Benign Prostatic Hyperplasia; Causes, Symptoms, Treatment

Benign Prostatic Hyperplasia

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Benign prostatic hyperplasia (BPH) is the nonmalignant enlargement of the prostate gland. It refers to stromal and glandular epithelial hyperplasia that occurs in the periurethral transition zone of the prostate that surrounds the urethra [rx]. BPH clinically manifest as lower urinary tract symptoms (LUTS) consisting of irritative (urgency, frequency, nocturia) and obstructive symptoms (hesitancy, a weak and interrupted urinary stream, straining to initiate urination, a sensation of incomplete bladder emptying).[] Prolonged obstructions may eventually lead to acute urinary retention (AUR), recurrent urinary tract infection (UTI), hematuria, bladder calculi, and renal insufficiency.[]

Benign prostatic hyperplasia (BPH) is a histological diagnosis associated with unregulated proliferation of connective tissue, smooth muscle and glandular epithelium within the prostatic transition zone.[] Prostate tissue is composed of two basic elements: A glandular element composed of secretory ducts and acini; and a stromal element composed primarily of collagen and smooth muscle. In BPH, cellular proliferation leads to increased prostate volume and increased stromal smooth muscle tone.

Causes of Benign Prostatic Hyperplasia

  • Age 40 or older
  • Family history of BPH (father or brother)
  • Ethnic background – BPH is less common in Asian men than in white men and African American men; African American men are more likely to develop BPH at a younger age than white men
  • History of chronic health problems, such as obesity, type 2 diabetes, and heart disease
  • Lack of physical exercise
  • Erectile dysfunction
  • Most experts consider androgens (testosterone and related hormones) to play a permissive role in the development of BPH. This means that androgens must be present for BPH to occur, but do not necessarily directly cause the condition. This is supported by evidence suggesting that castrated boys do not develop BPH when they age.
  • In an unusual study of 26 eunuchs from the palace of the Qing dynasty still living in Beijing in 1960, the prostate could not be felt in 81% of the studied eunuchs.[rx] The average time since castration was 54 years (range, 41–65 years). On the other hand, some studies suggest that administering exogenous testosterone is not associated with a significant increase in the risk of BPH symptoms, so the role of testosterone in prostate cancer and BPH is still unclear. Further randomized controlled trials with more participants are needed to quantify any risk of giving exogenous testosterone.[rx]
  • 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. DHT can act in an autocrine fashion on the stromal cells or in a 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 ten 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 such as finasteride is given to men with this condition. Therapy with a 5α-reductase inhibitor markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and BPH symptoms.[rx][rx]
  • Testosterone promotes prostate cell proliferation,[rx] but relatively low levels of serum testosterone are found in patients with BPH.[rx][rx] One small study has shown that medical castration lowers the serum and prostate hormone levels unevenly, having less effect on testosterone and dihydrotestosterone levels in the prostate.[rx]

Symptoms of Benign Prostatic Hyperplasia

  • Incomplete bladder emptying
  • Frequency of urination
  • Stopping and starting of urine stream
  • Urinary urgency
  • Weak urine stream
  • Straining to urinate
  • Wakening during the night to urinate (nocturia)
  • Affected man’s perceived quality of life
  • incomplete bladder emptying
  • nocturia, which is the need to urinate two or more times per night
  • dribbling at the end of your urinary stream
  • incontinence, or leakage of urine
  • the need to strain when urinating
  • a weak urinary stream
  • a sudden urge to urinate
  • a slowed or delayed urinary stream
  • painful urination
  • blood in the urine

Diagnosis of Benign Prostatic Hyperplasia

  • Digital rectal exam – The doctor inserts a finger into the rectum to check your prostate for enlargement.
  • Urine test – Analyzing a sample of your urine can help rule out an infection or other conditions that can cause similar symptoms.
  • Blood test – The results can indicate kidney problems.
  • Prostate-specific antigen (PSA) blood test –  PSA is a substance produced in your prostate. PSA levels increase when you have an enlarged prostate. However, elevated PSA levels can also be due to recent procedures, infection, surgery or prostate cancer.

After that, your doctor might recommend additional tests to help confirm an enlarged prostate and to rule out other conditions. These tests include:

  • Urinary flow test – You urinate into a receptacle attached to a machine that measures the strength and amount of your urine flow. Test results help determine over time if your condition is getting better or worse.
  • Postvoid residual volume test – This test measures whether you can empty your bladder completely. The test can be done using ultrasound or by inserting a catheter into your bladder after you urinate to measure how much urine is left in your bladder.
  • 24-hour voiding diary – Recording the frequency and amount of urine might be especially helpful if more than one-third of your daily urinary output occurs at night.

If your condition is more complex, your doctor may recommend:

