Question

Research the current treatments available to prostate gland enlargement to treat it. What determines the choice of treatment?

Answer 1

In benign prostatic hyperplasia (BPH) there will be a sudden impact on overall quality of life of patient. This disease occurs normally at the age of 40 or above and also is associated with sexual dysfunction. Thus, there is a need of update on current medications of this disease.

Watchful waiting

Watchful waiting (WW)is a management strategy in which the patient is monitored by his physician without receiving any active intervention for LUTS. WW refers to active monitoring of patients with BPH symptoms. Deciding on absolute indications for surgery is more straightforward than deciding on which men are the best candidates for WW. In men in whom surgery is not indicated, WW has been shown to be safe over a five-year period.

Drug mono-therapy:

Alpha one adrenoreceptor blockers

α₁-Adrenergic receptors (AR) mediate many of the physiological functions of the endogenous catecholamine's noradrenaline and adrenaline such as smooth muscle contraction or cellular hypertrophy. Moreover, they are the molecular target for clinically used drugs for the treatment of e.g. arterial hypertension or BPH. The predominance of α₁-AR in the bladder neck or prostate (40 times the bladder concentration) helped focus interest on α₁-adrenergic blocking agents in the treatment of symptomatic BPH. Presently, α₁-adrenoreceptor antagonists (α₁-blockers that include doxazosin, terazosin, tamsulosin, and alfuzosin) are common for treating BPH related LUTS.

Currently available α₁-blockers include the nonselective α₁-blockers, terazosin, doxazosin, and alfuzosin, and the highly selective α_1A-blocker, tamsulosin.

Silodosin is a new agent with high selectivity for α_1A-receptors, which predominate in the male bladder outflow tract relative to a1B-receptors. Silodosin has a rapid onset of action and a sustained efficacy on LUTS due to BPH.

Naftopidil is an alpha_1D-selective blocker, which has been recently reported to less likely induce ejaculatory disorders. Efficacies on LUTS of the two alpha-1 blockers, silodosin and naftopidil are almost equivalent, with a small advantage of silodosin on voiding symptoms.

5-alpha reductase inhibitors

5 ARIs inhibit the conversion of testosterone to dihydrotestosterone (DHT), the primary androgen involved in both normal and abnormal prostate growth. There are currently two 5 ARIs licensed for the management of BPH, finasteride and dutasteride. Dutasteride, the only 5 ARI to inhibit both type 1 and type II 5 a reductase, induces a more profound reduction of serum DHT in the range of 90–95% compared with 70–75% for finasteride.[32]

Finasteride was the first steroidal 5 a-reductase inhibitor approved by U.S. Food and Drug Administration (USFDA). In human it decreases the prostatic DHT level by 70–90% and reduces the prostatic size.

5-alpha reductase inhibitors

5 ARIs inhibit the conversion of testosterone to dihydrotestosterone (DHT), the primary androgen involved in both normal and abnormal prostate growth. There are currently two 5 ARIs licensed for the management of BPH, finasteride and dutasteride. Dutasteride, the only 5 ARI to inhibit both type 1 and type II 5 a reductase, induces a more profound reduction of serum DHT in the range of 90–95% compared with 70–75% for finasteride.

Finasteride was the first steroidal 5 a-reductase inhibitor approved by U.S. Food and Drug Administration (USFDA). In human it decreases the prostatic DHT level by 70–90% and reduces the prostatic size.

Epristeride, a novel 5 a-reductase inhibitor, is an interesting drug in the treatment of BPH. It belongs to class of carboxy steroid. It has been shown to be an uncompetitive inhibitor against both testosterone and NADPH. Its inhibitory action results from a preferential association to an enzyme binary complex containing NADP and hence, increases in testosterone concentration does not overcome its inhibition. It is a specific inhibitor of type II 5 a-reductase isoenzyme. It also attenuates the growth rate of some androgen responsive prostate cancers.

FK-143, 4-[3-[3-[bis (4-isobutylphenyl) methyl amino] benzoyl]-lH-indol-l-yl] butyric acid is a potent dual inhibitor of both human 5 a-reductase isozymes. This compound can be a potential drug for the treatment of BPH.

Combination therapies:

Combination therapy with doxazosin and finasteride has been shown to provide fast symptom relief, reduced prostate growth, reduced risk of AUR, and the need for BPH-related surgery.

The 4-yr CombAT data provide support for the long-term use of dutasteride and tamsulosin combination therapy in men with moderate-to-severe LUTS due to BPH and prostatic enlargement.

Desmopressin

Noctoria is one of the bothersome LUTS and also most difficult to eliminate in aging men. Nocturnal polyurea associated with circadian change of arginine vasopressine and atrial natriuretic peptide in the elderly has been suggested as the most dominant type of nocturia. Desmopressin is effective in treating nocturia to improve the patients QOL, although a few adverse events such as hypernatremia might occur.

