Benign prostatic hyperplasia

Benign prostatic hyperplasia
Classification and external resources

Diagram illustrating normal prostate (left) and benign prostatic hyperplasia (right).
ICD-10 N40.
ICD-9 600
DiseasesDB 10797
eMedicine med/1919
MeSH D011470

Benign prostatic hyperplasia (BPH) also known as benign prostatic hypertrophy (technically a misnomer), benign enlargement of the prostate (BEP), and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate in middle-aged and elderly men. To be accurate, the process is one of hyperplasia rather than hypertrophy, but the nomenclature is often interchangeable, even amongst urologists (see Textbook of Benign Prostatic Hyperplasia, Roehrborn CG et al. 2002, Chapter 6 "The Pathology of Benign Prostatic Hyperplasia, Bostwick DG). It is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of the prostate. When sufficiently large, the nodules compress the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra, which interferes the normal flow of urine. It leads to symptoms of urinary hesitancy, frequent urination, dysuria (painful urination), increased risk of urinary tract infections, and urinary retention. Although prostate specific antigen levels may be elevated in these patients because of increased organ volume and inflammation due to urinary tract infections, BPH is not considered to be a premalignant lesion.

Adenomatous prostatic growth is believed to begin at approximately age 30 years. An estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. In 40-50% of these patients, BPH becomes clinically significant.[1]

Contents

Signs and symptoms

Benign prostatic hyperplasia symptoms are classified as storage or voiding.

Storage symptoms include urinary frequency, urgency (compelling need to void that cannot be deferred), urgency incontinence, and voiding at night (nocturia).

Voiding symptoms include weak urinary stream, hesitancy (needing to wait for the stream to begin), intermittency (when the stream starts and stops intermittently), straining to void, and dribbling. Pain and dysuria are usually not present. These storage and voiding symptoms are evaluated using the International Prostate Symptom Score (IPSS) questionnaire, designed to assess the severity of BPH.[2]

BPH can be a progressive disease, especially if left untreated. Incomplete voiding results in stasis of bacteria in the bladder residue and an increased risk of urinary tract infection. Urinary bladder stones are formed from the crystallization of salts in the residual urine. Urinary retention, termed acute or chronic, is another form of progression. Acute urinary retention is the inability to void, while in chronic urinary retention the residual urinary volume gradually increases, and the bladder distends. Some patients that suffer from chronic urinary retention may eventually progress to renal failure, a condition termed obstructive uropathy.

Cause

A study published in 2008 in the journal of andrology "Andrologia"[3] reports on a newly discovered venous route by which free (active) testosterone reaches the prostate in extremely high concentrations, promoting the accelerated proliferation of prostate cells, leading to the gland's enlargement. The study suggests that BPH is caused by malfunction of the valves in the internal Spermatic veins manifesting as varicocele, a phenomenon which has been shown to increase rapidly with age,[4][5] roughly equal to the 10% per year increasing prevalence of BPH. The 6- to 8-fold elevated hydrostatic pressure then leads to retrograde venous drainage, allowing free communication with the prostatic circulation. Having measured a concentration of free testosterone of some 130-fold above serum level in the internal spermatic vein (the testes being the main source and the blood being undiluted in systemic circulation), the authors conclude that the elevated venous pressure causes hypertrophy and exposure to high concentrations of free testosterone causes hyperplasia in the prostate. The study also proposes a treatment method (Gat–Goren Technique) similar to that used in treating varicocele, which restores normal pressure in the venous drainage system, effectively reducing the volume of the prostate and clinical manifestation of BPH.

Androgens (testosterone and related hormones) are considered to play a permissive role in BPH by most experts. This means that androgens have to be present for BPH to occur, but do not necessarily directly cause the condition. This is supported by the fact that castrated boys do not develop BPH when they age. On the other hand, administering exogenous testosterone is not associated with a significant increase in the risk of BPH symptoms. Dihydrotestosterone (DHT), a metabolite of testosterone, is a critical mediator of prostatic growth. DHT is synthesized in the prostate from circulating testosterone by the action of the enzyme 5α-reductase, type 2. This enzyme is localized principally in the stromal cells; hence, those cells are the main site for the synthesis of DHT.

DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. DHT is 10 times more potent than testosterone because it dissociates from the androgen receptor more slowly. The importance of DHT in causing nodular hyperplasia is supported by clinical observations in which an inhibitor of 5α-reductase is given to men with this condition. Therapy with 5α-reductase inhibitor markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and, in many cases, BPH symptoms.