  • Transrectal ultrasound – An ultrasound probe is inserted into your rectum to measure and evaluate your prostate.
  • Prostate biopsy – Transrectal ultrasound guides needles used to take tissue samples (biopsies) of the prostate. Examining the tissue can help your doctor diagnose or rule out prostate cancer.
  • Urodynamic and pressure flow studies – A catheter is threaded through your urethra into your bladder. Water — or, less commonly, air — is slowly injected into your bladder. Your doctor can then measure bladder pressure and determine how well your bladder muscles are working. These studies are usually used only in men with suspected neurological problems and in men who have had a previous prostate procedure and still have symptoms.
  • Cystoscopy – A lighted, flexible instrument (cystoscope) is inserted into your urethra, allowing your doctor to see inside your urethra and bladder. You will be given a local anesthetic before this test.
  • Further Blood test  – This can check your levels of two chemical waste products: creatinine and blood urea nitrogen. High levels of these might mean your kidneys aren’t working as well as they should.
  • PSA test – This checks for levels of what’s called prostate-specific antigen, or PSA, in your blood. PSA is a protein your prostate makes. Both BPH and prostate cancer can raise your PSA level. This test alone can’t confirm that you have BPH. You will need other tests, too. If your level is high and your doctor suspects cancer, you’ll likely have a prostate biopsy.
  • Digital rectal exam – The doctor inserts a finger into the rectum to check your prostate for enlargement.
  • Urine test – Analyzing a sample of your urine can help rule out an infection or other conditions that can cause similar symptoms.
  • Prostate-specific antigen (PSA) blood test – PSA is a substance produced in your prostate. PSA levels increase when you have an enlarged prostate. However, elevated PSA levels can also be due to recent procedures, infection, surgery or prostate cancer.
  • Urinary flow test –  You urinate into a receptacle attached to a machine that measures the strength and amount of your urine flow. Test results help determine over time if your condition is getting better or worse.
  • Postvoid residual volume test – This test measures whether you can empty your bladder completely. The test can be done using ultrasound or by inserting a catheter into your bladder after you urinate to measure how much urine is left in your bladder.
  • 24-hour voiding diary – Recording the frequency and amount of urine might be especially helpful if more than one-third of your daily urinary output occurs at night.
If your condition is more complex, your doctor may recommend:

  • Transrectal ultrasound – An ultrasound probe is inserted into your rectum to measure and evaluate your prostate.
  • Prostate biopsy – Transrectal ultrasound guides needles used to take tissue samples (biopsies) of the prostate. Examining the tissue can help your doctor diagnose or rule out prostate cancer.
  • Urodynamic and pressure flow studies – A catheter is threaded through your urethra into your bladder. Water — or, less commonly, air — is slowly injected into your bladder. Your doctor can then measure bladder pressure and determine how well your bladder muscles are working. These studies are usually used only in men with suspected neurological problems and in men who have had a previous prostate procedure and still have symptoms.
  • Cystoscopy – A lighted, flexible instrument (cystoscope) is inserted into your urethra, allowing your doctor to see inside your urethra and bladder. You will be given a local anesthetic before this test.
  • Urodynamic tests – This group of tests checks how well you hold and release urine in your bladder and your urethra, which is the narrow tube in your penis through which pee and semen flow. You might get these tests at your doctor’s office or at a hospital.
  • A post-void residual measurement – checks how much urine is left in your bladder after you go to the bathroom. First, you will be asked to pee. Then the doctor will place a thin tube called a catheter into your urethra. The tube will be threaded into your bladder to remove any urine that’s left inside. That leftover liquid is measured. It can also be checked with an office ultrasound or bladder scanner. Cold jelly is placed over the bladder and the ultrasound measures the leftover urine.
  • Uroflowmetry measures how fast you release urine. This is called your flow rate. During the test, you’ll pee into a special toilet or container. A slow flow might mean you have weak bladder muscles or a blockage in your urinary tract.
  • Urodynamic pressure uses a meter to find out how much pressure needs to be on your bladder for you to pee. It also tests your flow rate. This test can show whether an enlarged prostate is blocking the flow out of your bladder.
  • Cystoscopy – This test lets the doctor see inside your urethra and bladder. You will first get medicine so you don’t feel pain. You might be given something so you aren’t awake during the test. The doctor will insert a tube called a cystoscope through your urethra into your bladder. The tube has a lens on one end that lets him look for problems inside your urinary tract.
  • Transrectal ultrasound – An ultrasound uses sound waves to make a picture of your prostate gland. It can show whether it is enlarged or you have a tumor. You can have this test at your doctor’s office or a hospital. A technician will insert a thin device called a transducer into your rectum. As the device moves around, it will show different parts of your prostate.
  • Biopsy – For this test, you will first get medicine so you don’t feel any pain. The doctor will use ultrasound, CT, or MRI scan to see your prostate gland. He will then use a needle to take a piece of tissue. The sample will be sent to a lab where a technician will look at it under a microscope to see whether it is cancerous.

Differential Diagnosis of Benign Prostatic Hyperplasia

Prostate

  • Benign prostatic hyperplasia
  • Prostatitis
  • Prostate cancer

Bladder

  • Bladder cancer
  • Bladder stones
  • Overactive bladder
  • Interstitial cystitis
  • Primary bladder neck hypertrophy
  • Radiation cystitis

Urethral

  • Urethritis
    • Gonococcal
    • Non-gonococcal
  • Urethral stricture

Neurologic and spinal cord

  • Parkinson disease
  • Multiple sclerosis
  • Cerebrovascular accident
  • Spinal cord trauma
  • Lumbosacral disc disease

Urinary tract infection

  • Bacterial
  • Tuberculosis
  • Viral
  • Fungal

Metabolic

  • Adult-onset diabetes mellitus
  • Nephrogenic diabetes insipidus

Pharmacologic agents

  • Diuretics
  • α-Agonists
  • Anticholinergics

Filling Cystometry (Cystometrography)

  • Filling cystometry adds limited information to the evaluation of most men with LUTS and is not recommended in routine cases. The test may have value in the evaluation of patients with known or suspected neurologic lesions and LUTS, but pressure-flow studies provide more specific information.
  • Filling cystometry, an invasive urodynamic study, provides information on bladder capacity, the presence and threshold of uninhibited detrusor contractions (UDCs), and bladder compliance. UDCs are present in approximately 60% of men with LUTS and correlate strongly with irritative voiding symptoms.
  • However, UDCs resolve in most patients after prostatectomy. Only about one-fourth of patients who have UDCs before treatment continue to have them afterward. Patients whose symptoms do not improve after surgery are more likely to have persistent UDCs; however, preoperative cystometrography does not help identify these patients.

