MEDICAL MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA* M I C H A E L M. KANE, M.D. D O U G L A S W. F I E L D S , M . D . E. D A R R A C O T T V A U G H A N , JR., M . D . F r o m the D e p a r t m e n t of Surgery/Division of Urology, T h e N e w York Hospital-Cornell Medical Center, N e w York, N e w York

Each year over 350,000 men undergo a surgical proc6dure for symptoms related to benign prostatic hyperplasia (BPH). Transurethral resection of the prostate (TURP) is the preferred operation for most prostate glands. When the gland is too big to remove endoscopically, open prostatectomy is a safe and eff~tive surgical procedure. Prostate surgery today is a~sociated with relatively little morbidity. 1,2 The :major side effect following prostatectomy is retrograde ejaculation. However, a recent retrospective study suggests long-term cardiovascular morbidity. 3 Thus, the search continues for effective nonsurgical approaches to managing clinical BPH. 4 An effective medical therapy for BPH would not only benefit high-risk patients who are poor surgical candidates, bur could conceivably lower health care costs in a :system already overburdened with financial constrNnts. 5 : Benign prostatic hyperplasia is the term used to describe new tissue growth that occurs in the prosta~e gland of men, usually beginning in the fifth decadg of life During the third to fourth decade of life, the prostate gland begins to develop BPH. About 50 percent of men age forty-five have histologic evidence of BPH, whereas nearly 100 percent of men in • 6ir ninth decade have histologie BPH. ~ The new :growth seen in BPH is under endocrine control and beans in the central area of the gland. This tissue, often referred to as adenoma, is made up of different ceil [ypes includin~v stromal, glandular, and muscul i!i' v ' ar components. Growth of the adenoma may eventu~ily lead to a complex of symptoms known as ~'p~ostatism" or clinical BPH. ~:Adapted from. Kant MM Fields DW, and Vaughan ED Jr: Medical managements of benign prostatic hyperplasia. Advances ifi Urology, Chicago, Year Book Medical Publishers, Inc., vol 3, PP 1-22, 1990.

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Difficulties with Clinical Trials The difficulties designing evaluable clinical trials for new treatments of patients with BPH are formidable (Tables I and II). Clearly, studies have to be randomized using a control group since there is a clinical improvement in as many as 50 percent of patients from close attention alone, which can influence a symptom score assessment.V-9 In addition, control series give a better assessment of the natural development of BPH and associated symptoms. While autopsy study 6 has shown the chronologic appearance of BPH, the clinical progression, size progression, and progressive effect of BPH on bladder anatomy and physiology have been poorly studied, although such data are important in view of the variability of symptoms in a given patient. For example, nocturia comes and goes, urgency varies with the season, and initiation and force of the urinary stream are dependent on the voiding circumstances. As a result it is not surprising to find a disparity of "clinical response" to changes in prostatic size or flow rate despite the use of standardized clinical response questionnaires. Second, there is no constant relationship of prostatic size to either patient's symptoms or bladder and renal decompensation. A patient with enormous lateral lobe hypertrophy may have minimal symptoms while only several grams of periurethral BPH may cause devastating bladder and upper tract damage. Thus, while we can accurately assess prostatic size with prostatic ultrasound or magnetic resonance imaging, it is unlikely that a given reduction in size will give a consistent reproducible response in patients' symptoms. Moreover, therapy that influences prostatic tone, e.g., ~-adrenergic blockade, does not alter prostate size.

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TABLE I.

BPH--current strategies of medical therapy

Tone reduction blockade Dibenzyline Prazosin Terazosin Size reduction hormonal manipulation Orchiectomy DES LH-RH analog 5-Alpha-reductase inhibitor Androgen receptor blockers Aromatase inhibitors Ketaconazole Megestrol Growth reduction Growth factor regulators

TABLE II.