Testosterone promotes prostate cell proliferation,[6] but relatively low levels of serum testosterone are found in patients with BPH.[7][8] One small study has shown that that medical castration lowers the serum and prostate hormone levels unevenly, having less effect on testosterone and dihydrotestosterone levels in the prostate.[9]

There is growing evidence that estrogens play a role in the etiology of BPH. This is based on the fact that BPH occurs when men have, in general, elevated estrogen levels and relatively reduced free testosterone levels, and when prostate tissue becomes more sensitive to estrogens and less responsive to DHT. Cells taken from the prostates of men that have BPH have been shown to grow in response to high estradiol levels with low androgens present. Estrogens may render cells more susceptible to the action of DHT.

On a microscopic level, BPH can be seen in the vast majority of men as they age, in particular over the age of 70 years, around the world. However, rates of clinically significant, symptomatic BPH vary dramatically depending on lifestyle. Men that lead a western lifestyle have a much higher incidence of symptomatic BPH than men that lead a traditional or rural lifestyle. This is confirmed by research in China showing that men in rural areas have very low rates of clinical BPH, while men living in cities adopting a western lifestyle have a skyrocketing incidence of this condition, though it is still below rates seen in the West.

Much work remains to be done to completely clarify the causes of BPH.

Diagnosis

Micrograph showing nodular hyperplasia (left off center) of the prostate from a transurethral resection of the prostate (TURP). H&E stain.
Microscopic examination of different types of prostate tissues (stained with immunohistochemical techniques): A. Normal (non-neoplastic) prostatic tissue (NNT). B. Benign prostatic hyperplasia. C. High-grade prostatic intraepithelial neoplasia (PIN). D. Prostatic adenocarcinoma (PCA).
Prostate with a large median lobe bulging upwards. A metal instrument is placed in the urethra (which passes through the prostate). This specimen was almost 7 centimeters long with a volume of about 60 cubic centimetres on transrectal ultrasound and was removed during a Hryntschak procedure or transvesical prostatectomy (removal of the prostate through the bladder) for benign prostatic hyperplasia.

Rectal examination (palpation of the prostate through the rectum) may reveal a markedly enlarged prostate, usually affecting the middle lobe.

Often, blood tests are performed to rule out prostatic malignancy: Elevated prostate specific antigen (PSA) levels needs further investigations such as reinterpretation of PSA results, in terms of PSA density and PSA free percentage, rectal examination and transrectal ultrasonography. These combined measures can provide early cancer detection.

Ultrasound examination of the testicles, prostate, and kidneys is often performed, again to rule out malignancy and hydronephrosis.

Screening and diagnostic procedures for BPH are similar to those used for prostate cancer. Some signs to look for include[10]:

Management

Lifestyle

Patients should decrease fluid intake before bedtime, moderate the consumption of alcohol and caffeine-containing products, and follow timed voiding schedules.

Medications

The two main medications for management of BPH are alpha blockers and 5α-reductase inhibitors.

Antimuscarinics such as tolterodine may also be used, especially in combination with alpha blockers.[23] They act by decreasing acetylcholine effects on the smooth muscle of the bladder, thus helping control symptoms of an overactive bladder.

Sildenafil citrate shows some symptomatic relief, suggesting a possible common etiology with erectile dysfunction.[24]

Herbal remedies

People often seek herbal remedies for BPH.[25] Several are approved in European countries, but none in the USA. Saw palmetto extract from Serenoa repens is one of the most extensively studied. It showed promise in early studies,[26] though later trials of higher methodological quality indicated no difference from placebo.[27][28][29]

Other herbal medicines that have research support in systematic reviews include beta-Sitosterol[30] from Hypoxis rooperi (African star grass) and pygeum (extracted from the bark of Prunus africana),[31] while there is less substantial support for the efficacy of pumpkin seed (Cucurbita pepo) and stinging nettle (Urtica dioica) root.[32] There is weak evidence that pollen extracts frp, rye grass (Secale cereale) may also correlate with modest symptomatic relief.[33]

Minimally invasive therapies

The European Urology Review[34] published in 2009 that two Israeli doctors, Yigal Gat and Menahem Goren, who discovered the main reason for the gland's enlargement, have also developed the Gat-Goren nonsurgical method for BPH.[35] Using an interventional radiological technique that reduces prostate volume and reverses BPH symptoms. The treatment, known as super-selective intra-prostatic androgen deprivation (SPAD) therapy, involves a percutaneus venography and sclerotherapy of the internal spermatic vein network including associated venous bypasses and retroperitoneal collaterals. The European Urology Review also declared that using the Gat Goren nonsurgical method results in decreased prostate volume, which leads to significant decreased nocturia, improved urine stream, and also improves emptying of the urinary bladder, since the reduction in prostate volume increases the diameter of the prostatic portion of the urethra and therefore may also prevent urinary retention.