Urethroscopy/Imaging of the Upper Urinary Tract

  • Urethroscopy and imaging of the upper urinary tract should be performed only if the LUTS are accompanied by a UTI, hematuria, or a positive urinary cytologic finding. Men with LUTS and no evidence of hematuria are at no greater risk for renal tumors or other upper tract abnormalities. There are no endoscopic findings that link LUTS to a prostatic origin.

Pressure-Flow Studies

  • Pressure-flow studies differentiate between patients with a low Qmax secondary to obstruction and those in whom a low Qmax is caused by a decompensated or neurogenic bladder. Pressure-flow studies correlate poorly with the severity of LUTS, implying that some men with high levels of BOO are symptomatic and that men with no BOO may have severe LUTS. Therefore, pressure-flow studies are limited in determining the cause of LUTS. Pressure-flow studies may identify high-pressure obstruction in symptomatic men with normal flow rates.

Postvoid Residual Urine Volume

  • PVR is the volume of fluid remaining in the bladder immediately after the completion of micturition. Studies indicate that residual urine volume normally ranges from 0.09 mL to 2.24 mL, with the mean being approximately 0.53 mL. Seventy-eight percent of healthy men have PVRs of less than 5 mL, and 100% have volumes of less than 12 mL.
  • PVR measurement can be performed by noninvasive (ultrasonography) or invasive (catheterization) methods. The most common method is ultrasonography. Small, portable, 3-dimensional ultrasound devices (BladderScan™, Diagnostic Ultrasound, Bothell, Wash) are widely used to measure PVR in the office setting.

Uroflowmetry

  • Uroflowmetry is the electronic recording of the urinary flow rate throughout the course of micturition. The results of uroflowmetry are nonspecific for causes of the symptoms. For example, an abnormally low flow rate may be caused by BOO (eg, hyperplastic prostate, urethral stricture, meatal stenosis) or by detrusor hypocontractility. Flow rate measurements are inaccurate if the voided volume is less than 150 mL. There is no consensus as to the maximum flow rate (Qmax) “cut point” discriminating obstruction from non-obstruction. Qmax values suggestive of BOO range from 12 mL/s to 15 mL/s.

Transrectal Ultrasonography

  • TRUS provides a more accurate assessment of prostate volume than does DRE. In most cases, a precise prostate volume measurement is not necessary for the evaluation of LUTS or selection of therapy.
  • Prostate volume is an important consideration when determining if a transurethral prostatectomy is technically feasible. Most surgeons are comfortable resecting upwards of 50 g of prostatic tissue with this method. More than 90% of prostatectomies can be performed via the transurethral route. Very large prostates are more safely approached using an open surgical technique. In selected cases in which the prostate is very large on DRE, a TRUS should be performed in order to determine the optimal approach to prostatectomy.

Serum Creatinine Measurement

  • The measurement of serum creatinine has been recommended in the initial evaluation of all patients with LUTS to exclude renal insufficiency caused by the presence of obstructive uropathy. However, in men with an elevated serum creatinine level, the etiology is rarely associated with acute or chronic urinary retention secondary to BPH. Obtaining a serum creatinine measurement may be an appropriate screen for renal disease unrelated to BPH.

Serum PSA Measurement

  • Advanced prostate cancer can lead to LUTS by producing urethral obstruction similar to that in men with BPH. In men with clinically localized cancer, the distribution of AUA symptom scores is similar to that in age-matched men in the general population, suggesting that it is the BPH that causes the symptoms.
  • Prostate cancer commonly coexists with BPH and, in most men with a 10-year or longer life expectancy, a finding of concomitant prostate cancer may well alter management of the BPH component. The detection of large nodular prostate cancer on DRE would no doubt alter therapy; however, the “early detection” of small-volume prostate cancer in an 80-year-old man is unlikely to be beneficial. A PSA test and DRE increase the detection rate of prostate cancer over DRE alone. Therefore, measurement of the serum PSA value should be performed in patients for whom the identification of cancer would clearly alter BPH management.

Urinalysis

  • A urinalysis must be done either by using a dipstick test or by examining the spun sediment to evaluate glucosuria and to rule out UTI and hematuria. The presence of UTI or hematuria requires additional testing to exclude genitourinary malignancies and other conditions unrelated to BPH.
  • Urine cytology should be considered in men with severe irritable symptoms, especially if they have a history of smoking. If a dipstick approach is used, the test should include leukocyte esterase and nitrite tests for the detection of pyuria and bacteriuria.

LUTS in non-BPH conditions

Bladder hypersensitivity

  • Sensory urgency may be the presenting symptom in the patients with DO, poor relaxation of the urethral sphincter, interstitial cystitis, BOO, or neurogenic voiding dysfunction. Recent investigations found the urothelial release of neurotransmitters such as acetylcholine, adenosine triphosphate, and the neuropeptide substance P, and the increased expression of the transient potential receptor vanilloid receptor subfamily and purinergic receptor P2X3 indicate that the urothelium plays an important role in the transduction of bladder sensation [,].
  • Adenosine triphosphate production increases with aging. These physiological changes in elderly men indicate that bladder hypersensitivity and overactive bladder (OAB) are responsible for DO and inadequate contractility in elderly men [].

Polyuria

  • A number of patients have a large daily urine output (>2800 mL). Patients may have polydipsia and high water intake, and therefore, they have a frequency with a voided volume >350 mL and are likely physiologically normal []. The metabolic status of these patients should be checked with evaluations of diuretic intake and conditions such as diabetes, azotemia, hyperlipidemia, and sleep apnea syndrome.