Minimally invasive therapies

Minimally invasive therapies (MITs) usually involve heating the prostate gland by various means (electrical, microwave, laser). Insertion can be directly into the prostate via a needle or into the urethra via a catheter, probe or endoscope.

Heating can be relatively low energy (e.g. microwave, laser or electrical methods) when the effects are thought to be due to aadrenoceptor blockade or damage and the net effect akin to ablockers.

It can be high energy, usually requiring anesthesia, when there is a more direct thermal coagulating or vaporizing effect on prostatic tissue with the intention of destroying or removing obstructing prostatic tissue, but with less bleeding than conventional surgery (e.g. KTP or Holmium laser vaporization).

According to different clinical studies TUMT (Transurethral microwave thermotherapy) proved to be an effective, safe, and durable therapy for the treatment of LUTS secondary to BPH. However, TURP still holds the steadier long-term results and is more effective to reduce obstruction as well as other LUTS. Other treatment options are transurethral needle ablation of the prostate (TUNA), high-intensity focused ultrasound (HIFU), interstitial laser thermotherapy (ILTT), water-induced thermotherapy (WITT), intra prostatic injection therapy with ethanol or hyperosmolar sodium chloride, and transurethral enzyme ablation of the prostate.

Phytotherapy

Cernilton, prepared from the rye-grass pollen Secale cereale, is one of several phytotherapeutic agents available for the treatment of BPH.

Babassu is the common name of a Brazilian native palm tree called Orbignya speciosa, whose kernels are commonly used (eaten entirely or as a grounded powder), in parts of Brazil for the treatment of urinary disorders. Orbignya speciosa nanoparticle (NanoOse) extract shows no toxicity in animals and acts incisively by promoting morphological cell changes, reducing cell proliferation as well as inducing necrosis/apoptosis on BPH cells and tissues.

Phellodendron or cork tree is a genus of deciduous trees in the family Rutaceae. The bark of the plant is used in Traditional Chinese Medical to clear heat, purge fire and moisten dryness. Studies suggested Phellodendron amurense is able to inhibit prostatic contractility suggesting that it may be useful in the treatment of urological disorders caused by prostatic urethral obstruction such as in the case of BPH.

The extract of Ganoderma lucidum Fr. Krast (Ganodermataceae) showed the strongest 5 a-reductase inhibitory activity.  These results showed that Ganoderma lucidum might be a useful ingredient for the treatment of BPH. Sexual function is one of the aspects in the treatment of LUTS associated with BPH that has gained increasing attention and Permixon, a lipido-sterolic extract of Serenoa Repens has no negative impact on male sexual function.

BPH and ayurveda

Ayurveda describes two conditions known as mootrakruchra and mootraaghaata, which coincide with the symptoms of prostatism. Mootrakruchra or strangury is characterized by severe pain in passing urine whereas in mootraaghaata, there is total suppression or intermittent flow of urine during urination.

Gokshura (gokhru), whose botanical name is Tribulus terrestris, has been traditionally used in treating urogenital conditions. Similarly, two other botanicals deserve mention here. Both varuna (Crataeva religiosa) and punarnava (Boerhaavia diffusa) have been shown to be effective for symptoms of BPH.

Yava-kshaara is one such substance obtained from dried wheat plant, before blooming. This contains altered form of potassium carbonate, which is indicated in enlargement of the glands with special concern to prostate.

Long-term insufficient zinc intake is also linked to BPH. Good dietary sources of zinc include meat, eggs, and seafood. Yassada bhasma, obtained by calcination of zinc is the specific medicine for this purpose. A daily dose of 125 to 250 mg with honey will give relief from the problem.

Ushira is popularly known as Khas, Khas or Khus grass in India.

Different parts of this grass is used for many diseases such as mouth ulcer, fever, boil, epilepsy, burn, headache, and enlarge prostate etc.

Swet Chandan (Santalum album)

Indigenous to southern part of India. Useful in the state of anxiety, mental tension, headaches, enlarge prostate, anger negativity and depression.

Khadir

Areca catechu has traditionally been used as an aphrodisiac and to reduce an enlarged prostate.

Shatavari

Asparagus racemosus helps relieve inflammation and improves urination – including urine retention.

Punarnava

Hog Weed (Boerhaavia diffusa) it is prescribed in case of all urinary problems that are caused due to prostate ailments.

Gorakhmundi

Globe thistle (Sphaeranthus hirtus) is very useful in enlargement of prostate.

Salam Mishri

Salep Orchid (Orchis mascula) the salep orchid is known as salam mishri in Ayurveda. It is prescribed in case of prostate problems brought on by vata vitiation.

