Endocrine therapies for symptomatic benign prostatic hyperplasia

ENDOCRINE THERAPIES FOR SYMPTOMATIC BENIGN PROSTATIC HYPERPLASIA JOSEPH E. OESTERLINC;,

From the Department

M.D

of Urology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

ABSTRACT-Objective. To provide a comprehensive overview of the various endocrine therapies being developed and investigated for the treatment of symptomatic benign prostatic hyperplasia (BPH). Methods. Peer-reviewed reports in the medical and urologic literature were examined for pertinent information relating to the role of luteinizing hormone-releasing hormone (LHRH) agonists, antiandrogens, Scr-reductase inhibitors, and aromatase inhibitors in the management of BPH. Special attention was given to the scientific rationale and clinical results for each therapy. Results. LHRH agonists, antiandrogens, and 5a-reductase inhibitors all reduce the androgenic stimulation to the prostate gland. In doing so, they decrease prostate size by 25 percent, but cause a modest improvement in symptom score (3-4 points) and peak urinary flow rate (approximately 2.5 mlfsec). All of these therapies cause a significant decrease in the serum prostate-specific antigen (PSA) concentration, and an effect is maintained as long as the treatment is continued. Side effects are most pronounced for the LHRH agonists, in which impotency and decreased libido are universal phenomena, and least significant for the 5ol-reductase inhibitors. Aromatase inhibitors eliminate the estrogenie stimulation to the prostate gland. Although substantial evidence exists to support the role of estrogens in the development and maintenance of BPH, no data from largescale randomized clinical trials are available to document the clinical usefulness of aromatase inhibitors in the treatment of symptomatic BPH. Conclusions. Medications that produce a state of androgen deprivation can reduce the static component of BPH. Of these agents, the 5ol-reductase inhibitors have the greatest promise because of their low toxicity profile. The role of the aiomatase inhibitors in the treatment of BPH remains to be determined.

Benign prostatic hyperplasia (BPH) refers to a nonmalignant enlargement of the prostate that is directly due to cellular hyperplasia of both the glandular and stromal elements of the gland. It is the most common neoplastic disease in the male population more than forty years of age, affecting men of all races and cultures to a similar degree.‘,’ Although most older men have either histologic (microscopic) or clinical (macroscopic) BPH, for the majority, the disease will not progress to a state warranting treatment.j Indeed, approximately 50-75 percent of men with moderate prostatism who are followed expectantly will have either stabilization or improvement of their symptoms in the absence of any therapeutic intervention? Yevertheless, BPH is the number one urologic discase treated by urologic surgeons today.

For the past fifty years, transurethral resection of the prostate (TURP) has been the mainstay of treatment for this condition. In recent times, approximately 350,000-400,000 TURPs have been performed annually in the IJnited States, making it the second most common operation performed in men older than sixty-five years of age; only cataract extraction is performed more frequently.” The expense associated with this surgical management is considerable. It is estimated rhat the total cost to the health care system in this countr)’ for TURP management of BPH is approximately $5 billion per year. I0 Although TURP is an effective treatment for most patients with symptomatic BPH, it is by no means perfect. From follow-up data, it appears that approximately 20-25 percent of patients

undergoing a TURP do not obtain a satisfactory long-term outcome. I’ Complications do occur and include retrograde ejaculation in most men (70-75%), impotence in 5-10 percent, some degree of urinary incontinence in 2-4 percent, and postoperative urinary tract infection in 5-10 percent of patients. Based on recent investigations published in the urologic literature, the risk of blood transfusion for patients undergoing a TURP is approximately 5-10 percent, and thus, a significant concern for many men in this era when various types of hepatitis and acquired immunodeficiency syndrome (AIDS) are increasing in prevalence. ‘L-‘+ Another concern with TURP is that the reoperation rate is approximately 15-20 percent when patients are followed for ten years or longer (2.2%/year). I5 Also, several large-scale investigations have shown that the life expectancy for patients undergoing a TURP is less than that for men who receive an open prostatectomy as treatment for symptomatic BPH.“,” Because of these issues, as well as the desire by men in our society to avoid surgery whenever possible, there has been tremendous interest in developing alternatives to TURP for the management of symptomatic BPH. These options include medical therapies, such as medications that produce a state of androgen deprivation (luteinizing hormone-releasing hormone [LHRH] analogues,” antiandrogew Iy and 5a-reductase inhibitorslO), a-adrenergic antagonists,l’ and aromatase inhibitors.22 Last year, finasteride (Proscar), a potent 5a-reductase inhibitor, became the first medication approved by the Food and Drug Administration (FDA) for the treatment of BPH. Terazosin (Hytrin) and doxazosin (Cardura), selective a,-adrenergic antagonists currently FDA approved for the treatment of hypertension, also are being used by clinicians for the management of BPH. Transurethral incision of the prostate (TUIP), a minimally invasive procedure, now has an official billing code and is being used with increasing frequency. When compared to TURP, TUIP is technically easier, can be performed more quickly, and has fewer side effects; patients can be discharged home the same or following day, and the convalescence period is shorter than for TURPZ3 Although enthusiasm for balloon dilation of the prostate is diminishing as results of recent studies indicate that it is not an effective, long-term treatment,” there is increasing interest in laser prostatectomyl’ and microwave therapy.2b Although both of the latter procedures are still investigational and not FDA approved for widespread clinical use, preliminary data suggest that they can im8