Psychological Factors

  • Psychological, social, and psychiatric factors might also cause frequency in male patients. These patients may have high levels of distress and anxiety. The symptoms may worsen in relation to work or stress and several diseases such as uremia, infection, or cancer.

Urothelial Dysfunction

  • Sensory urgency might be a micromotor urgency due to micromotion of the detrusor during rapid bladder filling such as in diuresis. Patients may have severe urgency when their bladder volume is small. This condition might be the cause of urothelial dysfunction such as in trigonal mucosal dysfunction.
  • Increased nerve growth factor levels have been found in bladder biopsies of patients with sensory urgency, chronic cystitis, and interstitial cystitis compared with levels in controls []. Intravesical onabotulinumtoxinA has been found to decrease symptoms of OAB and interstitial cystitis. The production of nerve growth factor was reduced after onabotulinumtoxinA treatment in patients with neurogenic or idiopathic DO [].

Overactive Bladder

  • DO can be due to idiopathic reasons, myogenic overactivity, poor cortical perfusion, postobstructive DO, the aging process, or detrusor hyperactivity with impaired contractility (DHIC). In men with LUTS, BOO should be excluded first. Patients with benign prostatic obstruction (BPO) but without OAB symptoms might develop de novo OAB after TURP, suggesting the destruction of the trigone mucosa might result in OAB [].
  • Treatment of patients with BPH with BOO and OAB should include agents relieving the urethral resistance and antimuscarinics as well when OAB symptoms cannot be resolved after treating with an alpha-blocker alone or combined with a 5 alpha-reductase inhibitor.

Nocturia and nocturnal polyuria

  • Nocturia is the third most bothersome LUTS. The prevalence of nocturia increases to 80% in patients over 80-year-old. It is one of the most common causes of a disturbed sleep pattern in the elderly. The causes of nocturia include DO, a hypersensitive bladder, BOO, nocturnal polyuria, or a small bladder capacity.
  • When the nocturnal urine volume >900 mL or more than 35% of the daily voided volume, nocturnal polyuria is likely. Lack of diurnal desmopressin rhythm can be the cause of nocturnal polyuria and can be treated with exogenous desmopressin []. For patients with combined nocturnal polyuria and BOO or OAB, combined multiple medications are necessary to relieve the complex male LUTS.

Poor relaxation of the urethral sphincter

  • Among the various causes of non-BOO male LUTS, poor relaxation of the urethral sphincter is most frequently encountered []. Patients might have symptoms of hesitancy, intermittency, small caliber urine, or postvoid dribble. Some patients might also have storage symptoms such as urgency or frequency.
  • Learned habits, chronic prostatitis, pelvic floor hypertonicity, occult neuropathy, or increased bladder sensitivity have been postulated to lead to poor relaxation of the urethral sphincter. These voiding symptoms might have a great impact on QoL, especially in young men.

Pain Symptoms

  • Several bladders or bladder outlet conditions can cause pain in men. Interstitial cystitis, BOO, a poorly compliant bladder, and transitional cell carcinoma can cause a painful bladder. Urinary tract infection, urethral stricture, BPO, and chronic prostatitis can cause a painful urethra. Treatment of pain symptoms in men is not easy and should be based on the exact diagnosis of the pain.
  • Transitional cell carcinoma of the bladder usually mimics interstitial cystitis in men with LUTS and painful bladder syndrome. Urine cytology and repeat random bladder biopsy are necessary to find early bladder carcinoma.

Postprostatectomy Male Lower Urinary Tract Symptoms

  • Over half of patients with postprostatectomy LUTS had a small total prostate volume and resected adenoma weight, indicating their LUTS were non-BPH or non-BOO conditions before TURP []. Detailed cystoscopy and video urodynamic study are necessary for these patients especially when they are diagnosed with residual BPH or BOO and are planning to undergo repeat transurethral surgery. DHIC, bladder hypersensitivity, or OAB can also cause male LUTS in the presence of a small BPH.

Other conditions

  • Urethral sphincter pseudodyssynergia in patients with chronic stroke, intracranial lesions, Parkinson’s disease, and spondylolisthesis can cause severe empty symptoms or storage symptoms in elderly men []. These patients might have BPH, but the LUTS are caused by conditions other than BPH. Urethral stricture or urethral meatal stenosis can also cause BOO and LUTS, especially in patients who have had transurethral procedures.

Common drugs used to treat benign prostatic hyperplasia

Alpha-blockersDosageSide effects
  • Terazosin
1 mg once daily to start; may increase up to 20 mg/dayAsthenia, hypotension, dizziness, somnolence
  • Doxazosin
1 mg once daily to start; may increase up to 8 mg once dailyOrthostatic hypotension, fatigue, dyspnea
  • Tamsulosin
0.4 mg once dailyDizziness, rhinitis, abnormal ejaculation
Alfuzosin10 mg once dailyFatigue, edema, rhinitis, headache, upper respiratory tract infection
5-ARIs
  • Finasteride
5 mg once dailyImpotence, decreased libido, decreased semen quantity at ejaculation, decreased semen PSA, gynecomastia (rare)
  • Dutasteride
0.5 mg once dailyImpotence, decreased libido, decreased semen quantity at ejaculation, decreased semen PSA, gynecomastia (rare)

Adapted from the Cleveland Clinical Journal of Medicine. 5-ARIs = 5-alpha reductase inhibitors; PSA = prostate-specific antigen.

