUTS for the duration of 52 weeks. In the Urtica root extract a significant decrease of the IPSS was observed as compared to placebo. In the second trial, 620 patients with BPH were enrolled and treated for 26 weeks. An impactful improvement was noted as compared to placebo, in all parameters evaluated – IPSS, urinary current (Qmax) and post-void residual (Nahara 2012), (Assessment report on Urtica dioica L., Urtica urens L., their hybrids or their mixtures, radix).

Cucurbita pepo . The seeds of Cucurbita pepo has shown anti-inflammatory and antiandrogen effect, as well as effect on reduction of prostate growth and detrusor activity. Improvement in IPSS was reported in all studies. Four trials reported improvement on quality of life. Adding Cucurbita pepo to the treatment of patients with BPH-LUTS proves to be useful for improvement of symptoms and quality of life (Damiano 2016).

Lycopene. Lycopene is a natural pigment, synthesized by plants and organisms. It is a non-vitamin A carotenoid. Its biologic actions include antioxidative activity, induction of intercellular communication and control over growth factors (Heber 2002). The following pharmacological effects of lycopene have been proven: inhibition of cancer cells growth, inhibition of the vascular endothelial growth factor (VEGF), modulation of proteins regulating cell cycle, inhibition of the insulin-like growth factor-1 (Kucuk 2001).

Zinc. Human prostate glandular epithelial cells have the unique capability of accumulating high levels of zinc. This is essential to inhibit m-aconitase activity so that citrate can accumulate for secretion into prostatic fluid, which is a major function of the prostate gland. In addition to these metabolic effects, zinc accumulation exhibits anti-proliferative effects via its induction of mitochondrial apoptogenesis. The anti-proliferative effects and the effects on invasion and migration occur through zinc activation of specific intracellular signaling pathways. Consequently, these effects impose anti-tumor actions by zinc. (Franklin 2007).

Selenium. Selenium is a mineral the body needs in small quantities (Thomas 1999). A study found that a combination of selenium, lycopene, and saw palmetto was more effective than saw palmetto alone at preventing hormone-dependent prostate growth (Altavilla 2011). Another study found that higher serum levels of selenium were associated with a reduced risk of BPH (Eichholzer 2012).


HIGHLIGHTS

  • Benign prostate hyperplasia (BPH) is one of the most common health problems in adult males. About 50% of males at the age of 51 to 60 are affected by BPH.
  • BPH is clinically manifested by increase of prostate volume. Lower urinary tract symptoms are related to the compression of urethra or dysfunction of the urinary bladder.
  • Most significant risk factors for development and progression of BPH are: age, family history, obesity and diabetes.
  • Etiology of BPH is not fully understood, but hormonal changes with aging and chronic inflammation are identified as contributing to the development of BPH.
  • There are well documented clinical data for effective treatments with prescription drugs, as well as some herbal products. For more advanced disease surgical treatment is indicated. 

