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Urogenital problems in elderly

Learning Objectives

With the advancing age and subsequent to that the changes in the Urinary Tract cause many problems in Elderly males. These problems in this module have been categorized under the following heads:
Benign hyperplasia of Prostate (BPH)
Carcinoma Prostate
Urinary Tract Infections
Urinary Incontinence

Benign hyperplasia of Prostate (BPH)

Incidence: At the age of 45 years: 50%of men will have histological evidence of BPH. Clinical evidence of BPH may be found in 14% of men between 40 to 49 years and 40%of men between 70 to 79 years.
Pathology: Hyperplasia of Transitional zone of prostate which increases in size to cause obstruction and/or irritation of bladder outlet. Initially bladder muscle hypertrophies to push out urine, but eventually fails and results in urinary retention.


Clinical Presentation: Enlarged Prostate may present as-


(a) Irritative urinary symptoms

  1. Frequency
  2. Dysuria
  3. Urgency i.e. difficulty in postponing urination.
  4. Nocturia
  5. Precipitancy i.e. Failure to control the outburst of urine.

(b) Obstructive symptoms

  1. Hesitancy i.e. Difficulty in starting the act of urination.
  2. Poor stream, broken stream
  3. Need to strain to pass urine
  4. Sense of incomplete evacuation of urine
  5. Prolonged urination

(c) Complications of BPH

  1. Retention of urine
  2. Overflow incontinence
  3. Hematuria
  4. Urinary tract infection
  5. Compromised renal function

Approach to a patient with suspected BPH

(a) History : Exclude other causes of obstructed urination-

  1. Obvious neurogenic bladder
  2. Stricture urethra, in which the flow of urine improves on straining
  3. Vesical calculus, in which there is a very good flow at times but it suddenly stops and results in severe pain.
  4. Carcinoma prostate, history of low backache painful skeletal metastasis

(b) Examination :

  1. Palpation of abdomen for distended bladder, hydronephrotic kidneys, any other mass.
  2. Digital rectal examination of prostate, which reveals smooth surface, Firm consistency and absence of any nodularity.

(c) Investigations:

  1. Microscopic analysis of urine for pyuria and if indicated culture
  2. Ultrasonogram to evaluate kidneys, urinary bladder, size and Echo texture of prostate, residual urine after voiding.
  3. Uroflometry.If available, this is a simple test to ascertain the degree. The degree of obstruction caused by prostatic enlargement. The Patient is asked to pass urine in computerized container and the rate of flow of urine is measured. The following are the Indications for active intervention:
    1. Peak flow rate less than 15 ml per second
    2. Average flow rate less than 10 ml per second.
  4. Transrectal ultrasound may be done to further evaluate the echo texture of prostate. A majority of malignant lesions would appear as hypo echoic areas.

Treatment of BPH
After adequate evaluation, one can generally classify patients of BPH into three categories:


  1. Primarily irritative BPh which includes patients with adequate uroflowrates and insignificant post void residual urine. These patients can be managed successfully by oral medication.
  2. Borderline obstruction, in which uroflometry reveals peak flowrate is around 10 ml per second and post void residual urine is between 50 to 100 ml. These Patients may be put on medical management with an understanding that They may require to under go surgical intervention at a later date and need to be followed very closely.
  3. Severe obstruction, as evident on uroflometry, episodes of retention, sonographic evidence of bilateral hydronephrosis.

Size of prostate is not related to severity of the symptoms.