Culture results of ocular specimens

DrugDosageMechanismSide effects
  • Finasteride
5 mg once daily5α-reductase inhibitorImpotence decreased libido, decreased semen quantity at ejaculation, decreased semen prostate-specific antigen, gynecomastia (rare)
  • Dutasteride
0.5 mg once daily5α-reductase inhibitorImpotence decreased libido, decreased semen quantity at ejaculation, decreased semen prostate-specific antigen, gynecomastia (rare)
  • Terazosin
1 mg once daily to start; may increase up to 10 mg/dayα1-adrenergic receptor antagonistAsthenia, hypotension, dizziness, somnolence
  • Doxazosin
1 mg once daily to start; may increase up to 8 mg once daily1-adrenergic receptor antagonistOrthostatic hypotension, fatigue, dyspnea
  • Tamsulosin
0.4/0.8 mg once dailyα1-adrenergic receptor antagonistDizziness, rhinitis, abnormal ejaculation
  • Alfuzosin
2.5 mg t.i.d./5 mg b.i.d./10 mg once dailyα1-adrenergic receptor antagonistFatigue, edema, rhinitis, headache, upper respiratory tract infection
  • Saw palmetto
160 mg twice dailyMixedAggravate chronic gastrointestinal disease such as peptic ulcer

Androgen Deprivation Therapy

  • The biological basis of androgen ablation therapy lies in the observation that the embryonic development of the prostate is dependent on the androgen dihydrotestosterone (DHT) [rx]. Furthermore, castration in men before puberty resulted into regression of prostatic enlargement.[] Androgen deprivation causes the reduction in prostatic volume that is believed to reduce the static component of BPH.[]
  • Reversible androgen deprivation can be achieved by the use of progestational agents (hydroxyprogesterone acetate,[] megesterone[]) capable of decreasing serum testosterone levels by inhibiting the release of luteinizing hormone. Suppression of sex steroid production on the basis of desensitization and down-regulationof pituitary gonadotropin releasing hormone (GnRH) receptor by agonistic GnRH analogs [] (nafarelin acetate, leuprolide) resulting in the blockage of gonadotropin release from the anterior pituitary gland is a well-established approach in the treatment of BPH.[,]
  • Furthermore, antiandrogens like cyproterone acetate] and flutamide[] competitively inhibit the ligand (DHT) binding to the androgen receptor and are used therapeutically in BPH. Several lines of evidence indicate the role of estrogen along with androgen in BPH. Estrogens are mainly produced in men by aromatase activity by the peripheral conversion of testicular and adrenal androgen into estradiol. The estrogenic effect presumably includes its stromal and epithelial interaction that regulates the proliferative activity of the prostate and alteration in the sensitivity of the prostate toward androgens.[] Aromatase inhibitors like atermestone[] and abiraterone[] that block the peripheral conversion have found application in pharmacological treatment of BPH.
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Androgen Deprivation Therapy

  • Though the androgen deprivation therapy has proved to be an effective treatment, their use was restricted because of associated side effects such as erectile dysfunction and loss of libido.[,] Therefore, search for the new drugs with more efficacies, selectivity, and relative broader therapeutic index was being pursued, and continued accrual resulted in the development of 5α-reductase inhibitors.

5α-Reductase Inhibitors

  • Steroidal 5α-reductase is a NADPH-dependent enzyme that catalyzes the irreversible conversion of 4-en-3-oxo-steroid, that is, testosterone (T), the major circulating androgen in male adults, to the corresponding 5α-H-3-oxo-steroid, that is, DHT. Two isozymes of 5α-reductase have been cloned, expressed, and characterized on the basis of differences in chromosomal localization, tissue expression pattern, and biochemical properties.[]
  • Within the prostate, locally produced DHT acts in a paracrine fashion to stimulate growth. However, excessive production of DHT is the cause of major androgen- related disorders such as prostate cancer, acne, female hirsutism, and BPH.[] Therefore, inhibitors of androgen action by 5α-reductase is a logical treatment of 5α-reductase activity disorder, that is, BPH. These agents suppress the DHT concentration by blocking the enzyme, resulting in shrinkage in the size of the prostate, increased peak urinary flow rates, and ultimately providing relief from the symptoms related to the static mechanical obstruction caused by BPH.[]
  • Furthermore, the rationale for use of 5α-reductase inhibitors is rooted in the observation that these are more specific to DHT androgens action without affecting or lowering T level, thus capable of decreasing long-term side effect of castration due to loss of T without compromising the efficacy of hormonal therapy.[,] Finasteride and dutasteride are commercially available 5α-reductase inhibitors currently being used in the treatment of BPH.

Finasteride

  • Finasteride (MK-906) synthesized in 1984, is chemically 17β-(N-tert-butyl-carbamoyl)-4-aza-5α-androst-1-en-3-one . It was the first 5α-reductase inhibitor approved in the United States in 1992 for the treatment of BPH.[] Finasteride is a competitive inhibitor of 5α-reductase type 2 with 10-fold high affinity than type 1 and forms a stable complex with enzyme. It has been reported that at clinical doses of 5 mg/day in human beings, it decreases the prostate DHT level by 70 to 90%, thus resulting in decreased prostate volume or size and improved urinary flow rate.[,]
  • It has neither androgenic, antiandrogenic, other hormone related properties, nor it interferes with the binding of T or DHT to the androgen receptor.[] The investigators found significant improvement in finasteride-treated groups in term of increased flow rates and decreased prostate-specific antigen level. The most commonly reported side effects on finasteride long-term usage are decreased libido, ejaculatory dysfunction, or impotence, while some of the patients showed rashes and breast enlargement.[]