prove voiding symptoms. Prostatic stents, in FDAapproved clinical trials, have been demonstrated to improve the peak urinary flow rate and decrease the obstructive symptom score to a level similar to that of TUIP and TURP.” Most recently, another therapeutic modality, transrectal highintensity focused ultrasound therapy, has been developed and is currently being investigated in clinical trials in both the United States and Europe.‘* At the present time, the management of BPH is in a state of transition. TURP is no longer the only therapeutic option available. Although surgical treatment will remain most instrumental, medical therapy will begin assuming a much greater position in the management of patients with prostatism. As a result, internists and primary care physicians will have greater involvement in the care of the BPH patient than has previously been the situation. In the discussion that follows, the various endocrine treatments for symptomatic BPH are reviewed. ANDROGEN DEPRIVATION THERAPY Although the exact pathogenesis of BPH is not well defined, it is clear that aging and the presence of androgens are required for this prostatic condition to develop. Numerous laboratory and clinical studies have demonstrated that the prostate gland is an androgen-sensitive organ. If the androgenic stimulation to the prostate is eliminated, the prostatic adenoma decreases in size,2”,‘0 outflow resistance through the prostatic urethra diminishes, and the patient’s ability to urinate improves. ” To produce a state of androgen deprivation means to interrupt the hypothalamic-pituitary-gonadal axis. Under normal physiologic conditions, testicular androgen production is under the control of the hypothalamus. Q Neurons in the preoptic area of the hypothalamus secrete the decapeptide, LHRH (gonadotropin-releasing hormone), in a pulsatile fashion directly from their terminals into the hypophyseoportal circulation. LHRH then interacts with its high-affinity receptor on the plasma membrane of the anterior pituitary cells to stimulate them to release the heterodimeric gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). LH travels via the peripheral circulation to reach the testes, where it binds to its high-affinity receptor on the surface of the Leydig cells. These Leydig cells are stimulated to produce and secrete primarily testosterone (4-androsten-17p-ol-3-one), which travels in the bloodstream either in a free state or bound to sex

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FIGliKE I. (A) Hypothalamic-pituitary-gonadal axis. Site of action of luteinizing hormone-releasing hormone (LHRH) agonists is indicated. LH = luteinizing hormones; T= testosterone. (Reprinted with permission from Oesterling.64) (B) Mechanism by which testosterone stimulates prostatic cell activity. Site of action of antiandrogens and Sa-reductase inhibitors. DHT= dihydrotestosterone; DHT-R = dihydrotestosterone-receptor complex; R = cytoplasmic receptor for androgens; T = testosterone; T-R = testosterone-receptor complex. (Reprinted with permission from Monda and Oesterling.651

hormone-binding globulin (SHBG) or albumin. At the target organ (prostate gland), unbound testosterone binds to its high-affinity receptor within the prostatic cell, where the majority is converted to dihydrotestosterone (DHT) by the enzyme 5areductase. ” lnside the p rostatic cell, the remaining testosterone ancl DHT bind to the same highaffinity androgen-receptor protein, enter the nucleus. and interact with specific DNA-binding sites. .-\ndrogen-dependent genes undergo tran-

scription, and the resulting mRNA is translated into specific proteins. Overall, there is an increase in protein biosynthesis, with the end result being cellular hypertrophy and hyperplasia. Each of the three most commonly used agents IO inhibit testicular androgen production (LHRH agonists, antiandrogens, and Sa-reductase inhibitors) interfere with the hypothalamic-pituitary-gonadal axis (Fig. 1 A,B) to impose an effect on the enlarged prostate gland.