Treatment options in BPH :


(a) Oral medication

  1. Alpha-adrenergic antagonists (e.g., terazosin). Bladder neck has circular smooth muscle fibers which constitute internal or involuntary sphincter. These are innervated by adrenergic fibers rich in alpha-receptors. Drugs blocking these receptors are expected to increase the outflow of urine from bladder by relaxing the smooth muscle fibers of bladder neck. A variety of alpha adrenergic antagonists have been studied. The selective alpha one blockers which spare alpha two receptors result in much lower incidence of side effects like postural hypotension, nasal congestion and light headedness. Terazosin demonstrates some of these side effects and therefore concomitant anti hypertensive treatment may need to be revised. However newer agents like Tamsulosin and Alfuzosin are devoid of these side effects. The once daily recommended oral dose of Tamsulosin is 0.4 mg and that of Alfuzosin is 10mg.
  2. 5 alpha reductase inhibitors: 5 alpha reductase is the enzyme which is necessary for conversion of Testosterone molecule to it's active metabolite Diydrotestosterone (DHT). Depriving BPH tissue of DHT support causes reduction in size of the prostate gland thereby improving urinary flow rates. It takes around 12 weeks of regular treatment before any sonographic evidence of reduction in the size of the prostate can be demonstrated. These drugs are well tolerated and have been shown to be safe over long periods of followup.
  3. Finasteride in the oral once daily dose of 5 mg has been studied for more than 10 years with improvements in flowrates without significant side effects.
  4. Dutasteride is a newer molecule which has been shown to inhibit both isoforms of the enzyme and hence is more potent as well as faster acting. Dutasteride has been recommended in the dose of 0.5mg per day a single oral dose.

(b) Minimally invasive options

  1. Prostatic stent : A prostatic stent is a self-retaining expandable flexi metallic device which can be positioned in the prostatic urethra to keep it open. It is passed under cystoscopic vision in operating room under mild sedation and local anaesthesia. Advantages of this procedure include avoidance of spinal or general anaesthesia, short operating time, low risk of water intoxication. Thus it can be useful in cases of obstructive BPH who may not be medically fit enough to undergo anesthesia. Disadvantages of this procedure include poor tolerance of the stent by the patient, as it may be associated with dysuria, terminal hematuria, and frequent urination. Migration of stent is also a possibility. Other problems in Indian scenario are prohibitive cost (Rs.20, 000 per stent) and limited availability. Overall it is a poor alternative to an indwelling catheter.
  2. Transurethral needle ablation of prostate (TUNA) : Along a urethral catheter, metallic needles are inserted into prostate and radio frequency energy is delivered to the adenoma. This causes rise in the temperature of the localized area which then degenerates and shrinks. Multiple sites along the prostatic urethra are treated in this manner expecting to overcome urethral obstruction. Advantages include all those of avoidance of major anesthesia. Disadvantages include unpredictable long-term results and multiple sessions of treatment.

(c) Surgical options

  1. Trans urethral resection of prostate (TURP): This is the gold standard of surgical treatment of prostate. Indications: Obstruction causing retention of urine retention.

Advantages:

  1. resection of adenoma can be done through urethral passage;
  2. resected specimen is available for histopathological examination.3. mechanical clearing of urinary passage is achieved.

Disadvantages:

  1. Technically demanding procedure.
  2. Steep learning curve.
  3. Morbidity associated with the procedure, e.g. complications.

Complications of TURP:

(i) Intra operative:

  1. Primary hemorrhage needing abandoning of procedure.
  2. Water intoxication, causing cerebral edema and death. In experienced hands using latest equipment and irrigation fluids the risk of this serious complication is around 0.5%. However, patients with Compromised renal and cardiac function run a higher chance of this syndrome called TURP syndrome.

(ii) Immediate post operative:

  1. Reactionary hemorrhage. This occurs after approximately7days of surgery .It may be treated by conservative means and transfusions if required. Occasionally cystoscopic evacuation of clots may be required.
  2. Retention of urine. It may occur due to presence if clots, retained prostates chips or inadequate operation.
  3. Infection. Presents as dysuria, fever, epididymo orchitis , secondary hemorrhage
  4. Incontinence of urine. Incidence 0.5%. If external sphincter is divided by mistake Trans urethral laser prostatectomy. Endoscopic procedure done using Holmium laser contact fiber.