While medication is often prescribed as the first treatment option, there are many patients who do not achieve success with this line of treatment. Those patients may not achieve sustained improvement in symptoms or they may stop taking the medication because of side-effects.[36] There are options for treatment in a urologist's office before proceeding to surgery. The two most common types of office-based therapies are Transurethral microwave thermotherapy (TUMT) and Transurethral Needle Ablation (TUNA). Both of these procedures rely on delivering enough energy to create sufficient heat to cause cell death (necrosis) in the prostate. The goal of the therapies is to cause enough necrosis so that, when the dead tissue is reabsorbed by the body, the prostate shrinks, relieving the obstruction of the urethra. These procedures are typically performed with local anesthesia, and the patient returns home the same day. Some urologists have studied and published long-term data on the outcomes of these procedures, with data out to five years. The most recent American Urological Association (AUA) Guidelines for the Treatment of BPH in 2003 lists minimally invasive therapies including TUMT and TUNA as acceptable alternatives for certain patients with BPH.[37]

Transuretheral microwave therapy (TUMT) was originally approved by the FDA in 1996, with the first generation system by EDAP Technomed. Since 1996, other companies have received FDA approval for TUMT devices, including Urologix, Dornier, Thermatrix, Celsion, and Prostalund. Multiple clinical studies have been published on TUMT. The general principle underlying all the devices is that a microwave antenna that resides in a urethral catheter is placed in the intraprostatic area of the urethra. The catheter is connected to a control box outside of the patient's body and is energized to emit microwave radiation into the prostate to heat the tissue and cause necrosis. It is a one-time treatment that takes approximately 30 minutes to 1 hour, depending on the system used. It takes approximately 4 to 6 weeks for the damaged tissue to be reabsorbed into the patient's body. Some of the devices incorporate circulating coolant through the treatment area with the intent of preserving the urethra while the microwave energy heats the prostatic tissue surrounding the urethra.

Transuretheral needle ablation (TUNA) operates with a different type of energy, radio frequency (RF) energy, but is designed along the same premise as TUMT devices, that the heat the device generates will cause necrosis of the prostatic tissue and shrink the prostate. The TUNA device is inserted into the urethra using a rigid scope much like a cystoscope. The energy is delivered into the prostate using two needles that emerge from the sides of the device, through the urethral wall and into the prostate. The needle-based ablation devices are very effective at heating a localized area to a high enough temperature to cause necrosis. The treatment is typically performed in one session, but may require multiple sticks of the needles depending on the size of the prostate.

Surgery

If medical treatment fails, and the patient elects not to try office-based therapies or the physician determines the patient is a better candidate for transurethral resection of prostate (TURP), surgery may need to be performed. In general, TURP is still considered the gold standard of prostate interventions for patients that require a procedure. This involves removing (part of) the prostate through the urethra. There are also a number of new methods for reducing the size of an enlarged prostate, some of which have not been around long enough to fully establish their safety or side-effects. These include various methods to destroy or remove part of the excess tissue while trying to avoid damaging what remains. Transurethral electrovaporization of the prostate (TVP), laser TURP, visual laser ablation (VLAP), ethanol injection, and others are studied as alternatives.

Newer techniques involving lasers in urology have emerged in the last 5–10 years, starting with the VLAP technique involving the Nd:YAG laser with contact on the prostatic tissue. A similar technology called Photoselective Vaporization of the Prostate (PVP) with the GreenLight (KTP) laser have emerged very recently. This procedure involves a high-power 80-watt KTP laser with a 550-micrometre laser fiber inserted into the prostate. This fiber has an internal reflection with a 70-degree deflecting angle. It is used to vaporize the tissue to the prostatic capsule. KTP lasers target haemoglobin as the chromophore and typically have a penetration depth of 2.0 mm (four times deeper than holmium).