BPH--diffieulties of clinical trials

Patient variability Symptoms Size Selection Pathologic variability Glandular Stromal Technical variability Flow rate Urodynamies Determination of prosate size Ultrasound MRI CT

In addition, two prostates of the same size are not necessarily comparable. The pathology of BPH consists of an array of changes. In fact, the differences in pathologic findings might indicate that we may be dealing with a family of diseases rather than the single entity now called BPH. Typical glandular BPH shows large acini lined with tall columnar cells, whereas BPH can be characterized by smaller, more compact glands with increased fibromuscular stroma found between the acini. Finally, without showing all gradations, there can be a dramatic paucity of glandular structures in a fibrostromal gland. Thus, one type of medical intervention cannot be expected to elicit a similar regression or response in all three of these prostates. Perhaps, glandular BPH will be best treated by the appropriate anti-androgen and the fibromuscular gland with an a-adrenergic blocker (Fig. 1). In brief, pathologic

MEDICAL

TREATMENT BPH

STROMAL

GLANDULAR

ALPHA-BLOCKADE

ANTI-ANDROGEN

FIGURE 1. Schematic of hypothetical treatment~. plan based on prostatic pathology. variability remains a major confounding factor in~ the evaluation of clinical trials. A way of evaluating clinical response is to stud~ bladder function, or simply the restoration of nor~ real voiding. Here again, proper stratification an~ patient selection makes clinical studies difficult• Fo'i example, residual urine of over 100 mL as an inelu sion criterion could actually be an index of bladde! deeompensation, whereby a reduction of prostatf~ size might not correct underlying bladder patholo~ or symptoms. In contrast, if patients without resi~ ual or marked flow reduction are selected, is t~ prostate truly obstructive? 1°,11 Moreover, once ~! tients are selected, how can these parameters be f0 lowed in a quantifiable fashion9 The most monly utilized parameter is urinary flow rate, 1~n~ accompanied by ultrasound assessment of bladel[ residual urine• However, there is considerable vari ~ bility in patients' day-to-day flow rate dous effect of voided volume, which control. Recent studies have revealed tingly small improvement in flow rat duetions in prostatic size and an ira] symptoms• Although restoration of bla, or power is a more useful parame! dynamic studies on a repetitive basis in study are dlfheult to perform and revolve sore rlS~ to the subject.13 In conclusion, it is mandatory that prospecti~ ~i~ randomized studies of new medical an interventional oral techniques be earriq over, we need to better define the res now gold standard of treatment, the resection of the prostate (TURP). H studies will be extremely difficult to 1~ rately because of the reasons outlined i: Moreover, confounding variables not even well-planned studies may bias the predictable fashion.

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EFFECTOR

o .oo?; Norepinephrine ----'-~l u2 runcT~or~

~6uRE 2. Schematic o] alpha-adrenergic synaptic ~eurohumoral transmission with nerve stimulation ~orepinephrine released into synaptic gap. Receptors (al, possibly c~, and t) located on e]]ector cell ~fibromuscular stroma). Presynaptic o~2 inhibits ~rther norepinephrine release. Medical Strategies At the risk of being overly simplistic, we tend to ~hink of medical intervention as combatting three ~speets of BPH: tone, size, or growth (Table I). At ~resent all interventional strategies are directed toh a r d the symptomatic prostate and objective void~ng parameters. Thus, reduction in prostatic size or idrenergie tone can be attempted; both of these trategies will be discussed in some detail. However, it would be more logical to prevent ;PH from the onset. The etiology of BPH remains nclear and is the subject of numerous (although intdequate) experimental studies. 14 Autopsy study :hows that BPH starts during the third to fourth dectde, so any intervention should be initiated when the )atient is young, have minimal side effects, and aopefully require limited drug administration. At ,resent, reduetious in prostatic size resulting from aedieal intervention have promptly reversed on eesiation of treatment. 15,1~ A lifetime of treatment be,tinning when a patient is in his thirties to prevent a ]isease which may never become clinically apparent aardly seems reasonable. However, some inroads are being made which may lead to growth inhibition. Treatment of Prostatic Tone

'~ce-Adrenoceptor antagonists In 1975, Caine, Raz, and Zeigler 17 elucidated the ihnportant concept that urinary tract obstruction from benign prostatic enlargement results from a :;combination of two components: a constant mechanical component resulting from the anatomic po;sition of the hyperplastic gland in relation to the prostatic urethra; and a dynamic component, related to increased prostatic tone. The dynamic component is related to the tone of the muscular tissue in the prostate and its capsule.