9

LHRH agonists possess a protein structure similar to that of LHRH and bind with great affinity to the LHRH receptor on the plasma membrane of the gonadotropic cells in the anterior pituitary gland. When these analogues (nafarelin, buserelin, goserelin, and leuprolide) are administered in a continuous, nonpulsatile manner, there is “desensitization” (down-regulation) of the LHRH receptor complex on the pituitary cells.3’,‘5 With fewer receptors on the cell surface, the degree of cellular stimulation is decreased, and less gonadotropin is synthesized and secreted. Eventually, after several weeks of LHRH agonist therapy, FSH and LH cease to be secreted. As a result, there is no stimulation of the Leydig cells of the testes to produce testosterone, and the serum testosterone concentration declines to the castration level (~50 pg/dL). As a result, the critical level of prostatic androgens necessary to maintain a hyperplastic state (BPH) is not reached, and significant prostatic involution occurs. Since the early 198Os, when LHRH agonists were investigated in animal models, several human clinical trials to assess the effect of LHRH analogue therapy on prostatism have been conducted. The first patient treated with a LHRH agonist for BPH was reported by Schroeder and colman had leagues in 1986. 3h This 61-year-old recurrent episodes of urinary retention and was a very poor surgical risk. After three months of buserelin therapy (400 pg, three times per day, intranasally), the prostatic volume, as determined by transrectal ultrasonography, decreased by 55 percent, the postvoid residual urine volume was minimal, and the patient was able to urinate freely. In 1987, Peters and WalshI reported on nine patients with BPH who were treated with nafarelin acetate (400 pg/day subcutaneously) for six months and then followed for an additional six months. For all nine patients, prostatic size decreased as determined by transrectal ultrasonography. This decline in prostatic volume stabilized after 4 months of therapy; the mean reduction was 24.2 percent. By six months after cessation of the therapy, all prostates had returned to the pretreatment size. The peak urinary flow rate increased to more than 15 mUsec in three patients (33%); no significant change was noted in the postvoid residual urine volume. With respect to symptoms, three (33%) of the nine patients noted a substantial clinical improvement, as determined from a standard symptom questionnaire. 10

In another study, Matzkin and colleagues” reported on 20 patients who were treated with the depot form of goserelin: each patient received a monthly intramuscular injection of 3.2 mg. Of the 20 patients entered into the study, 17 (85%) completed twelve months of therapy. Prostatic size decreased in all patients after six months of therapy (p < 0.01); the maximal decrease in prostatic volume, however, was not achieved until nine months after initiation of the treatment. Therapy after this point did not result in further shrinkage of the prostate gland. Of significance, however, is the fact that this decrease in prostatic size did not correlate with a clinical objective improvement. Overall, the mean peak urinary flow rate increased from 9.8 f 0.5 to 11.4 f 1.l mUsec at six months and to 15.7 + 2.7 mL/sec at twelve months. By six months, six patients (35%) had a urinary flow rate of more than 15 mUsec, and eight men (47%) had an increase in urinary flow rate of more than 3 mL/sec compared with the pretreatment measurement. The postvoid residual urine volume did not decrease significantly for any of the patients during treatment. With respect to symptoms, 10 patients (59%) showed a significant improvement, including seven men (41%) who had an increase in the peak urinary flow rate of at least 3 mUsec or had achieved a peak urinary flow rate of 15 mUsec. By three months after cessation of the therapy, prostatic volumes returned to 95% + 10.5 percent of the pretreatment values, urinary flow rates decreased, and symptoms deteriorated. These observations indicate that this therapy must be continued indefinitely in order to maintain the therapeutic effect. The most significant side effects associated with LHRH agonist therapy are impotence and diminished libido, which occur in nearly all men receiving the medication. ‘H.37Hot flushes and gynecomastia also occur in approximately 50 percent of patients. Another untoward effect of this therapy is a marked artificial lowering of the serum prostate-specific antigen (PSA) concentration. In a report by Weber and colleagues3” the mean PSA value decreased by more than 80 percent to reflect the inhibitory action of the LHRH agonist therapy on the prostatic epithelium. In conclusion, LHRH agonists are effective in eliminating the androgenic stimulation to the prostate gland. The prostatic epithelium involutes, and prostatic size decreases by approximately 20-25 percent after three to six months of therapy However, not all patients receiving this therapy have a successful outcome; only 30-40 percent of men with BPH will have improvement as

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determined by subjective or objective criteria. The side effects associated with LHRH agonist therapy are bothersome and significant. As a result, these agents should be reserved for elderly symptomatic patients who are considered to be at high risk for surgical or anesthetic intervention. Patients who are alread), impotent are perhaps the most ideal candidates for this therapy. This treatment is expensive. with the annual charge being as much as $5,000. It is also somewhat inconvenient for good patient compliance. since the route of administration is subcutaneous or intramuscular and it must bc given at regular twenty-eight-thirty-day in tcrvals.