Another procedure termed Holmium Laser Ablation of the Prostate (HoLAP) has also been gaining acceptance around the world. Like KTP, the delivery device for HoLAP procedures is a 550 um disposable side-firing fiber that directs the beam from a high-power 100-watt laser at a 70-degree angle from the fiber axis. The holmium wavelength is 2,140 nm, which falls within the infrared portion of the spectrum and is invisible to the naked eye. Whereas KTP relies on haemoglobin as a chromophore, water within the target tissue is the chromophore for Holmium lasers. The penetration depth of Holmium lasers is <0.5 mm, avoiding complications associated with tissue necrosis often found with the deeper penetration and lower peak powers of KTP.

HoLEP, Holmium Laser Enucleation of the Prostate, is another Holmium laser procedure reported to carry fewer risks compared with either TURP or open prostatectomy[38]. HoLEP is largely similar to the HoLAP procedure; the main difference is that this procedure is typically performed on larger prostates. Instead of ablating the tissue, the laser cuts a portion of the prostate, which is then cut into smaller pieces and flushed with irrigation fluid. As with the HoLAP procedure, there is little bleeding during or after the procedure.

Both wavelengths, KTP and Holmium, ablate approximately one to two grams of tissue per minute.

Post surgery care often involves placement of a Foley Catheter or a temporary Prostatic stent to permit healing and allow urine to drain from the bladder.

Epidemiology

Disability-adjusted life year for benign prostatic hypertrophy per 100,000 inhabitants in 2004.[39]
     no data      less than 20      20-28      28-36      36-44      44-52      52-60      60-68      68-76      76-84      84-92      92-100      more than 100

The prostate gets larger in most men as they get older, and, overall, 45% of men over the age of 46 can expect to suffer from the symptoms of BPH if they survive 30 years. Incidence rates increase from 3 cases per 1000 man-years at age 45–49 years, to 38 cases per 1000 man-years by the age of 75–79 years. Whereas the prevalence rate is 2.7% for men aged 45–49, it increases to 24% by the age of 80 years.[40]

For some men, the symptoms may be severe enough to require treatment.

See also

Further reading

Christensen, TL; Andriole, GL (February 2009). "Benign Prostatic Hyperplasia: Treatment Strategies". Consultant 49 (2). http://www.consultantlive.com/display/article/10162/1376744. 