Roughly a third of the tissue within the prostatic capsule is a fibromuscular mass anatomically and functionally related to the urethra and bladder, is Sympathetic stimulation results in contraction of the intrinsic smooth muscle within the prostate and its capsule. 19 This response is mediated mostly by c~-reeeptors 2°al (Fig. 2). Increased sympathetic tone, which may result from stress, cold, or use of sympathomimetie agents, may cause muscle contraction within the prostate or capsule, resulting in a transient blockade of urinary outflow. By abolishing or reducing to a minimum this dynamic component with pharmacologic blockade of the ~-adrenergie receptors, it is often possible to minimize the patient's symptoms. The first reliable study demonstrating a possible therapeutic effect from a pharmacologic agent was reported by Caine, Perlberg, and Meretyk in 1978. 22 In a placebo-controlled, doubleblind study, phenoxybenzamine, a nonselective agent that blocks both alpha-1 and alpha-2 receptors, was given to patients with clinical BPH. Approximately 70 percent of the patients treated with the drug experienced objective improvement of outflow obstruction, including a reduction in overall urethral pressure, significant increase in urinary flow, and decrease in residual volumes. Changes in the subjective parameters (e.g., frequency of mieturition, urgency, hesitancy, and a feeling of obstruction) are difficult to assess, beeause of both the known spontaneous variations in symptoms and a marked placebo effect of all treatments for BPH. Subsequently numerous clinical trials have reported the effectiveness of ~-adrenergic blockers for the treatment of patients with symptomatic BPH. 23-al Although the results of these reports are consistent (all except Brooks 27 showing improvement), the studies often lacked proper controls or double-blind protocols. Clinical BPH has been managed effectively with a-adrenergie blockers for a number of years. By blocking sympathetic stimulation, these drugs effectively relax the inherent musculature of the prostatic stroma and capsule, thereby decreasing tone. However, the effectiveness of alpha blockade in relieving symptoms of prostatism depends on the underlying level of sympathetic activity present in the particular patient. When this is increased over baseline, there is an appreciable improvement in symptoms. Alternatively, if the underlying sympathetic aetivity is already at a minimum, therapy will result in minireal or no improvement. Thus, numerous studies have shown phenoxybenzamine to be effective in reducing obstructive as well as irritative symptoms associated with BPH. However, because the drug has tested positive in in

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vitro mutagenicity tests (Ames test and mouse-lymphoma assay), it has been removed from many hospital formularies, obviously limiting its use on a long-term basis. Short-term usage often necessary for only one or two days (10-20 mg/day) for acute aggravation of voiding symptoms is useful. The problems with phenoxybenzamine have led to the search for an alternate alpha-blocking agent. Although there is evidence for a postsynaptie alpha2 receptor in the prostate, 32 further studies suggest that the dominant receptor is the classic alpha-1 postsynaptie type. 2°,21 Thus, the pharmaceutical industry is developing new and more effective alpha blockers. Two agents are currently available for clinical use, although they are not approved for the treatment of BPH. Prazosin was introduced in 1977 as an alpha-1 adrenergic antagonist antihypertensive, which acts as a competitive antagonist at the alpha1 receptor. Several studies have shown benefit in patients with BPH. 28,~8,2° However, clinicians believe that it is less effective than phenoxybenzamine in reducing symptoms of outlet obstruction. Caine a3 has reported prazosin is less effective than phenoxybenzamine in controlling irritative symptoms. The other such agent now available is terazosin, another alpha-1 antagonist antihypertensive. This drug is currently under study in a cooperative trial for patients with BPH, and one preliminary study suggests that it may be effective. 3° The ideal alpha-blocking agent for patients with BPH has not yet been developed. Overall, the accumulated data strongly suggest that c~-adrenergie agents do ameliorate symptoms in patients with BPH and will play a role in medical management in the future. At present, pharmacologic alpha-blockade of patients with clinical BPH is indicated for the following: (1) patients who require symptomatic relief but are poor surgical risks, (2) relief of acute retention brought on by increased sympathetic discharge, and (3) preventing retention related to increased sympathetic tone (e. g., postoperative retention).a4 Whereas alpha-adrenoceptor inhibitors attempt to alleviate bladder outlet obstruction and prostatism by relieving the dynamic component of the disease, hormonal manipulation aims at shrinking the size of the prostate, thereby decreasing the Constant, mechanical obstruction of urinary outflow. Clinical Experience with Hormonal Manipulation The first recorded attempt at management of clinical BPH with hormonal manipulation was reported by White in 1895, 3s in a series of 111 men