Lata Karanj

Caesalpinia bonducella has also been found to exert a soothing, anti-inflammatory action, which makes it particularly beneficial for improving an enlarged prostate

Varunadi Vati

The herbal tablets made from the bark of this tree are recommended in Ayurveda for prostate enlargement or BPH.

Kachnaar Guggul

This is another effective herbal remedy for Enlarged prostate gland. Traditionally in Ayurvedic medicine, this herbal supplement is used for all types of excessive growth of various tissues including prostate gland.

Tribulus Power

Tribulus power capsules are used along with other herbal supplements as effective herbal remedy for enlarged prostate gland.

The combined therapy of Bangshil and For-tege is described to act synergistically and relieves prostatic congestion and associated urinary symptoms and particularly symptoms like burning micturition, frequent micturition, difficult micturition,

TURP:

In the case of TURP, short-term (mainly perioperative) complications include death, bleeding, clot retention, transurethral resection (TUR) syndrome (hypernatremia resulting in mental confusion, nausea, vomiting, and raised blood pressure), urinary tract infection, and inability to void, among which, bleeding is the most common. Some of these complications (e.g. bleeding and TUR syndrome) may be serious and life-threatening. Short-term complications of TURP include death, bleeding, clot retention, TUR, urinary tract infection, and inability to void. Long-term complications of TURP include failure to void, retrograde ejaculation, impotence, partial or complete incontinence, and retreatment.

Prostatic Urethral Lift (UroLift):

In contrast to the other therapies that ablate or resect prostate tissue, the prostatic urethral lift procedure involves placing UroLift implants into the prostate under direct visualization to compress the prostate lobes and unobstruct the prostatic urethra.

Transurethral Incision of the Prostate (TUIP):

Like transurethral resection of the prostate (TURP), it is done with an instrument that is passed through the urethra. But instead of removing excess tissue, the surgeon only makes one or two small cuts in the prostate with an electrical knife or laser, relieving pressure on the urethra.

Prostatectomy

Prostatectomy is a very common operation. About 200,000 of these procedures are carried out annually in the U.S. A prostatectomy for benign disease (BPH) involves removal of only the inner portion of the prostate (simple prostatectomy).

Open Prostatectomy

An open prostatectomy is the operation of choice when the prostate is very large — e.g., >80 grams (since transurethral surgery cannot be performed safely in these men). However, it carries a greater risk of life-threatening complications in men with serious cardiovascular disease, because the surgery is more extensive than TURP or TUIP.

Miscellaneous:

Another report describes an improved synthesis of enantiomerically pure (S)-2-[4-(Dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1 H-isoindole-5-carboxamide (RWJ 69442), a potent and selective α_la-adrenergic receptor antagonist for the treatment of BPH.

The conditions that determine the choice of treatment are:

In the initial evaluation of a man presenting with LUTS, the evaluation of symptom severity and bother is essential.

Medical history should include relevant prior and current illnesses as well as prior surgery and trauma.

Current medication, including over-the-counter drugs and phytotherapeutic agents, must be reviewed.

A focused physical exa-mination, including a digital rectal ex-am (DRE), is also mandatory. Urinalysis is required to rule out diagnoses other than BPH that may cause LUTS and may require additional diagnostic tests

A formal symptom inventory (e.g., International Prostate Symptom Score (IPSS) or AUA Symptom Score) is recommended for an objective assessment of symptoms at initial contact, for follow-up of symptom evolution for those on watchful waiting and for evaluation of response to treatment

Testing of prostate-specific antigen (PSA) should be offered to patients who have at least a 10-year life expectancy and for whom knowledge of the presence of prostate cancer would change management, as well as those for whom PSA measurement may change the management of their voiding symptoms (estimate for prostate volume).

Among patients without prostate cancer, serum PSA may also be a useful surrogate marker of prostate size and may also predict risk of BPH progression.

• Symptom inventory (should include bother assessment)

• PSA (selected patients)

Optional:

• Serum creatinine

• Urine cytology (if irritative symptoms are significant component of LUTS)³

• Uroflow

• Voiding diary

• Post-void residual

• Sexual function questionnaire

Treatment guidelines:

Principles of treatment

Therapeutic decision-making should be guided by the severity of the symptoms, the degree of bother and patient preference. Information on the risks and benefits of BPH treatment options should be explained to all patients who are bothered enough to consider therapy. Patients should be invited to participate as much as possible in the treatment selection.

Standard of Care:

Patients with mild symptoms (e.g., IPSS <7) should be counselled about a combination of lifestyle modification and watchful waiting. Patients with mild symptoms and severe bother should undergo further assessment.