Dutasteride

  • Dutasteride belongs to class of 4-aza-steroids and chemical name is 17-N-{2, 5-bis (trifluoromethyl) phenyl)}-3-oxo-4-aza-5α-androst-1-ene-17-carboxamide. [] It was approved by US FDA in 2002 for the symptomatic treatment of BPH. Unlike finasteride, dutasteride has been reported to be a nonselective competitive inhibitor of both 5α-reductase type 1 and 5α-reductase type 2 isozymes.
  • At clinical dose of 0.5 mg/day, it has been shown to decrease DHT levels >90%, by forming a stable complex with a slow rate of dissociation constant. Dutasteride was found to improve urinary flow rate, decrease the risk of AUR and need for surgery by reducing the size of enlarged prostate.[] Improved efficacy of dutasteride (0.5 mg/day) over finasteride (5 mg/day) in terms of symptom score, maximal urinary flow rate, and quality of life has been reported in recently published article by Kumar et al.[]

Alpha Adrenergic Blockers

  • The rationale for using α-adrenergic blockers is based on the fact that noradrenaline acts at α1-adrenergic receptors (α 1-AR) in the neck and sphincter of the urinary bladder to promote contraction and urinary retention, and control the smooth muscles in the prostate capsule and prostate urethra.[,]
  • Therefore, selective α1-AR antagonists relieve the obstruction due to dynamic component by relaxing the smooth muscle in and around the prostate and bladder neck without affecting the detrusor muscle of the bladder wall. Molecular studies have further identified three subtypes of the α1-AR(α1A, α1B, and α1D). Their relative distribution and concentration in the prostate, bladder, neck, brain, and vascular smooth muscle have been exploited to develop uroselective α1-adrenergic antagonists and reduce side effects. The α1Bsubtype is predominant in blood vessels, whereas α1A is predominant in prostate.[]
  • Prazosin was the first selective α1-AR antagonist investigated for BPH treatment.[] Prazosin contains a piperazinyl quinazoline nucleus and is selective α1-adrenergic antagonist, with affinity 1000-fold greater than that for α2-receptor. The adverse effects related to prazosin were postural hypotension along with stuffy nose, headache, and retrograde ejaculation on continuous use for a long period.[]
  • The advent of selective α1-drugs, terazosin and doxazosin , the structural analog of prazosin, originally developed as antihypertensive agents.[] Terazosin and doxazosin with long half life are given once a day with dose titration over 1 to 2 weeks due to first dose syncope to a maximum of 10 mg for terazosin and 8 mg for doxazosin.[]

Tamsulosin

  • Tamsulosin hydrochloride is a competitive antagonist of α1-AR with the chemical name (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide.[] It was the third uroselective α1-AR antagonist with 10-fold more selectivity for α1A-receptor subtype compared with α1B-receptor subtype, approved for use in the treatment of symptomatic BPH.[]
  • It is well absorbed orally with half-life of 5 to 10 hours and extensively metabolized by the cytochrome P450 system.[] A significant reduction in urinary flow has been observed after single dose (0.4 or 0.8 mg) administration of tamsulosin as compared with placebo.[] Tamsulosin have minimal cardiovascular effects and the risk of dizziness is less as compare with doxazosin and prazosin.[] The drug also demonstrated a lower probability of orthostatic hypotension, but a higher rate of ejaculatory dysfunction (10%), and does not appear to cause erectile dysfunction or reduced sexual drive.[]

Alfuzosin

  • Alfuzosin is a quinozoline-based α1-AR antagonist with similar affinity for all α1receptor subtypes .[,] It is available in an immediate (2.5 mg t.i.d.), sustained (5 mg b.i.d.), and extended release formulation (10 mg/day) to improve compliance.[] According to AUA guidelines, alfuzosin has comparable clinical efficacy with tamsulosin and the other approved alpha blockers and does not cause ejaculatory dysfunction.[]

Alpha blockers

  • Selective α1-blockers are the most common choice for initial therapy.[rx] They include alfuzosin,[rx][rx] doxazosin,[rx] silodosin, tamsulosin, and terazosin. They have a small to moderate benefit.[rx] All five are equally effective but have slightly different side effect profiles.[rx] Alpha blockers relax smooth muscle in the prostate and the bladder neck, thus decreasing the blockage of urine flow. Common side effects of alpha blockers include orthostatic hypotension (a head rush or dizzy spell when standing up or stretching), ejaculation changes, erectile dysfunction,[rx] headaches, nasal congestion, and weakness.

Combination Therapy

  • The scientific rationale for combining 5α-reductase inhibitors and α1-AR antagonists is based on their different and complementary modes of action, helpful to manage static and dynamic component in patients with an enlarged prostate gland having symptoms of bladder outlet obstruction.
  • The rationale for this recommendation is a rapid relief of symptoms by the α1-AR antagonists, without targeting the underlying disease process and a mid or more sustained relief of symptoms by the 5α-reductase inhibitors.[] The efficacy and safety of the treatment with different combinations versus treatment with either agent alone has been investigated by different groups in large mulitcentral trials.[,]
  • The combination of avodart and tamsulosin (CombAT)[,] study is underway to further examine the role of combination (dutasteride and tamsulosin) over the α1-AR antagonists (tamsulosin). It would be a major step in assessing the combination therapy and the findings will assist in making treatment decision. These studies demonstrated a higher incidence of impotence with combination therapy compared with 5α-reductase inhibitors, in addition to higher incidence of α1-AR antagonists-mediated dizziness, hypotension.[] Cost-effectiveness studies by Nickel suggest that the combination therapy is more suitable for men at high risk for BPH progression (i.e., with high symptom score, large prostate volume and low qmax value) who are able to tolerate the increased side effects.