Reference

Altavilla D, Bitto A, Polito F, et al. The combination of serenoa repens, selenium and lycopene is more effective than serenoa repens alone to prevent hormone dependent prostatic growth. The Journal of Urology. 2011;186:1524-1529.
Andriole GL, Roehrborn C, Schulman C, et al. Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia. Urology. 2004;64:537–543
Aoki A, et al. Clinical evaluation of the effect of tamsulosin hydrochloride and cernitin pollen extract on urinary disturbance associated with benign prostatic hyperplasia in a multicentered study. Hinyokika Kiyo. 2002 May;48(5):259-67.
Assessment report on Urtica dioica L., Urtica urens L., their hybrids or their mixtures, radix [Book].
Barendrecht, M.M., et al. Do alpha1-adrenoceptor antagonists improve lower urinary tract symptoms by reducing bladder outlet resistance? Neurourol Urodyn, 2008. 27: 226.
Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol. 1984 Sep;132(3):474-9.
Briganti A. et al. Benign Prostatic Hyperplasia and Its Aetiologies. EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 865–871
Chambliss WG. A critical review of Graminex flower pollen extract for symptomatic relief of lower urinary tract symptoms (LUTS) in men. National Center for Natural Products Research, 2003.
Chess-Williams R, Chapple CR, Yamanishi T, Yasuda K, Sellers DJ. The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro. J Auton Pharmacol. 2001;21:243–248.
Damiano R, Cai T, Fornara P, Franzese CA, Leonardi R, Mirone V. The role of Cucurbita pepo in the management of patients affected by lower urinary tract symptoms due to benign prostatic hyperplasia: A narrative review. Arch Ital Urol Androl. 2016 Jul 4;88(2):136-43
Djavan B., Eckersberger E., Espinosa G., Kramer G. Complex Mechanisms in Prostatic Inflammatory Response. European Association of Urology, 2009.
Eichholzer M, Steinbrecher A, Kaaks R, et al. Effects of selenium status, dietary glucosinolate intake and serum glutathione s-transferase a activity on the risk of benign prostatic hyperplasia. BJU International. 2012;Epub.
Epidemiology and Risk Factors, Curr Bladder Dysfunct Rep. 2010 Dec; 5(4): 212–218.
Franklin R.B. and Costello L.C. Zinc as an anti-tumor agent in prostate cancer and in other cancers. Department of Biomedical Sciences, University of Maryland Baltimore, Dental School, Baltimore, MD 21201, USA. Arch Biochem Biophys. 2007 July 15; 463(2): 211–217.
Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with a-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. European Urology. 2012;61:994-1003.
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. European Urology Volume 63, Issue 3, March 2013, Pages 506-516
Guess H.A., Arrighi H.M., Metter E.J., Fozard J.L. Cumulative prevalence of prostatism matches the autopsy prevalence of benign prostatic hyperplasia Prostate, 17 (1990), pp. 241-246 
Gupta A., Gupta S., Pavuk M., Roehrborn C.G.  Anthropometric and metabolic factors and risk of benign prostatic hyperplasia: a prospective cohort study of air force veterans. Urology, 68 (2006), pp. 1198-1205
Heber D, Lu QY. Overview of mechanisms of action of lycopene. Exp Biol Med (Maywood). 2002 Nov;227(10):920-3.
Hsieh TF, Yang YW, Lee SS, Lin TH, Liu HH, Tsai TH, et al. Use of 5-alpha-reductase inhibitors did not increase the risk of cardiovascular diseases in patients with benign prostate hyperplasia: a five-year follow-up study. PloS one. 2015; 10(3):e0119694. Epub 2015/03/25
http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/#note_168
Joseph M.A., Wei J.T., Harlow S.D., Cooney K.A., Dunn R.L., Jaffe C.A., et al.Relationship of serum sex-steroid hormones and prostate volume in African American men Prostate, 53 (2002), pp. 322-329
Kellogg J., Benign Prostatic Hyperplasia and Male Lower Urinary Tract Symptoms: 
Kok Bin Lim. Epidemiology of clinical benign prostatic hyperplasia. Asian J Urol. 2017 Jul; 4(3): 148–151.
Kramer G, Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol 2007;51: 1202–16.
Kristal A.R., Arnold K.B., Schenk J.M., Neuhouser M.L., Goodman P., Penson D.F., et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the Prostate Cancer Prevention. Trial Am J Epidemiol, 167 (2008), pp. 925-934
Kristal A.R., Arnold K.B., Schenk J.M., Neuhouser M.L., Weiss N., Goodman P., et al. Race/ethnicity, obesity, health related behaviors and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. J Urol, 177 (2007), pp. 1395-1400
Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiology, Biomarkers and Prevention, 2001;10:861-868.
Lee C. and Kuo H.. Pathophysiology of benign prostate enlargement and lower urinary tract symptoms: Current concepts. Ci Ji Yi Xue Za Zhi 2017 Apr-Jun; 29(2): 79–83.