Advantages:

  1. Very minimal blood loss,
  2. Short hospital stay,
  3. advisable in high-risk patients.

Disadvantages:

  1. High cost of equipment,
  2. Long operative time,
  3. Results yet to be standardized.

Laser Prostatectomy

It has been over two decades that various forms of laser generators have been used to ablate the obstructing prostatic adenoma. However in last 5 years two such modalities have gained stability while others have largely failed to survive.

a. Holmium Laser enucleation of Prostate (HOLEP). This involves high power (100 watts) laser energy generated using Holmium Yag medium to be delivered through an end firing contact probe. By moving this probe all around the adenoma it can be enucleated and dropped into the urinary bladder, where it could be morcellated and sucked out piecemeal. The probe works like the finger of a surgeon performing open prostatectomy.


Advantages:

  1. Almost blood less surgery, minimal blood loss
  2. Excellent vision through the telescope as there is no bleeding
  3. Normal saline may be used as irrigant
  4. Short catheter period; less than 24 hours
  5. Quick recovery
  6. Early return to work
  7. Very low incidence of stricture urethra and reactionary haemorrhage
  8. Advisable in patients with coagulation disorder

Disadvantages:

  1. High cost of equipment
  2. Recurring cost of fibre
  3. Steep learning curve

b. Photoselective Vaporisation of Prostrate (PVP) Using KTP laser This involves vaporization of prostrate tissue using a side firing laser beam generated by KTP laser. Since the laser frequency happens to fall in the green light zone, it is selectively absorbed by the red color. Therefore it coagulates all blood vessels and bleeding surfaces. It vaporizes the obstructing adenoma and therefore is effective in making the patient catheter free quickly. However it is too slow a process and a large residual adenoma still says behind.


Advantages:

  1. It makes a patient rapidly catheter free with minimum morbidity
  2. It can be done under sedation and local anesthesia in very sick patients

Disadvantages:

  1. Cost is much higher than holmium laser as the fibre is not reusable
  2. Tissue is not available for histopathology
  3. Should not be performed on infected prostate and residual prostate tissue may continue to produce symptoms.

Trans urethral electrovaporisation of prostate

In order to overcome the disadvantage of bleeding in TURP, the loop electrode has been modified into a ceramic roller electrode called Vapotrode. contact of this electrode on the prostatic surface causes charring and dessication of tissues in addition to vaporization of superficial layers. If done properly, there is minimal blood loss and good vision is preserved throughout the procedure.


Advantages:

  1. Minimal blood loss.
  2. Less hospital stay
  3. Less risk of water intoxication.

Disadvantages:

  1. No material available for histopathology.
  2. Depth of tissue charing and thermal damage may not be always controllable leading to mishaps e.g. damage to sphincter.

Open prostatectomy

Indications:

  1. Very large gland i.e. more than 120 grams.
  2. in patients with high risk of water intoxication e.g. poor cardiac ejection fraction, chronic renal failure

Techniques:

  1. Trans vesical (Freyer‘s)
  2. Retropubic (Millin‘s)

Advantages: May be done where sophisticated equipment is not available.

Disadvantages:

  1. Prolonged hospital stay.
  2. Blood loss may necessitate transfusion.

Carcinoma Prostate

Incidence: In autopsy series histological evidence of foci of Adenocarcinoma may be found up to 67% of men above the age of 80 years


Pathology: Malignant change involves the peripheral zone of prostate which is fortunately easily felt on digital rectal examination. Histologically, 95%of these are Adenocarcinoma.Other varieties include Transitional cell carcinoma, Sarcoma and Melanoma. Adenocarcinoma spreads along the neurovascular bundles on either side and settles in pelvic lymph nodes, i.e. obturator, internal iliac, external iliac and para aortic


Hematogenous metastasis occurs into bones e.g. lumbar spine, pelvic bones, femur humerus, ribs etc. Hepatic, pulmonary and intra cranial metastasis signify grave prognosis.