Phytotherapy

  • Numerous plant based products (phytotherapy) are commonly used for self treatment of lower urinary tract symptoms and can be prescribed in some European countries. Systematic reviews have suggested that both saw palmetto and Pygeum africanum provided modest improvement in urinary symptoms and flow. However, a recent high quality randomised trial found that saw palmetto was no more effective than placebo in men with BPH and moderate to severe symptoms. Ongoing trials are assessing long term effectiveness and safety of varying doses of both saw palmetto and Pygeum africanum.
  • Finasteride and dutasteride have both been shown to reduce PSA levels by approximately 50% after 6 months.[ This PSA suppression is maintained over time. If PSA rises while on a 5-ARI, a check on drug compliance is in order. If the patient has been taking the drug as prescribed, a referral should be made to a urologist.

Phytochemical Agents

  • The use of plant-derived nonnutritive compounds with protective or disease-preventive properties for urinary symptoms with BPH has gained widespread interest, probably due to perceived reduction in side effects, and desire to maintain control over their treatment.[,]
  • However, the use of these phytochemicals is controversial as most of the studies have not been subjected to the rigorous preclinical pharmacological testing and formal clinical trials. Moreover, the active ingredients and dosage of active medication is unknown, quality is not publicly controlled, and mechanism of action is not clear.[] The extensively studied phytotherapeutic agent Serenoa repens (saw palmetto) has shown mild to moderate efficacy in reducing nocturia, increasing maximal urinary flow, and improving Symptom Score in men with BPH.[]

Saw Palmetto

  • Saw Palmetto, extract of the berries of the dwarf palm tree of S. repens (family Arecaceae) is most widely used.[] The liposterolic extract contains β-sitosterol, chemically related to cholesterol, which has inhibitory effects on 5α-reductase. Various additional mechanisms have also been suggested, including inhibition of binding of DHT to cytosolic androgen receptors in prostate cells and anti-inflammatory effect.
  • However, it has no effect on prostate volume or the prostate-specific antigen test, but slightly decreases the prostate epithelium. It does not cause impotence, but the herb may aggravate chronic gastrointestinal disease such as peptic ulcer.[] It has been reported that oral administration of 160 mg S. repens twice daily for 1 to 3 months is generally superior to placebo in improving subjective and objective symptoms of BPH. ProSafe Forte is a phytochemical composition specially developed by Danor to prevent and ameliorate BPH and prostatic carcinogenesis.[] Serenoa repens is currently available in France, Germany, and Spain.[]

Others

  • Novel approaches like gene therapy,[] COX-2/LOX-5 inhibitors,[] vitamin D 3analogues,[] antibody-dendrimer conjugates,[] oxytocin antagonists,[] and radionucleotide therapy[] are currently exploring their role in BPH. NX-1207 has been recently announced as new treatment for the BPH.

NX-1207

  • NX-1207, originally derived for treatment of Alzheimer’s disease, was later on tested for its potential role in treatment of BPH. This novel drug, developed by Nymox, is currently under Phase 3 clinical trial. It has been reported that men treated with single dose (2.5 mg dose) of NX-1207 had statistically significant improvements; the drug is administered in an office procedure that takes only a few minutes without any pain or discomfort. In addition, there were no sexual- or blood pressure-related side effects. Unlike currently approved BPH medications, NX-1207 treatment does not require the patient to take pills daily for the rest of his life (http://www.Nymox.com,).[,]

Surgical treatment

  • Surgical interventions are considered in case of severe symptoms and complications like urinary retention, renal failure and infection that are weighed carefully against the risk and benefits of the various treatment options.

Invasive procedures

  • The gold standard for the surgical treatment was the removal of obstructing tissue by open prostatectomy[] in early 1900s, which is now replaced by transurethral resection of the prostate (TURP). TURP is the hallmark of the urologist, the one against which other therapeutic measures are compared. It takes 20 to 30 minutes to resect an average gland weighing 30 g and carry the risks for complications like bleeding, infections, retrograde-ejaculation and low semen, low PSA level, and hospital stay including impotence and incontinence. Transurethral incision of the prostate (TUIP) or bladder neck incision is recommended for smaller gland weighing <25 g and has been found to be less invasive than TURP, but the long-term effectiveness in comparison with TURP is yet to be determined.[]

Minimal Invasive Procedures (MIT)

  • Over the last few years, the number of MIT has been established to achieve sa substantial improvement in the symptoms attributed to BPH. These MIT utilizes an endoscopic approach to ablate the obstructing prostatic tissue.

Transurethral electrovaporization (TUVP)

  • TUVP is the modification of TURP and TUIP, and utilize high electrical current to vaporize and coagulate the obstructing prostate tissue. Long-term efficiency is comparable with TURP, but a number of patients has been found to experience irritative side effects.[]

Transurethral Microwave Thermotherapy (TUMT)

  • More specific destruction of malignant cells without affecting normal cells can be achieved by raising the temperature of the cells using low-level radiofrequency (microwave) in the prostate up to 40 to 45°C (hyperthermia), 46 to 60°C (thermotherapy), and 61 to 75°C (transrectal thermal ablation).[] TUMT has been found to be safe and cost effective, with reasonable improvement in urine flow rate and minimal impairment on sexual function.[]

Transurethral needle ablation (TUNA)

  • It is a simple and relatively inexpensive procedure which utilizes needle to deliver high-frequency radio waves to destroy the enlarged prostatic tissue. TUNA is a successful treatment for small-sized gland and it poses a low or no risk for incontinence and impotence.[]

Laser ablation

  • Laser prostatectomy has become an increasingly widespread form of MIT. Four types of lasers have been used to treat LUTS, namely neodymium: yttrium-aluminum-garnet (Nd: YAG) laser, holmium YAG laser (Ho:YAG), potassium titanyl phosphate (KTP), and diode laser. It has been found to be safe and effective technique, with significant improvement in urinary flow rates and symptoms. Short operative time, minimal blood loss and fluid absorption, decreased hospital stay, impotence rates, and bladder neck contractures are few of the advantages of laser prostatectomy over the TURP and other conventional techniques.[]