References

  1. ↑ eMedicine - Transurethral Microwave Thermotherapy of the Prostate (TUMT) : Article by Jonathan Rubenstein
  2. ↑ Barry MJ, Fowler FJ, O'Leary MP, et al. (November 1992). "The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association". The Journal of Urology 148 (5): 1549–57; discussion 1564. PMID 1279218. 
  3. ↑ - Benign Prostatic Hyperplasia - Andrologia 2008- novel mechanism, new treatment
  4. ↑ Canales BK, Zapzalka DM, Ercole CJ, et al. (September 2005). "Prevalence and effect of varicoceles in an elderly population". Urology 66 (3): 627–31. doi:10.1016/j.urology.2005.03.062. PMID 16140091. 
  5. ↑ Levinger, U.; Gornish, M.; Gat, Y.; Bachar, G. N. (2007). "Is varicocele prevalence increasing with age?". Andrologia 39 (3): 77. doi:10.1111/j.1439-0272.2007.00766.x. PMID 17683466. 
  6. ↑ Feldman BJ, Feldman D (October 2001). "The development of androgen-independent prostate cancer". Nature Reviews. Cancer 1 (1): 34–45. doi:10.1038/35094009. PMID 11900250. 
  7. ↑ Lagiou P, Mantzoros CS, Tzonou A, Signorello LB, Lipworth L, Trichopoulos D (1997). "Serum steroids in relation to benign prostatic hyperplasia". Oncology 54 (6): 497–501. doi:10.1159/000227609. PMID 9394847. 
  8. ↑ Roberts RO, Jacobson DJ, Rhodes T, Klee GG, Leiber MM, Jacobsen SJ (October 2004). "Serum sex hormones and measures of benign prostatic hyperplasia". The Prostate 61 (2): 124–31. doi:10.1002/pros.20080. PMID 15305335. 
  9. ↑ Page, S. T.; Lin, D. W.; Mostaghel, E. A.; Hess, D. L.; True, L. D.; Amory, J. K.; Nelson, P. S.; Matsumoto, A. M. et al. (2006). "Persistent Intraprostatic Androgen Concentrations after Medical Castration in Healthy Men". Journal of Clinical Endocrinology & Metabolism 91 (10): 3850. doi:10.1210/jc.2006-0968. PMID 16882745. 
  10. ↑ PreventProstateCancer.info: A Brief Overview of Benign Prostatic Hyperplasia (BPH) [1]
  11. ↑ Roehrborn CG; Nuckolls JG; Wei JT; Steers W (October 2007). "The benign prostatic hyperplasia registry and patient survey: study design, methods and patient baseline characteristics". BJU International 100 (4): 813–9. doi:10.1111/j.1464-410X.2007.07061.x. PMID 17822462. 
  12. ↑ Black L; Naslund MJ; Gilbert TD Jr; Davis EA; Ollendorf DA (March 2006). "An examination of treatment patterns and costs of care among patients with benign prostatic hyperplasia". Am J Manag Care 12 (4 Suppl): S99-S110. PMID 16551208. 
  13. ↑ Hutchison A; Farmer R; Verhamme K; Berges R; Navarrete RV (January 2007). "The efficacy of drugs for the treatment of LUTS/BPH, a study in 6 European countries". European Urology 51 (1): 207–15 discussion 215–6. doi:10.1016/j.eururo.2006.06.012. PMID 16846678. 
  14. ↑ MacDonald R; Wilt TJ; Howe RW (December 2004). "Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects". BJU International 94 (9): 1263–70. doi:10.1111/j.1464-410X.2004.05154.x. PMID 15610102. 
  15. ↑ MacDonald R; Wilt TJ (October 2005). "Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects". Urology 66 (4): 780–8. doi:10.1016/j.urology.2005.05.001. PMID 16230138. 
  16. ↑ Roehrborn CG (December 2001). "Efficacy and safety of once-daily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a randomized, placebo-controlled trial". Urology 58 (6): 953–9. doi:10.1016/S0090-4295(01)01448-0. PMID 11744466. 
  17. ↑ Djavan B; Marberger M (1999). "A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction". Eur Urol 36 (1): 1–13. doi:10.1159/000019919. PMID 10364649. 
  18. ↑ Aua Practice Guidelines, Committee (2003). "AUA guideline on management of benign prostatic hyperplasia. Chapter 1: Diagnosis and treatment recommendations". J. Urol. 170 (2 Pt 1): 530–47. doi:10.1097/01.ju.0000078083.38675.79. PMID 12853821. 
  19. ↑ 19.0 19.1 Gormley GJ; Stoner E; Bruskewitz RC; Imperato-McGinley J; Walsh PC; McConnell JD; Andriole GL; Geller J; Bracken BR; Tenover JS; et al (October 22, 1992). "The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group". New England Journal of Medicine 327 (17): 1185–91. PMID 1383816. 
  20. ↑ Roehrborn CG; Boyle P; Nickel JC; Hoefner K; Andriole G (September 2002). "Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia". Urology 60 (3): 434–41. doi:10.1016/S0090-4295(02)01905-2. PMID 12350480. 
  21. ↑ Roehrborn CG; Bruskewitz R; Nickel JC; McConnell JD; Saltzman B; Gittelman MC; Malek GH; Gottesman JE; Suryawanshi S; Drisko J; Meehan A; Waldstreicher J (March 2004). "Sustained decrease in incidence of acute urinary retention and surgery with finasteride for 6 years in men with benign prostatic hyperplasia". J Urol 171 (3): 1194–8. doi:10.1097/01.ju.0000112918.74410.94. PMID 14767299. 