Clinical presentation

  1. Incidental: Upon routine histological examination of prostatectomy specimen, foci of Adenocarcinoma may be found.
  2. Asymptomatic i.e. picked up on routine screening.
  3. Presenting as lower urinary symptoms and picked up on digital rectal examination
  4. Symptomatic due to distant metastasis e.g. painful skeletal deposits of tumor

Diagnosis

Digital rectal examination (DRE) : A good clinician should be able to pickup and differentiate nodular hard prostate from smooth, firm benign prostate. Sensitivity of DRE to pickup Ca prostate is around 80%i.e.only about 20% of tumors would be missed on this simple examination. However the specificity of DRE is only 50% i.e. 50% of the nodules thus picked up would turn out to be lesions other than malignancy. Deseases mimicking malignancy include granulomatous prostatitis, prostatic calcifications and occasionally calculus impacted in prostatic urethra. Abdominal Ultrasound (USG): this is a useful investigation to study the gross morphology of prostate. In addition, it gives information regarding status of kidneys, any lymph nodes and residual urine after voiding.


Trans Rectal Ultrasound (TRUS): Finer details of echo texture of prostate can be readily made out by TRUS. Around 40% of the malignant foci are hypoechoic, 30% are hyper echoic and rest are isoechoic. Pericapsular invasion by the tumor is important in planning the treatment and is best-identified by TRUS.


Prostate Specific Antigen (PSA): It is a protein normally present in prostate cells. Serum levels of PSA are related to prostatic volume. In adenocarcinoma prostate, the level of PSA is raised and corresponds to the tumor load. However, PSA levels may also be found high in prostatitis and after instrumentation of urinary tract. Even DRE is expected to raise the serumPSA levels transiently. On the other hand PSA values may be within normal range in the presence of small foci of adenocarcinoma. Therefore, PSA is not to be used for the primary diagnosis of malignancy. It is used as a screening modality in addition to DRE and TRUS. The main role of PSA is in following already diagnosed case of adenocarcinoma prostate and assessing the response to treatment or relapse.


Trans rectal biopsy of prostate: Trucut Needle biopsy of prostate is the investigation to clinch the diagnosis of adenocarcinoma prostate. If a nodule is felt on DRE then digitally guided biopsy may be performed. Sometimes TRUS guided biopsy may be required if the nodule is better seen on TRUS than felt by the finger. Histological examination of biopsy specimen reveals tumor grade, a measure of tumor aggressiveness. A common grading system adopted is called Gleason scoring.


Staging
Once the diagnosis of Ca prostate (CaP) is established, staging is required for planning further treatment. Following is usual plan of staging investigations: TRUS gives information regarding local spread and differentiates extra capsular disease from localized intra prostatic disease.

Contrast enhanced CT scan of abdomen would identify intra abdominal lymphadenopathy and any metastasis in liver. However it is not a sensitive modality to pickup small pelvic lymph nodes.
X-ray chest PA view should be done in all cases to look for any pulmonary metastasis.
Skeletal survey should be done with radionucleide labelled MDP bone scan. Hot spots signify areas of increased vascularity and suggest metastatic deposits. However inflammatory lesions would also appear, as hotspots and conventional radiography of the concerned region must be done in case of doubt. Metastatic deposits appear as osteoblastic (osteo sclerotic) lesions on conventional X ray studies.
TNM Staging system of CaP

Primary tumor


TX minimum requirements to assess the primary tumor cannot be met.
T0 No tumor present
T1 No palpable tumor
T2a Palpable tumor less than 1.5 cm
T2b Palpable tumor more than 1.5 cm
T3 Palpable tumor extending into or beyond the capsule
T4 Tumor involving surrounding pelvic structures.

Nodal involvement
Nx Minimum requirements to assess the pelvic lymph nodes cannot be met.
N0 No involvement of regional lymph nodes
N1 Involvement of single homolateral lymph node.
N2 Involvement of bilateral contra lateral or multiple regional lymphnodes.
N3 pelvic lymph node mass fixed to parieties

Distant metastasis
Mx Minimum requirements to assess distant metastasis cannot be met.
M0 No distant metastasis.
M1 Distant metastasis present.