LJnlike the LHRH agonists, which work at the level of the anterior pituitary gland to inhibit testicular production of testosterone, antiandrogens exert their effect at the target organ, the prostate gland. The)~ bind with high affinity to the androgen receptor located in the cytoplasm of the prostatic cell, preventing testosterone and DHT from doing so (Fig. lB).‘” In this manner, these agents produce a state of androgen deprivation without lowering the serum testosterone and DHT levels. The antiandrogen that has undergone the most thorough investigation to date is flutamidc (cK,cx,~trifluoro-2-methyl-$‘-~~itro-m-propiontoluidide). It is an orally administered, nonsteroidal compound that is metabolized in the liver to its active form, hydroxyllutamide. Hydroxyflutamide effectively competes with both testosterone and DHT for the androgen receptor. +’ Flutamide has no androgenic, estrogenic, antiestrogenic, progestational, or antiprogestational action; as a result. the serum testosterone level is not lowered and there are no to few hormonally related side effects.‘” At the prcsent time, it is approved by the FDA for use as combination therapy in the management of advanced prostate cancer. No other antiandrogen has FDA approval lor clinical use in the United States. Caine and associates, “’ in 1975, conducted the first double-blind, placebo-controlled study using tlutamide for the treatment of BPH. Thirty patients with symptomatic BPH received flutamidc, 100 mg three times per day for twelve weeks. There was a significant improvement in the peak urinary flow rate for the flutamide group when compared with the control cohort, but no statistically significant difference was found with regard 10 prostatic size or postvoid residual urine volume. The flutamide-treated group had a slightly greater improvement in obstructive voiding symptoms than did the placebo cohort.

Stone,+’ in 1989, reported on a randomized, double-blind, placebo-controlled clinic:al trial e\.aluating the efficacy of flutamide for treating patients with bladder outlet obstruction caused by BPH. In this study, 28 patients received flutamide (750 mg/day), and 30 received a placebo. Prostatic size, as measured by transrectal ultrasound, urinary flow rate, and voiding symptoms were assessed for all patients. There was a 41 percent decrease in prostatic volume and a 46 percent rncrexe in peak urinary flow rate for patients receiving flutamide for six months. No significant change in prostatic volume or urinary flow rate was obscr\,cd for the control group. Both groups had a significant decrease in urinary symptoms:, however, there was no statistically significant difference between the two groups. This latter obserlration highlights the tremendous ob.jective response rat<‘ of placebo groups in antiandrogen studies. In another randomized, double-blind, placebocontrolled clinical trial, Stone and Clejan+’ monitored the effect of antiandrogen therapy on the serum PSA concentration. For patients receiving flutamide, the serum PSA level decreased by 65 percent, whereas there was no change for the placebo cohort (p < 0.001). There was no correlation between the decrease in serum PSA level and the improvement in peak urinar), flow or svmptom score. The major side effects of flutamnde therapy include gynccomastia and breast tenderness in approximately 50 percent of patients. Gastrointestinal upset as manifested by nausea, diarrhea. and flatulence, also occurs in a substantial number of patients receiving flutamide. However,, libido and potency appear to be unaffected by the antiandrogen treatment, because the serum testosterone level is not decreased. In summary, antiandrogcns represent an improvement over LHRH agonist therapy in that they are oral medications and have no signihcant effect on sexual function. However, the) are associated with breast and gastrointestinal untoward effects in many patients. As with LHRH agonists, they decrease prostatic size by approximately 20-25 percent, improve voiding function in 30 percent of patients, cause a factitious lowering of the serum PSA concentration, and arc expensive. The annual cost to the patient for flutamide therapy is approximately $2,500.