  22. ↑ Kaplan SA, McConnell JD, Roehrborn CG, et al. (2006). "Combination therapy with doxazosin and finasteride for benign prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total prostate volume of 25 ml or greater". J. Urol. 175 (1): 217–20; discussion 220–1. doi:10.1016/S0022-5347(05)00041-8. PMID 16406915. 
  23. ↑ Kaplan SA; Roehrborn CG; Rovner ES; Carlsson M; Bavendam T; Guan Z (November 15, 2006). "Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial". JAMA 296 (19): 2319–28. doi:10.1001/jama.296.19.2319. PMID 17105794. 
  24. ↑ McVary KT, Monnig W, Camps JL, Young JM, Tseng LJ, van den Ende G (2007). "Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial". J. Urol. 177 (3): 1071–7. doi:10.1016/j.juro.2006.10.055. PMID 17296414. 
  25. ↑ Lieber MM (June 1998). "Pharmacologic therapy for prostatism". Mayo Clinic Proceedings 73 (6): 590–6. doi:10.4065/73.6.590. PMID 9621869. 
  26. ↑ Boyle P; Robertson C; Lowe F; Roehrborn C (April 2000). "Meta-analysis of clinical trials of permixon in the treatment of symptomatic benign prostatic hyperplasia". Urology 55 (4): 533–9. doi:10.1016/S0090-4295(99)00593-2. PMID 10736497. 
  27. ↑ Bent S, Kane C, Shinohara K, et al. (February 2006). "Saw palmetto for benign prostatic hyperplasia". N. Engl. J. Med. 354 (6): 557–66. doi:10.1056/NEJMoa053085. PMID 16467543. 
  28. ↑ Dedhia RC, McVary KT (June 2008). "Phytotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia". J. Urol. 179 (6): 2119–25. doi:10.1016/j.juro.2008.01.094. PMID 18423748. 
  29. ↑ Wilt T, Ishani A, Mac Donald R (2002). "Serenoa repens for benign prostatic hyperplasia". Cochrane Database Syst Rev (3): CD001423. doi:10.1002/14651858.CD001423. PMID 12137626. 
  30. ↑ Wilt T; Ishani A; MacDonald R; Stark G; Mulrow C; Lau J (2000). "Beta-sitosterols for benign prostatic hyperplasia". Cochrane Database Syst Rev (2): CD001043. doi:10.1002/14651858.CD001043. PMID 10796740. 
  31. ↑ Wilt T; Ishani A; Mac Donald R; Rutks I; Stark G (2002). "Pygeum africanum for benign prostatic hyperplasia.". Cochrane database of systematic reviews (Online) (1): CD001044. doi:10.1002/14651858.CD001044. PMID 11869585. 
  32. ↑ Wilt TJ, Ishani A, Rutks I, MacDonald R (2000). "Phytotherapy for benign prostatic hyperplasia". Public Health Nutr 3 (4A): 459–72. doi:10.1017/S1368980000000549. PMID 11276294. 
  33. ↑ Wilt T; Mac Donald R; Ishani A; Rutks I; Stark G (2000). "Cernilton for benign prostatic hyperplasia". Cochrane Database Syst Rev (2): CD001042. doi:10.1002/14651858.CD001042. PMID 10796739. 
  34. ↑ Reversal of Benign Prostate Hyperplasia by Super-selective Intraprostatic Androgen Deprivation Therapy -European Urology Review 2009
  35. ↑ www.prostata.co.il - The Gat Goren Method's official website
  36. ↑ Table 5. Roehrborn CG.Current medical therapies for men with lower urinary tract symptoms and benign prostatic hyperplasia: achievements and limitations. Rev Urol. 2008 Winter;10(1):14-25. PMID: 18470272
  37. ↑ AUA Clinical guidelines for management of BPH
  38. ↑ Holmium Laser Enucleation of the Prostate; Results at 6 Years, Gilling PJ, Aho, TF, Frampton CM, et al. Eur Urol 2008 Apr:53(4):744-9
  39. ↑ "WHO Disease and injury country estimates". World Health Organization. 2009. http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html. Retrieved November 11, 2009. 
  40. ↑ Verhamme KM, Dieleman JP, Bleumink GS, et al. (2002). "Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care--the Triumph project". Eur. Urol. 42 (4): 323–8. doi:10.1016/S0302-2838(02)00354-8. PMID 12361895. 
Male diseases of the pelvis and genitals (N40-N51, 600-608)
Internal
Testicular
Orchitis · Hydrocele testis · Testicular torsion · Male infertility (Azoospermia, Oligospermia)
Epididymis
Epididymitis · Spermatocele · Hematocele
Prostatitis (Acute prostatitis, Chronic bacterial prostatitis, Chronic prostatitis/chronic pelvic pain syndrome, Asymptomatic inflammatory prostatitis) · Benign prostatic hyperplasia
External
Balanoposthitis/Balanitis · Phimosis · Priapism · Sexual dysfunction (Erectile dysfunction) · Peyronie's disease · Penile fracture · Balanitis xerotica obliterans
Other
Hematospermia · Retrograde ejaculation

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