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with urinary tract obstruction who were treated by castration. Of those surviving the procedure, 87 percent showed a rapid deerease in prostatic volume. In 1896, Cabot a6 reported findings in 61 similar eases. These reports notwithstanding, clinical studies of castration have been inconsistent; some patients show relief of urinary retention, whereas others show no improvement at all. 3v,38Moreover, it is difficult to evaluate the conclusions made from these early studies since objective parameters, such as flow rates and residual volumes, w e r e n o t measured. As already m e n t i o n e d , subjective measurements of prostatism are known to be inaccurate. Even if effective, surgical eastration would rarely be an acceptable treatment for patients with BPH. However, the development of drugs for medically, reversibly castrating males has allowed further study of the efficacy of hormonal manipulation i n the management of clinical BPH. Gonadotropin-releasing hormone (GntlH) analogs, by blocking the release of luteinizing hormone (LH), effectively reduce serum testosterone levels t o castrate levels. Peters and Walsh 15studied the effects~ of the LHItH analog, nafarelin acetate, in patients: with decreased urinary flow secondary to prostatic hyperplasia. Nine patients with bladder outlet ob! struction and peak urine flow rates below 15 mL/sec were treated with subcutaneous nafarelin acetate: for a period of six months. All patients had a persisti ent reduction in testosterone levels to below castrate levels. In all patients, prostate size regressed t o i mean of 75.8 percent of initial size. Three of 9 pa: tients had clinical improvement with treatment determined by improvement in subjective elinic~ symptoms as well as flow rates of greater than if mL/see. However, they found no improvement ii residual volumes with treatment. :! Keane and associates, s° using the LHtlH analol buserelin, tested 20 patients with outflow obstru~ tion secondary to benign prostatic hyperplasia. Th~ maintained serum testosterone at castrate levels f6 up to six months and found no significant improve ment in flow rate or residual volume. In both of these studies, testosterone levels we~ maintained at below castrate levels, which tends produce side effects such as headaches, flushing, IO~!i~ of libido, and impotence. Alternatively, with anff!~I androgens--a group of drugs that block the effe6 of androgen at the target-tissue level by eompetir with androgens at the androgen receptor--the si~ effeets associated with testosterone inhibition ai avoided. 4° Flutamide is an antiandrogen that inhi! its binding of dihydro-testosterone (DHT) to the s[! roid receptor in the prostate gland, producing an 11 crease in LH and serum testosterone levels.

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HYPOTHAtJ~US

Megestrol Aminoglutethimide ADRENALCORTEX TESTIS

5c¢ reductase inhibitors Megestrol

Flutamine Cyproterone Megestrol PROSTATE

FIGURE 3.

Sites of medical intervention to combat BPH.

rmed a double-blind, placebo,~flutamide in 30 patients with itient was treated for a total of aide had no more effect than arine, prostatic size, or histo:atic biopsies. Although the insignificant increases in flow receiving flutamide, they did dues of before and after flow did not report the percent inen in patients treated with fluinical relevance of such a study In contrast, in a recently ready involving 64 evaluable paeported a 27 percent shrinkage nimal change in flow rate, and m in residual urine after three e (750 mg/day). T h e r e was ,rostatic size in a small group of :r treatment period. antiandrogens, megestrol aceacetate, act to block the D H T aese two drugs not only block the periphery, b u t also cenrich in turn induces inhibition Lthesis. Hence, they act at both

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the hypothalamic-pituitary axis and at receptor level to reduce serum levels of testosterone and to inhibit activity of DHT. Megestrol also inhibits 5alpha reduetase and 3-hydroxy steroid dehydrogenase activity giving an additional adrenal effect43 (Fig. 3). Geller and associates, 44 in a double-blind study, compared the effects of megestrol acetate versus placebo in 61 patients with clinical BPH and decreased maximum and mean urine flow rates. They reported that after twenty weeks of treatment, there were statistically significant increases in maximum and mean urine flow rates in the treated patients versus those receiving placebo. However, mean flow rates as well as maximum flow rates improved by an average of only 30 percent. Seventy percent of the patients treated with the drug reported complete loss of libido and erection. Clinical symptoms (nocturia, hesitancy, urgency, force of stream, dribbling) improved in both placebo-treated and megestroltreated patients at rates that were not significantly different. The report did not mention if there were changes in residual volume after drug therapy. The most recent hormonal approach has been based on the observation that prostatic enlargement does not occur in individuals genetically deficient in