The concept of using 5a-reductasc inhibitors to treat BPH evolved from information gained from two independent studies of a rare autosomal

FIGURE

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recessive genetic metabolic disorder, Sa-reductase deficiency. +.+‘, Walsh and colleagues’+ and Imperato-McGinley and coworkers’l observed that the genetic males with this disorder are born with ambiguous genitalia, but normal male internal ducts and normally differentiated testes. Biochemical investigation demonstrated that there is a deficiency of 5a-reductase in these patients. At puberty, with an increase in testosterone, the voice deepens and the penis enlarges. Evaluation of these postpubertal men shows a very small prostate despite normal libido. Because the postpubertal Sa-reductase-deficient man has a small prostate, it became evident that medical treatment that inhibited the 5a-reductase enzyme might be useful in the management of symptomatic BPH. Finasteride [N-(2-methyl-2-propyl)-3-0x0-4aza-5cr-androst-l-ene-17l3-carboxamide] is a potent, oral 5a-reductase inhibitor that has been studied extensively (Fig. 2). This synthetic 4-azasteroid compound does not interfere with the binding of testosterone or DHT to the androgen receptor, nor does it possess any androgenic, antiandrogenic, or other hormonally related properties.‘h The selective nature of the 5a-reductase inhibitors to decrease DHT without other hormonal effects makes them a potentially ideal medication for the treatment of BPH. In a randomized, double-blind, placebo-controlled clinical trial involving 895 men, Gormley and coworkers’” examined the efficacy of finasteride as a treatment for symptomatic BPH. For the patients receiving finasteride, 5 mg once daily, the total symptom score decreased by 2.5 units compared with a one unit decline for the placebo cohort; this difference of 1.5 units for the two groups was statistically significant (p < 0.05). The mean peak urinary flow rate increased by 1.6 mUsec for the finasteride-treated group and did not change for the placebo cohort (p < 0.01). The 12

mean decrease in prostatic volume for the finasteride-treated men was 19 percent after twelve months of therapy. In general, three to six months of treatment are required to achieve the maximum therapeutic effect. These results have been confirmed in an international clinical trial as well.+’ Overall, the untoward effects were minimal. Approximately 4-5 percent of the finasteride-treated men experience decreased libido, ejaculatory dysfunction, or impotence. Finasteride also causes a 50 percent reduction in the serum PSA level. Based on additional analyses, it appears that the appropriate serum PSA reference range for men receiving Iinasteride is 0.0-2.0 ng/mL rather than 0.0-4.0 ng/mL, when using either the Tandem-R PSA assay or the IMx PSA assay.” Finasteride, while being a potent 5a-reductase inhibitor and causing a marked decrease in the serum and tissue DHT concentration, is only moderately effective as a treatment for symptomatic BPH. For most patients, the clinical improvement is minimal. Perhaps the most attractive feature of finasteride is its excellent toxicity profile; indeed, the untoward effects are minimal. Also, the cost is significantly less than for either an LHRH agonist or an antiandrogen; the annual charge to the patient for hnasteride is approximately $730. However, as finasteride gains increasing clinical use, it will be necessary to determine its true effect on the subsequent development of prostate cancer and the ability of serum PSA to identify these lesions when they develop. AROMATASE

INHIBITORS

Aromatase inhibitors are compounds that selectively inhibit the enzyme aromatase, which converts testosterone to 17P-estradiol 11,3,5( lO>estratrien-3,17P-dial] and androstenedione to estrone [1,3,5(10)-estratrien-3-ol-17-one] (Fig. 3).“” Today, there is much enthusiasm for these compounds, because it is believed that estrogens have a pivotal role in the pathogenesis of BPH.‘” It is well known that prostatic enlargement is a disease of the elderly; the incidence of BPH increases progressively with advancing age so that more than 90 percent of men eighty years of age or older have this condition.s It is also during this time, when the incidence of BPH is increasing, that the rate of testosterone production by the Leydig cells decreases.5’,‘1 Starting with the third decade of life, the serum free (biologically active form) testosterone concentration shows a slow, continuous decline, whereas the free estrone and 178estradiol concentrations remain relativelv

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/i‘ Aromatase inhibitor 1~1~,1’Rf 3 Mechanism by which aromatase converts aromattzable androgens to estrogens. Aromatase inhibitors block the activity of the aromatase enzyme. 17p-HSDH == 17/3hydroxysteroid dehydrogenase. FlGliKF