Mangera A., Mangera A., Apostolidis A., Andersson K.A., Dasgupta P., Giannantoni A., Roehrborn C., Novara G., Chapple C. An Updated Systematic Review and Statistical Comparison of Standardised Mean Outcomes for the Use of Botulinum Toxin in the Management of Lower Urinary Tract Disorders. EUROPEAN UROLOGY 65 (2014) 981–990
Matsui M., Motomura D., Karasawa H., Fujikawa T., Jiang J., Komiya Y., Takanashi S., Taketo M.M. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M2 subtype. Proc. Natl. Acad. Sci. U.S.A. 2000;97:9579–9584.
McConnell J.D. et al. The Long-Term Effect of Doxazosin, Finasteride, and Combination Therapy on the Clinical Progression of Benign Prostatic Hyperplasia. N Engl J Med 2003; 349:2387-2398
Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol Feb. 2006;147(Suppl.2):S88-S119
Nahara A and Dixit VK. Ameliorative effects of stinging nettle (urtica dioica) on testosterone-induced prostatic hyperplasia in rats. Andrologia. 2012;44 Suppl 1:396-409.
Nishant D. Patel and J. Kellogg Parsons. Epidemiology and etiology of benign prostatic hyperplasia and bladder outlet obstruction. Indian J Urol. 2014 Apr-Jun; 30(2): 170–176.
Parsons J.K. Modifiable risk factors for benign prostatic hyperplasia and lower urinary tract symptoms: new approaches to old problems. J Urol, 178 (2007), pp. 395-401
Parsons J.K., Bergstrom J., Barrett-Connor E. Lipids, lipoproteins and the risk of benign prostatic hyperplasia in community dwelling men. BJU Int, 101 (2008), pp. 313-318
Parsons J.K., Sarma, K. McVary, J.T. Wei Obesity and benign prostatic hyperplasia: clinical connections, emerging etiological paradigms and future directions. J Urol, 182 (Suppl. 6) (2009), pp. S27-S31
Parsons J.K., Bergstrom J., Barrett-Connor E. Lipids, lipoproteins and the risk of benign prostatic hyperplasia in community dwelling men. BJU Int, 101 (2008), pp. 313-318
Parsons J.K., Im R. Alcohol consumption is associated with a decreased risk of benign prostatic hyperplasia. J Urol, 182 (2009), pp. 1463-1468
Parsons J.K., Messer K., White M., Barrett-Connor E., Bauer D.C., Marshall L.M.  Obesity increases and physical activity decreases lower urinary tract symptom risk in older men: the osteoporotic fractures in men study. Eur Urol, 60 (2011), pp. 1173-1180
Parsons J.K. Benign Prostatic Hyperplasia and Male Lower Urinary Tract Symptoms: Epidemiology and Risk Factors. Curr Bladder Dysfunct Rep. 2010 Dec; 5(4): 212–218.
Parsons JK, Carter HB, Partin AW, et al. Metabolic factors associated with benign prostatic hyperplasia. J Clin Endocrinol Metab. 2006;91(7):2562–2568. 
Parsons JK. Modifiable risk factors for benign prostatic hyperplasia and lower urinary tract symptoms: new approaches to old problems. J Urol. 2007 Aug; 178(2):395-401.
Parsons, H.B. Carter, A.W. Partin, B.G. Windham, E.J. Metter, L. Ferrucci, et al.Metabolic factors associated with benign prostatic hyperplasia J Clin Endocrinol Metab, 91 (2006), pp. 2562-2568
Porst H, Roehrborn CG, Secrest RJ, Esler A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med 2013;10:2044–52.
Prins G.S. and Korach K.S. The Role of Estrogens and Estrogen Receptors in Normal Prostate Growth and Disease.,  Steroids. 2008 Mar; 73(3): 233–244.
Rodriguez C.J. et al. Validity of tests for initial diagnosis and its concordance with final diagnosis in patients with suspected benign prostatic hyperplasia. Actas Urol Esp [online]. 2006, vol.30, n.7, pp.667-674. ISSN 0210-4806.
Sanda M.G., Beaty T.H., Stutzman R.E., Childs B., Walsh P.C. Genetic susceptibility of benign prostatic hyperplasia J Urol, 152 (1994), pp. 115-119
Sanda MG, Beaty TH, Stutzman RE, Childs B, Walsh PC. Genetic susceptibility of benign prostatic hyperplasia. J Urol. 1994 Jul; 152(1):115-9.
Sarma A.V., Parsons J.K., McVary K., Wei J.T.  Diabetes and benign prostatic hyperplasia/lower urinary tract symptoms–what do we know? J Urol, 182 (Suppl. 6) (2009), pp. S32-S37
Smith P, Rhodes NP, Ke Y, Foster CS. Upregulation of estrogen and androgen receptors modulate expression of FGF–2 and FGF–7 in human, cultured, prostaticstromal cells exposed to high concentrations of estradiol. Prostate Cancer Prostatic Dis 2002;5:105–10.
Tacklind J, MacDonald R, Rutks I, Stanke JU, Wilt TJ. Serenoa repens for benign prostatic hyperplasia. The Cochrane Library, 2012;5.
Tanguay S., MD FRCSC et al. Diagnosis and management of benign prostatic hyperplasia in primary care. Can Urol Assoc J. 2009 Jun; 3(3 Suppl 2): S92–S100
Taylor B.C., Wilt T.J., Fink H.A., Lambert L.C., Marshall L.M., Hoffman A.R., et al.Prevalence, severity, and health correlates of lower urinary tract symptoms among older men: the MrOS study Urology, 68 (2006), pp. 804-809
Thomas JA. Diet, micronutritents and the prostate gland. Nutrition Reviews. 1999;57(4):95-103.
Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215–24
Wilt TJ and Ishani A. Pygeum africanum for benign prostatic hyperplasia. The Cochrane Library. 2011;9.
 

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