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PROSTATE

FIGURE 4. Conversion of testosterone to active dihydrotestosterone by enzyme 5-alpha-reductase. Medical management can inhibit 5-alpha-reductase or block androgen receptor.

testosterone 5-alpha-reduetase. This is the enzyme that converts testosterone to dihydrotestosterone, the predominant intraeellular androgen in the prostate. 45 Hence, the inhibition of DHT formation is another potential approach to BPH therapy in which the side effects of general androgen blockade would be minimized (Fig. 4). These so-called 5alpha-reduetase inhibitors increase intraeellular testosterone levels. Marts, Padilla, and Petrow 46 compared the effects of castration and treatment with 6-methylene progesterone (6MP), a potent 5-alpha-reduetase inhibitor, on rat ventral prostate. They found that when compared with intact controls, prostates of adult rats treated with 6MP were reduced in weight by 45 percent while prostates of castrated rats were reduced by 86 percent. The serum testosterone levels of eastrated rats were 90 percent lower, whereas rats treated with 6MP actually had increased levels of circulating testosterone. DHT levels within the ventral prostate of rats treated with 6MP were reduced by over 63 percent despite the faet that testosterone levels within the ventral prostate rose by over 100 percent. The net result was a considerable shift in the testosterone:dihydrotestosterone ratio in the rats treated with 6MR It is interesting to note that the prostates of rats treated with 6MP were histologically indistinguishable from those of the controls, whereas prostates of rats treated by castration or treated with DES showed the expected involution of primarily epithelial cells. In other words, it appears that there was an equal reduction of stromal and epithelial tissue in the prostates of rats treated with

10

the 5-alpha-reduetase inhibitor. their study with flutamide had sin unclear why drugs that block the; of DHT seem to cause atrophy of epithelial cell components, where testosterone synthesis predomff epithelial cell line. Major clinical trials are now in 5-alpha-reduetase inhibitor, prose (MK906). This agent when givel dose of 50 mg results in a 92 pel prostatic DHT. 4v The drug has n patients for prolonged periods an lyzed after six months of treatn eently reviewed the preliminary f tial centers. So far, there have be effects, and most important, ther verse effect on libido or sexual pc of 1 mg or 5 mg in a single daily d tion in prostate size by about 1~ months and 28 percent at six mow but significant increase in urinary imately 2 ce/sec after 24 weeks). I: some variability during the stud) control patients did not change a tant, the patients appeared to hay prove with treatment. As prediete ies with other agents, the pro, returned to pretreatment size w] withdrawn. At this time, there evaluation of the effect of MK906 omy or a study to identify which likely to respond to the drug. Hc results are most encouraging. Although assessment of syrup ment is difficult, the patients con symptom score evaluation mo devised by Boyarsky in 1977. 48Par on a 0-4 scale were frequency, n~ terminal dribbling, urgency, sJ stream, dysuria, flow interruptior incomplete emptying. In additiol to rate their overall urinary statt with 5 being no change, 0 much b~ worse. Utilizing the sum of five toms, the treatment group show¢ provement throughout the twenty tial review with a mean change of control. The control group showe during the same period, indieatin~ effect. The treatment was extremely w. ever, some patients, after being c prostate was the trouble, opted __ than ehronie medical treatment.