High-intensity focused ultrasound (HIFU)

  • Effective protein denaturation and coagulative necrosis of prostatic tissue have been achieved by using HIFU frequencies of 4 MHZ. Significant increase in uroflow and a decrease in postvoid residual volume have been observed, but the cost is three times higher than that of TURP.[]

Transurethral Ethanol Ablation of the Prostate

  • Transurethral injection of absolute ethanol into the lateral lobes of prostate produces necrotic effect on prostatic tissues, leading to fibrosis and shrinkage. Significant improvement has been reported in AUA symptoms score. Continual research is going on to dilute negative factors like urinary retention, pain, dysuria, and prolonged period of catheterization with the aim to deliver safe, effective, and economical potential treatment.[]

Water-Induced Thermotherapy

  • It is a simple technique that uses a cylindrical balloon to circulate hot water, resulting in even coagulation necrosis in the prostate by raising the temperature of the prostatic cells up to 60 to 70°C, without having major effect on nontargeted tissues.[]

Plasma kinetic tissue management system (Gyrus)

  • Gyrus is a new technique under development and vaporizes the obstructing tissue by using plasma energy in a saline environment. Procedure has been found to be safe and effective with minimal risk of water intoxication (TURP syndrome) and generally reserved for patients on high risk.[]

Dietary polyphenols identified with 5α-reductase inhibitory actions.

PolyphenolsSourceActivity
MyricetinRed wine5α-reductase inhibition (rx)
BaicaleinScutellaria baicalensis and Scutellaria lateriflora5α-reductase inhibition (rx)
FisetinStrawberries, apples, grapes5α-reductase inhibition (rx)
DaidzeinSoybeans5α-reductase inhibition (rx)
KaempferolApples, broccoli, onions, tomatoes5α-reductase inhibition (rx)
Caffeic acid-phenethyl esterPropolis5α-reductase inhibition (rx)
Octyl gallateOctanol and gallic acid (produced from plant tannins)5α-reductase inhibition (rx)
Dodecyl gallatesGallic acid (from plan tannins)5α-reductase inhibition (rx)

Surgery for BPH

There are different types of surgical procedures that can help treat BPH when medications are not effective. Some procedures are either not invasive or minimally invasive and can often be done in your doctor’s office or clinic (outpatient procedures). Others are more invasive and need to be done in a hospital (inpatient procedures).

Outpatient procedures

Outpatient procedures involve inserting an instrument into your urethra and into the prostate gland. They include:

  • Transurethral needle ablation (TUNA): Radio waves are used to scar and shrink prostate tissue.
  • Transurethral microwave therapy (TUMT): Microwave energy is used to eliminate prostate tissue.
  • Water-induced thermotherapy (WIT): Heated water is used to destroy excess prostate tissue.
  • High-intensity focused ultrasonography (HIFU): Sonic energy is used to eliminate excess prostate tissue.

Inpatient procedures

Inpatient procedures might be recommended if you have any of the following symptoms:

  • kidney failure
  • bladder stones
  • recurrent urinary tract infections
  • incontinence
  • a complete inability to empty the bladder
  • recurrent episodes of blood in the urine

Inpatient procedures include:

  • Transurethral resection of the prostate (TURP): It is the most commonly used surgical treatment for BPH. Your doctor inserts a small instrument through your urethra into the prostate. The prostate is then removed piece by piece.
  • Simple prostatectomy: Your doctor makes an incision in your abdomen or perineum, which is the area behind your scrotum. The inner part of your prostate is removed, leaving the outer part. After this procedure, you may have to stay in the hospital for up to 10 days.
  • Transurethral incision of the prostate (TUIP): This is similar to TURP, but your prostate isn’t removed. Instead, a small incision is made in your prostate that will enlarge your bladder outlet and urethra. The incision allows urine to flow more freely. You aren’t always required to stay in a hospital with this procedure.

Dietary polyphenols identified with BPH suppressing properties.

PolyphenolSourceMechanisms of action
Epigallocatechin-gallateGreen teaSuppression of oxidative stress, diminution of inflammatory markers (IL-Iβ, IL-I6, and TNF-α; inhibition of IGF-I and IGF-II and upregulation of PPAR-α and PPAR-γ (Jinglou and Hongping, 2016)
LignanFlaxseeds, sesame seeds5α-reductase inhibition (Evans et al., 1995)
GenisteinFava beans, soybeans5α-reductase inhibition (Evans et al., 1995)
Biochanin ASoy, Peanuts5α-reductase inhibition (Evans et al., 1995)
EnterolactoneFlaxseed and sesame sees5α-reductase inhibition (Evans et al., 1995)
FlavocoxidScutellaria baicalensisand Acacia catechuInhibition of growth factor expression and suppression of inflammation through inhibition of cyclooxygenase-2 and 5-lipoxygenase activities (
EquolSoyaBinding to 5α-DHT by sequestering 5α-DHT from the androgen receptor (rx)
AnthocyaninSoyaSuppression of cellular proliferation through induction of apoptosis (rx).
LycopeneTomatoUpregulation of caspase-3 and suppression of IL-6 (rx)
KolavironGarcinia kolaInhibition of 5α-reductase and suppression of oxidative stress in the prostatic tissue (rx)
Secoisolariciresinol diglucosideFlaxseedStimulation of increased expression of G-protein-coupled estrogen receptor 1 (rx)

References

Benign Prostatic Hyperplasia

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