At the time of diagnosis upto40% of cases have distant metastasis


Treatment


A. Localised CaP

  1. Observation : In elderly men with localized CaP, the progression may be so slow that they are hardly inconvenienced by the disease. These men may be put on a surveillance regime and periodic PSA, DRE and TRUS may be al that is needed. Many of these people would die due to unrelated illness with their disease rather than die of it.
  2. Radical Prostatectomy : The treatment of choice in otherwise healthy relatively young men with localised CaP. However upon histological examination of excised specimen 30 to40% may show extra prostatic spread missed on preoperative staging procedures. Complications of this procedure include incontinence in almost all patients in immediate postoperative period which improves in about85 to 90 % over6month period. Another significant complication is impotence which is permanent and occurs in up to 90% of cases. Operative mortality in most series is around 1%.
  3. Radiotherapy :Locally advanced disease may be treated with radiotherapy.6000 to7000 rads is administered spread over 6to7weeks duration. The field of radiotherapy includes prostate and surrounding pelvic tissues along with lymph nodes in an inverted Y field. Good tumor control is achieved in most cases but needle biopsy done several years later still shows viable tumor cells in most cases. Side effects of radiotherapy include radiation cystitis, enteritis and proctitis. In order to avoid these side effects, interstitial radiotherapy using surgically implanted radioactive iodine seeds has been given.

Advanced CaP
1.Endocrine manipulation:Prostatic epithelial cells demonstrate apoptosis i.e. spontaneous cell death, in the absence of androgens. The aim of endocrine manipulation is to cut off the supply of testosterone to prostatic cells. This can be done
by -

  1. Surgical casteration. Bilateral orchidectomy may be performed under local anesthesia as a day care procedure. Immediate fall of serum testosterone levels is achieved to negligible levels. Other benefits include low non-recurring cost without the problem of patient compliance.
  2. Medical manipulation.
    - Anti androgens e.g. Futamide is a non-steroidal competitive inhibitor of testosterone at the target cell. It is given in a dose of 100mg three times a day.
    - LHRH analogues e.g.Leuprolide is used to prevent the production of testosterone from Leydig cells of testes by suppressing the release of LH from pituitary gland It is available is a depot preparation administered every three weeks subcutaneously.

The above two compounds can be used in combination as Complete Androgen Blockage as an alternative to surgical casteration. High cost of treatment and poor patient compliance makes medical treatment less popular than orchidectomy in India. Results of hormonal manipulation

Initially there is a good response to treatment but after a variable period, which depends upon the tumor grade and load, there is a flare of disease and is called ‘escaped desease ‘or‘hormone refractory disease‘. Not much can be done at this stage. Second line drugs like Ketoconazole may be tried in the dose of 400mg three times a day. Painful bony metastasis may require palliative radiotherapy. Several chemotherapeutic agents have been used with very little benefit. Those which have been tried include Cyclophosphamide, DTIC, Estramustine and Streptozocin.

Urinary Tract Infections

Incidence of bacteriuria (urine culture positive for bacteria) increases with age. Above 65 years of age, 20%females and 10% males will have bacteriuria. Bacteriology: The most common organism isolated are E.Coli, Klebsiella and Proteus. Less commonly isolated organism include Enterococci, coagulase negative Staphylococci and group‘B‘ Streptococci. In young females, vaginal flora consists of lactobacilli which prohibit the growth of uropathogens. In postmenopausal state, colonization if vagina by gram-negative uropathogens increases on slightest opportunity. These then invade the vulnerable urothelial lining of urethra and bladder. In males, increasing prostate size and residual urine may be triggering factors for initiation and perpetuation of infection.

Co-morbid conditions predisposing to urinary infections:
1. Diabetes Mellitus
2. Neuropathic bladder
3. Poor local hygiene e.g. unclean perineum, use of diapers.
4. Instrumentation of urinary tract.