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Summary n e n t o f c l i n i c a l B P H is a reality. n o n s u r g i c a l t r e a t m e n t n o w rect at relieving the dynamic comBPH. Pharmacologic treatment ceptor antagonists may be used anage patients with prostatism c a l risks b u t w h o c o u l d b e n e f i t a t h e t i c tone. I n a d d i t i o n , a l p h a r e l i e v e a c u t e r e t e n t i o n , a n d to zhen i n c r e a s e d s y m p a t h e t i c disT h u s far, n o n s u r g i c a l t h e r a p y h e m e c h a n i c a l o b s t r u c t i o n asso~y p r o s t a t i c size r e d u c t i o n has nsistent objective improvement. :ugs a r e n o w b e i n g i n v e s t i g a t e d ze f o r r e d u c i n g p r o s t a t i c size in C l i n i c a l trials a r e c o m p l i c a t e d tctors, e s p e c i a l l y v e r y v a r i a b l e ~r, r e d u c t i o n in p r o s t a t i c size ino t p e r m a n e n t a n d r e g r o w t h oc:hdrawal, necessitating chronic s e a r c h s h o u l d b e a i m e d at t h e a t a n e a r l y age. H o w e v e r , this .r u n d e r s t a n d i n g of t h e p a t h o )I m a y n o t be a single, v a r i a b l e I o f diseases w i t h a n u m b e r of ;ourses. I n t h e f u t u r e , w e s h o u l d t i o n to histologic v a r i a b i l i t y , to at p a t h o l o g i c f o r m s of B P H lolL1p a t t e r n s , o k e e p t h e i r p r e d o m i n a n t posim patient with BPH, they will l e d of m e d i c a l t r e a t m e n t trials ~ r n a t i v e t r e a t m e n t strategies to

525 East 68th Street New York, New York 10021 (DR. VAUGHAN) References ,tgrewe HL, Cockett ATK, and Peters PC: ctomy immediate and postoperative comve study of thirteen participating institupatients, J Urol 141:243 (1989). t Holtgrewe HL: Current status of trans,, World J Urol 6:194-197 (1989). vlortality and reoperation after open and of the prostate for benign prostatic hyper320:1120 (1989). ;rative management of benign prostatic hy1283 (1989). t a h Transurethral prostatectomy: practice at operation in American urology, J Urol

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6. Berry SJ, Coffey DS, Walsh PC, and Ewing LL: The development of human benign prostatic hyperplasia with age, J Urol 132:474 (1984). 7. Ekman P, Johansson B, Ohlsen H, and Ringertz H: Drug therapy in benign prostatic hypertrophy, Seand J Urol Nephrol [suppl] 60:77 (1981). 8. Van Poppel H, et ah The efficacy of bromocriptine in benign prostatie hypertrophy, Br J Urol 60:150 (1987). 9. Reeee-Smith H, Memon A, Smart CJ, and Dewbury K: The value of permixon in benign prostatic hypertrophy, Br J Uro158: 36 (1986). 10. Coolsaet B, and Elbadawi A: Urodynamies in the management of benign prostatic hypertrophy, World J Urol 6:215 (1989). 11. Ekman P: Nonsurgical treatment of benign prostatic hypertrophy, World J Urol 6:209 (1989). 12. Siroky MR, Olsson CA, and Krane B]: The flow rate nomogram, J Urol 122:665 (1979). 13. Schafer W. Rubben H, Noppency R, and Deutz F]: Obstructed and unobstructed prostatic obstruction, World J Urol 6: 198 (1989). 14. Benign Prostatic Hyperplasia, vol II, U.S. Dept. of Health and Human Services, N.I.H. Publication 87-2881, 1985. 15. Peters CA, and Walsh PC: The effect of nafardin acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperptasia, N Engl J Med 317:599 (1987). 16. Stoner E: The role of 5-alpha reductase inhibitor in benign prostatic hyperplasia, presented at Annual Meeting of American Urological Association, May 7, 1989, Dallas, Texas. 17. Caine M, Raz S, and Zeigler M: Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck, Br J Urol 47:193 (1975). 18. McNeal JE: The zonal anatomy of the prostate, Prostate 2: 35 (1981). 19. Shapiro E, and Lepor H: Alpha-1 adrenergic receptors in canine lower genitourinary tissues: insight into development and function, J Urol 138:979 (1987). 20. Hieble JP, Boyce A], and Caine M.. Comparison of the alpha-adrenoreceptor characteristics in human and canine prostate, Fed Proc 45:2609 (1986). 21. Somers WJ, e t al: An in vivo evaluation of alpha adrenergic receptors in canine prostate, J Urol 141:1230 (1989). 22. Caine M, Perlberg S, and Meretyk S: A placebo-controlled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction, Br J Urol 50:551 (1978). 23. Boreham PF, Braithwaite P, Milewski P, and Pearson H: Alpha-adrenergic blockers in prostatism, Br J Surg 64:756 (1977). 24. Abrams PH, Shah PJR, Stone R, and Choa RG: Bladder outflow obstruction treated with phenoxybcnzamine, Br J Urol 54:527 (1982). 25. Gerstenberg T, Blaabjerg J, Nielsen ML, and Clausen S: Phenoxybenzamine reduces bladder outlet obstruction in benign prostatic hyperplasia, a urodynamic investigation, Invest Uro118: 29 (1980). 26. Hedlund H, Andersson K-E, and Ek A: Effects of prazosin in patients with benign prostatic obstruction, J Urol 130:275 (1983). 27. Brooks ME, Sidi AA, Hanani Y, and Braf ZF: Ineffectiveness of phenoxybenzamine in treatment of benign prostatic hypertrophy, a controlled study, Urology 21:474 (1983). 28. Mantorana G, et ah The effect of prazosin in benign prostatic hypertrophy, a placebo controlled double-blind study, IRCS Med Sci 12:11 (1984). 29. Kirby RS, et ah Prazosin in the treatment of prostatic obstruction, a placebo-controlled study, Br J Urol 60:136 (1987). 30. Dunzendorfer U: Clinical experience with symptomatic management of BPH with Terazosin, Urology (Snppl 6) 32:27 (1988). 31. Kawabe K, and Niijima T: Use of an alpha-l-blocker, YM19.617, in mieturition difficulty, Urol Int 42:280 (1987). 32. Shapiro E, and Lepor H: Alpha~ adrenergic receptors in hyperplastie human prostate: identification and characterization using (aH)-rauwolseine, J Urol 135" 1038 (1986). 33. Caine M: The present role of alpha-adrenergie blockers in