‘i.‘-i Thus, the ratio of free estrogens to lrcc testosterone becomes elevated during the !‘ears u,hen BPH is most prevalent. Additional support for the role of estrogens in the de\,elopment and maintenance of BPH stems trom the most recent work of Partin and colleagues. ji To determine whether endocrine factors influence the volume of BPH, they measured 23 different hormones in the serum of men with low\,olurne prostate cancer who underwent radical prostatectom): The hormonal concentrations were correlated with the volume of BPH tissue found in the surgical specimen. When BPH volume and hormonal values were corrected for age, BPH volume correlated positively with the serum free tcstostcronc, 1i’P-estradiol, and estriol values. Patients uith large \,olumes of BPH had high free testosterone and estrogen values; this finding suggcsts. as one possibility, that serum estrogens ma> act s)xcrgistically with androgens to promote the growth of BPH. Further evidence for the involvement of estrogens in the development of BPH originates from biochemical investigations demonstrating that estrogen receptors arc present in prostatic tissue.jh,‘; Ekman and coworkers,” in human specimens, characterized two classes of estradiol-binding sites, high affinity and low affinity, in both normal prostate and human RPH tissue. Although these receptors are present in both the nucleus and the c)rtoplasm. the cells containing them were predominantly located in the stroma. Also of signific‘ancc for the association between estrogens and the pathogenesis of BPH is that aromatasc activit) in the periurethral and transition zones of BPH prostates is higher than in the same regions of J>rostatcs without BPH. iH.iC)This observation inplies that the concentration of estrogens in these areas of prostates with benign hyperplasia would in prostate he greater than th c concentration glands containing no BPH.

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To eliminate this estrogen factor, ,1romatase inhibitors have been developed and arc being investigated in clinical trials worldwide.“” In 1987, Schweikert and Turin” trcatcd J 3 patient5 who had complete urinary retention M,ith the aromatase inhibitor, testolactone. In 5cv1.n patients (5-t%), spontaneous micturition occurred after a mean treatment period of eight week>. Six men (46%) continued to require cathelcr drainage because of incomplete bladder ernpty’ng: thr-ee 01 these patients did begin to void spontaneously but remained catheter dependent because of the high postvoid residual urine volume. Prostatic volume decreased in all patients; the mean volume rcduction for the patients who were able to urinate was 26 percent, whereas the mean decrease for the patients who still required cathctcrlzation was 15 percent. This study was the hrst to demonstrate that an aromatase inhibitor could be an effective treatment for symptomatic ESPH. More recently, another aromatasc Inhibitor, atamestane ( I-methyl-l ,4-androsta~lic,nc-3,17dione) has been investigated (Fig. 41.” In an open-label clinical trial involving -14 patients, 44 (87%) completed the three-month trcatmcnt period.“’ Daytime urinary frequency decreased lrom 7.5 f 5.8 (mean + standard deviation) to 6.2 _t 2.3, and nocturia declined from 2.9 2 1 .H to 2.2 + 2.1. The mean peak urinary flow rate increased Irom 7.6 f 3.9 to 9.5 k 5.1 mYsec, whilr the postvoid residual urine volume decreased from 85.‘) + 09.9 to 61.3 + 61 .I) rnL. The decrease in prostatic volume for the entire group wa\ 14 pcrccnt. During the treatment period, no significant adhersc effects were noted. Given these encouraging results, several multicenter, randomized, double-blind, placebo-controlled clinical trials arc now untlcrway to confirm the efficacy and safety of atamestanc. The results of these well-dcfincd studies should be available in 1994. 13

Without question, there is substantial evidence to suggest that estrogens may be influential in the development and maintenance of BPH. Preliminary data indicate that aromatase inhibitors, which inhibit estrogen biosynthesis in the male, can decrease obstructive voiding symptoms, improve urinary flow rate, and reduce prostatic size in men with symptomatic BPH. These medications are oral agents, have no significant known side effects, and hold promise as a medical treatment for BPH. SUMMARY In 1993, medical therapy for BPH is a reality. Androgen deprivation therapy (LHRH agonists, antiandrogens, or Sa-reductase inhibitors) has been shown to be effective by reducing the static component of BPH. Of these agents, the Sa-reductase inhibitors have the greatest promise because of their toxicity profile. Aromatase inwhich function via a different hibitors, mechanism, also have been demonstrated to have efficacy for symptomatic BPH and few associated side effects. Although the early results for these medications are encouraging, several issues relating to longterm medical treatment remain unanswered. All types of medical therapy must be taken indefinitely in order to maintain a therapeutic effect. Thus, the medical approach to the management of BPH could become very expensive for the fiftysix-year-old man with an additional life expectancy of twenty-five years. Patient compliance and durability of the effect from the medication are two other issues for which no data exist at the present time. After several years of medical therapy, will the patient still require a surgical procedure? It is only with extended follow-up of a large number of patients in properly designed clinical trials that meaningful answers will be obtained. Joseph