Symptoms of urinary tract infection (UTI)

  1. Lower tract symptoms:
    (i) Dysuria
    (ii) Frequency
    (iii) Urgency
    (iv) Hematuria
  2. Systemic symptoms:
    (i) Fever (ii) Confusion
    (iii) Anorexia
    (iv) Vomiting
    (v) Pain abdomen

Diagnosis

  1. Urine analysis:Microscopic examination for pyuria. Special care must be taken to obtain a clean catch midstream sample.
  2. Bacteriological culture:To diagnose UTI, 10^5 colony forming units (CFU) per ml of unspun urine must be demonstrated. However in a frank symptomatic patient even 10^3CFUper ml may be sufficient to diagnose UTI.
  3. Ultrasound of abdomen must be performed to screen the urinary organs to exclude any morphological problem, calculus disease, post void residual urine.

Treatment
Appropriate antimicrobial as per the culture report may be given. Special problems encountered in elderly include:

  1. Low tolerance to medication
  2. Poor compliance
  3. Higher incidence of compromised renal function needing appropriate dose adjustment.
  4. Interactions with concomitant drug therapy
  5. Controversies regarding asymptomatic bacteriuria.

Urinary Incontinence

Incontinence may be defined as an involuntary loss of urine through intact urinary tract.
Prevalence of incontinence in population above 65 years of age is about 12%in females and 7%in males.
Types of incontinence

(a) Urge incontinence :It is defined as uncontrollable desire to pass urine. It occurs in cases of hyperactive detrussor (bladder muscle). The various causes include

  1. Early prostatism
  2. UTI
  3. Senile strophic urethro trigonitis
  4. Detrussor hyper reflexia as in various intra cranial lesions e.g. Parkinsonism, CVA, Senile dementia, acute confusional states etc.

(b) Stress incontinence : Genuine stress incontinence occurs in females due to sagging of perineal floor muscles and consequent lowering of bladder neck Some degree of stress incontinence is usual in healthy adult women But if it is severe enough to interfere in day to day activity then it requires to be treated surgically.


(3) Overflow incontinence occurs when the bladder is unable to empty and is persistently filled with urine to its capacity. Any further production of urine would overflow without notice. Usually it is associated with severe back pressure changes in the kidneys in the form of hydro urethro nephrosis. Renal function may be compromised in long standing cases. Various causes of overflow incontinence include:


  1. BPH
  2. Ca Prostate
  3. Stricture urethra
  4. Vesical calculus
  5. Hypotonic detrussor (e.g. due to spinal injury, autonomic neuropathy, DM etc.)

Management of incontinence
Investigations:

  1. urine microscopic and culture to exclude infection.
  2. USG to evaluate full bladder volume and residual urine
  3. Detailed uro dynamic evaluation.

Treatment:
(1) Appropriate treatment of infection with anti microbial.
(2) Bladder sedatives:


  1. Anticholinergic agents are used to reduce the frequency and strength of Detrusor muscle contractions. The latest of these is Tolterodine which is highly selective anticholinergic agency specific to detrusor muscle and has very little effect on the muscuraine receptors in the salivary glands. Therefore the incidence of dry mouth is much less with this agent as compared to earlier agents like oxybutinine. Tolterodine is also available as a sustained release formulation where by the oral dosage frequency has been reduced to convenient once a day. While oxybutine has been recommended as 2.5 or 5 mg two to three times a day, Tolterodine is recommended as 2 mg twice a day or as sustained release formulation 4 mg once a day. There may be a feeling of abdominal distension and constipation as a side effect of these medications.
  2. Smooth muscle relaxants : Flavoxate hydrochloride has a specific effect on the smooth muscle of urinary bladder and causes reduction in the force of contraction in addition to its anticholinergic action. This is used as 100 mg three times a day and is used as a useful adjunct in acute cystitis with severe urgency. It is a well tolerated molecule with few side effects, which include nausea, vomiting dry mouth, nervousness, vertigo, headache, blurred vision and tachycardia.
  3. Antidepressants:
    (i) Impramine :Apart from elevating the mood in elderly it causes reduction in bladder pressure by relaxing the detrusor muscle. Also the adrenergic activity helps to maintain the sphincter tone thus reducing the episodes or urge precipitancy. However the side effects include increase blood pressure, dry mouth, tachcardia, palpitation, constipation, impotence, difficulty in accommodation of vision and retention or urine. The dose recommended is 25 mg three times a day. It should be cautiously used in cases of coronary heart disease, CVA and history of convulsions.