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the treatment of benign prostatic hypertrophy, J Urol 136:1

(1986). 34. Caine M: Alpha adrenergic mechanisms in dynamics of benign prostatic hypertrophy, Urology (Suppl 6) 32:16 (1988). 35. White ]W: The results of double castration in hypertrophy of the prostate, Ann Surg 22: l (1895). 36. Cabot AT: The question of castration for enlarged prostate, Ann Surg 24:265 (1896). 37. Robinson W]: Failure of castration to cause atrophy of the prostate, Med Rec 49:822 (1896). 38. Huggins C, and Stevens RA: The effect of castration on benign hypertrophy of the prostate in men, J Urol 43:705-7]4

(1940). 39. Keane PF, et al: Response of the benign hypertrophied prostate to treatment with an LHRH analogue, Br J Urol 62:162 (1988). 40. Scott WW, and Wade JC: Medical treatment of benign nodtflar prostatic hyperplasia with cytoprone acetate, J Urol 1Oh 81 (1969). 41. Caine M, et al: The treatment of benign prostatic hypertrophy with flutamide (SCH 13521): a placebo-controlled study, J Uiol 114:564 (1975). 42. Stone NN, et ah A double-blind randomized controlled

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study of the effect of flutamide on benign clinical efficacy, J Urol 141: 240A (1989). 43. Geller J, et ah Effect of megestrol roid metabolism and steroid-protein bind tare, J Clin Endocrinol Metab 43:1000 (i 44. Geller J, Nelson CG, Albert JD, megestrol acetate on uroflow rates in pat: tatic hypertrophy, Urology 14:467 (1979) 45. Imperato-McGinley J, Peterson R] mary and secondary 5-alpha-reductase d Sanisi M, Motta M, and Martini L (Eds): Basic and Clinical Aspects, New York, Ra 46. Marts SA, Padilla GM, and Petrow effects of castration and 6-methylene pro t ductase inhibitor, on the rat ventral prosl 65:626 (1987). 47. MeConnell JD, et ah An inhibito MK-906, suppresses prostatic dihydrotes benign prostatic hyperplasia, J Urol 141: 48, Boyarsky S, et ah A new look at b by the Food and Drug Administration r~ investigation of benign prostatic hypert~ Genitourin Surg 68:9.9 (1977).

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Medical management of benign prostatic hyperplasia.

Medical management of clinical BPH is a reality. The only effective nonsurgical treatment now recommended is aimed at relieving the dynamic component ...
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