E. &sterling, M.D. Dcpurtment (~j’Urology Mayo Clinic 200 First Street, SW Rothcstct; Minnesota 55905

REFERENCES 1. Walsh PC: Human benign prostatic hypcrplasia: etiological considerations. Prog Clin Biol Res 145: l-25, 1984. 2. @sterling JE: Bemgn prostatic hyperplasia: its natural history, epidemiologic characteristics, and surgical treatment. Arch Fam Med 1: 257-266. 1992. 3. Barry MJ: Epidemiology and natural history of benign prostatic hyperplasla. Urol Clin North ,4m 17: 495-507, 1990. 4. Clarke R: The prostate and the endocrines: a control SE-

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ries. Br J Ural 9: 254-271, 1937. 5. Craigcn AA. Hickling JB, Saunders CR. and Carpenter RG: Natural history of prostate obstruction: A prospective survey. J R Coil Gen Pratt 18: 226-232, 1969. 6. Birkhoff JD. Wlederhorn AR, Hamilton ML, and Zinsstr HH: Natural history of benign prostatic hypcrtrophy and acute urinary retention. Urology 7: 48-52, 1976. 7. Ball AJ> Feneley RC, and Abrams PH: The natural history of untreated “prostatism ‘~BrJ Ural 53: 613-616, 1981. 8. Barnes RW. and Marsh C: Progression of obstruction and symptoms, In Hinman F Jr, and Boyarsky S (Eds): Benign Prostatic Hypertrt&y, New York, Sprmger-Verlag, 1983, pp 711-713. 9. Graves EJ: Detailed diagnoses and procedures, Natlonal Hospital Discharge Survey, lY8T. Vital Health Stat [ 131 100: 295. 1989. 10. Graverson PH. Gasser TC. Wasson JH. Hinman F Jr. and Bruskewltz RC: Controversies about indications for transurethral resectlon of the prostate. J crol 141: 475-481, 1989. 1 I. Lepor H, and Rigaud C: The efficacy of transurethral resection of the prostate in men wtth modcratc symptoms of prostatism. J Ural 143: 533-537, 1990. 12. Mebust WK, Holtgrewr HL, Cockctt (AT. Peters PC, and Writing CommIttee: Transurethral prostatcctomy: immediate and postoperative complications. A cooperattve stud) of 13 participating institutions evaluating 3,885 patients 1 Urol 141: 243-247, 1989. 13. Holtgrewc HL, Mebust WK. Dowd JO, Cockett AT. Peters PC, and Proctor C: Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Ural 141: 248-253, lY8Y. 14. Fowler FJ Jr, W’ennberg JE, Timothy RP, Barry MJ, Mulley AG Jr, and Hanley D: Symptom status and quality of life following prostatectom): JAMA 259: 3018-3022, 1088. 15. Wennberg JE, Roos N, Sola L, Schori A, and Jaffe R: Use of claims data systems to evaluate health care outcomes: mortality and reoperation following prostatectomy. JAMA 257: 933-936, 1987. 16. Roos NP, Wennbcrg JE, Malenka DJ, Fisher ES. McPherson K, Andersen TF, Cohen MM. and Ramsey E: Mortality and reoperation after open and transurcthral resection of the prostate for benign prostatic hyperplasia. N Engl J Med 320: 1120-I 124, 1989. 17. Malenka DJ. Roos N. Fisher ES. McLerran D, Whale) FS, Barry MJ, Bruskewitz R, and Wennberg JE: Further stud) of the increased mortality following transurethral prostatectomy: a chart-based analysis. J Urol 144: 224-227, IYYO. 18. Peters CA, and Walsh PC: The effect of nafarelin acetate, a lutetnizing hormone-releasing hormone agonist, on benign prostatic hyperplasia. N Engl J Med 317: 599-604, 1987. 19. Caine M, Perlberg S, and Gordon R: The treatment of benign prostatic hypertrophy with flutamide (SCH 13521): a placebo-controlled study. J Ural 114: X4-568, 1975. 20. Gormley GJ, Stoner E, Bruskewitz RC, ImperatoMcGinley J, Walsh PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS, Et ul: The effect of finasteridc in men with benign prostatic hyperplasia. N Engl J Med 327: 1185-1191, 1992. 21. Caine M, Pfau A. and Perlbcrg S: The USC of alphaadrenergic blockers in benign prostatic obstruction. Br ] Urol 48: 255-263, 1976. 22. Schweikert HU, and Tunn UW: Effects of the aromatase inhibItor. testalactone on human benign prostatic hyperplasla. Steroids 50: 19 t-200, 1987.