Optional:

Treatment options for patients with bothersome moderate (e.g., IPSS 8 – 18) and severe (e.g., IPSS 19 – 35) symptoms of BPH include watchful waiting/lifestyle modification, as well as medical, minimally invasive or surgical therapies.

Lifestyle modifications with watchful waiting

Standard of Care:

Patients on watchful waiting should have periodic physician-monitored visits.

Optional:

Physicians can use baseline age, LUTS severity, prostate volume and/or serum PSA to advise patients of their individual risk of symptom progression, acute urinary retention or future need for BPH-related surgery (these risk factors identify patients at risk for progression).

Optional:

A variety of lifestyle changes may be suggested for patients with nonbothersome symptoms. These can include the following:

• Fluid restriction particularly prior to bedtime

• Avoidance of caffeinated beverages, spicy foods

• Avoidance/monitoring of some drugs (e.g., diuretics, decongestants, antihistamines, antidepressants)

• Timed or organized voiding (bladder retraining)

• Pelvic floor exercises

• Avoidance or treatment of constipation

Medical treatment:

Alpha-blockers

Optional:

Alpha-blockers are an excellent first-line therapeutic option for men with symptomatic bother who desire treatment.

5 alpha-reductase inhibitors

Optional:

The 5 alpha-reductase inhibitors (dutasteride and finasteride) are appropriate and effective treatments for patients with LUTS associated with demonstrable prostatic enlargement.

Combination therapy (alpha-blocker and 5 alpha-reductase inhibitor)

Optional:

The combination of an alpha-adrenergic receptor blocker and a 5 alpha-reductase inhibitor is an appropriate and effective treatment strategy for patients with LUTS associated with prostatic enlargement.

Role of anticholinergics medications

Level 1 Evidence would suggest that for selected patients with bladder outlet obstruction due to BPH and concomitant detrusor overactivity, combination therapy with an alpha-receptor antagonist and anticholinergic can be helpful.

Phytotherapies

Optional:

If patients are interested in complementary approaches (phytotherapeutic or other supplements) for LUTS secondary to BPH, they may be counselled that some plant extracts, such as Serenoa repens (saw palmetto berry extract) and Pygeum africanum (African Plum), have shown some efficacy in several small clinical series.

Transurethral resection of the prostate (TURP)

Monopolar TURP remains the gold standard treatment for patients with bothersome moderate or severe LUTS who request active treatment or who either fail or do not want medical therapy.

Laser prostatectomy

Holmium laser enucleation (HoLEP) can be used effectively in larger glands and in patients on anticoagulation with reported reduced hospitalization, bleeding and duration of catheterization. Greenlight laser or photoselective vaporization prostatectomy (PVP) is a suitable treatment option for most men considering surgical alternatives, particularly for those on anticoagulation.

Absolute indications to recommend TURP include: urinary retention (intractable) and renal insufficiency (caused by BPO). Relative indications to recommend TURP include: failure of medical therapy, recurrent cystitis, bladder calculi and persistent prostatic bleeding.

TUIP is appropriate surgical therapy for men with prostate gland volumes less than 30 grams. These patients should experience symptom improvements similar to TURP with a lower incidence of retrograde ejaculation.

Open prostatectomy remains indicated for men whose prostates, in the view of the treating urologist, are too large for TURP for fear of incomplete resection, significant bleeding or the risk of dilutional hyponatremia (TUR syndrome).

Minimally invasive surgical therapies (MIST)

Transurethral microwave therapy (TUMT);

TUMT is a reasonable treatment consideration for the patient who has moderate symptoms, small to moderate gland size and a desire to avoid more invasive therapy for potentially less effective results.

Transurethral needle ablation (TUNA)

TUNA may be a therapeutic option for the relief of symptoms in the younger, active individual in whom sexual function remains an important quality of life issue (less risk of retrograde ejaculation

Stents

Temporary and permanent stents may be considered in patients with severe urinary obstruction secondary to BPH who are medically unfit for surgery (or waiting to become medically fit for surgery or MIST)

Patients with symptomatic prostatic enlargement in the absence of significant bother may be offered a 5 alpha-reductase inhibitor to prevent progression of the disease.

Men with AUR due to BPH should be offered a trial of voiding 2 to 7 days after catheterization while receiving an alpha-blocker. Recent data suggest that in patients with AUR, the use alpha-blockers (specifically tamsulosin and alfuzosin) during the period of catheterization will increase the chances of successful voiding after catheter removal and may decrease the risk of future prostate surgery.

The BPH patient with an elevated serum PSA and negative prostate biopsy may be counselled on the proven benefits of using finasteride, a Type 2 selective 5 alpha-reductase inhibitor or dutasteride, a dual Type 1 and 2, 5 alpha-reductase inhibitor for prostate cancer risk reduction