    (ii) Duloxetine : This is another antidepressant which acts by inhibiting sertonin receptors. It acts on Onuf's nucleus situated in the sacral spinal cord in addition to having intracranial action. Elderly patients with stress incontinence may be helped by this drug. The usual dose is 20 t0 30 mg twice a day. Side effects include dryness of mouth, insomnia, fatigue, constipation, dizziness and sweating. It should be used very cautiously in patients with renal failure or chronic liver disease. There is also a risk of precipitating narrow angle glaucoma.

(3) Collection Appliances e.g. Pads, Catheters, etc.
(4) Intermittent self-catheterization

Further Reading

  1. Rajee TP, Hemal AK. Urge syndrome. Obs Gyne 1998;3 (3):152-6.
  2. Blaivas G. The neurophysiology of micturation: A clinical study of 550 patients. Journal 127:958-63
  3. Smith P. Age changes in the female urethra. Br Med J 1972;42:667-76.
  4. Kozlowski IN, JT. Carcinoma of the prostate. In: Gillenwater JY, Grayhack JT, Howards SS, Duckett JW (eds). Adult and Ped Urol, 2nd ed. St Louis: Mosby Year Books 1991;1277-393.
  5. Epstein J, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of non-palpable cancer. JAMA 1994;271:368-74.
  6. Veterans Administration Co-operative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967;124:1011-7.
  7. Byar DP and Corle DK. Hormone therapy for prostate cancer: Results of the Veteran Administration Co-operative Urological Research Group Studies. Natl Cancer Inst Monograph ,1988;7:165-70.
  8. Crawford ED, Eisenberger MA, McKod DG, Spaulding JT, Benson R, Dorth FA, Blumentstein EA, Davis MA, Goodman PJ. A controlled trail of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419-24.
  9. Hemal A, Urogenital Problems; Geriatric Care in India Ed Sharma OP 1999;60:522-23.
  10. Labrie F, Dupont A, Belanger A, et al. Combination therapy with flutamide, and survival. J Steroid Biochem 1985;23:833-841.
  11. Taylor CD, Elson P, Trump DZ. Importance of continued testicular suppression in hormone refractory prostate cancer. J Clin Oncol 1993;137:1-10.
  12. Boscia JA, Kaye D. Asymptomatic bacteruria in the elderly. Infect Dis Clin North Am 1994;1:893-905.
  13. Childs SJ, Egan RJ. Bacteruria and urinary infections in the elderly. Urol Clin North Am 1996;23(1):43-54.
  14. Schaeffer AJ. Infections and inflammations of the genitourinary tract. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ (eds). Campbell’s Urology, 7th ed. Philadelphia: WB Saunders 1998;601-3.
  15. Debruyne F, Barkin J, van Eryzz P, et al. Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol. 2004 Oct;46(4):488-94
  16. Clans G Rehrborm. The Clinical Benefits of Dutasteride. Treatment for LUTS and BPH. Reviews in Urology, vol 6, suppl 9
  17. Landis JR, Kaplan S, Swift S, Veisi E. Effiecacy of antimuscarinic therapy for overactive bladder with varying degree of incontinence severity. J Urol 2004; 191:752-756.
  18. Norton PA, Zinner NR, Yalcin I et al. duloxetine versus placebo for the treatment of women with stress urinary incontinence. Am J Obstretric Gynecol 2002; 187: 40-8.
  19. Wong DT, Bymastu FP, Mayle DA, et al. A new inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology 1993;8:23-33.
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