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23. 0rand1 .A I IO: LlY-13I.1473 24

1 cpor

~zcd.

rransurerhral

inctsion

H, SF,pherd

D. Mach]

srudy

comparing

douhlc-blind

IOOII dilaltotl of the prosta” and 01 syptomartc benign pros’atic h3Y-h-f-‘, 1902 25. Vmin 2h

of thr

pt-oqate

(,, and Dcrus J: Random the eftccti\ cncss of balcystoscop~ for hyperplasia.

44

prostate-or 5: 120-l

from h!~pcrthcrmia 35, 1YY 1.

01 hcntgn tratlwectal 14Y: LIT>\.

2Y.

prostattc high-intcnsit\ 19Y3.

\+ hilt

JM’:

ttopliy

01 llir

30

llrlggtns

prosrate (., and II. The

wcrc,tiotl:

The

hypcrplasta focuwd

twult

b) thermal ultrasound

of double

3 I. prostate 32 bcntgn 705-T

A-1 jurg

(.abor

inn

Phc 24:

questton 26%3OY~

Huggtrts C , and hypcrlroph) I t. 1Y-t0

Stwt’ns of the

of casiratton 1896. Rr\: The proscacc

34.

t irll>loq\. 11 I

( onn

hormone IWI. 35 Blum

PM.

and

.tnd

tt\

III~

11. and

36

schrocdct-

I7 mcnt

ccl..

7th

Crow

Ic!. LVF

analogues. Ccjnn

h)perplasia bwerelin: Ii. Chctl prostattc

natl[ltrc)ptn-releasing c’ncc J Ltrol 145:

on 43:

of the testes and Db’ c Fds). TL’x-I-

Phlladelphta, Jr:

PM:

\I’R

\aundcr<.

J Med

324:

93-l

03.

C;onad~)troptn-rcle;llng

hormone release, a ItganclNat1 Acad Sc.1 I!S.A 79: M. Bosch

[t-cared a report on

RJ, and

Kurth

by castration 6 case\. Eur.

J. I-cwysohn hypcrtrophy

hormone 309-312. 19YI.

hor-

KW

or Ilrol

the 12:

0, and Bral %: Treathy a long-acting go-

analoguc

one-!‘car

expert-

hcnigti

prn\ialtc

hypcrplasia.

3‘) Mc( ~,nnsll 10. Androgcn treatment 01 hcntgn prostatic \I11 17: hhl-h’il.). IYYO 40 Sufrtn cr. ,Ind <.ofley 1tot1 oi ‘1 IIC'M nonstcrotdal 42+43-t.

41 t.imldc.

42.

J Urol

ablation hyperplasia.

DS: Flutamide. anttandrogcrt.

141:

and

987-992.

blockade Llrol Cltn

Mechantwl Invest

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l’rol

of ac13:

IL)76

T\cri

R.

Irattons frotn North

Pharmacolog)~

and

pharmacoktnctic

llrolog) iSupp1 4) 34: 19-21. 1989 ‘itonc NN. Flutatnidr in treatment of benign

5
hvpcrtroph) I:rolog\, (suppl 4) 30: 6-t-68. 1989. ~3. Stone 1N. and Clejan SJ: Response of prostate VUume. l”“‘t;tt’~ip”‘.ific antigen, and tcstoStertme to flutatnide

h\pcrpl;i.t‘t

JD, Hart-od

12:

MI.

(~ctld\rctn

JL. Mac-

Famtlial tnc-,~rnplcte tnalc 2. Dccrvdscd dthydrotcsto~pcrttic.cw~rr~tal trypospalY7-t.

Gt.tcrr-crtj 5cr-reduc.taw

I

T, (ierrnan tn man

O.IUIICI-

deftc.tcnc!

pserttlohcrrn;t(lht-(~(ltttsm

Sctcntc

(MK-906) in the trcatttlcnt 01 hentgn rhc Ftnastcridv \tud\ i;rcqi~ f’rwtatc

H;I.

Hej.5~

rhe effect

in mc‘n

40.

\ Androl

cltntcal dr\,cloptncrIt VI ,I ia-rt,ductase J Srcrotd Btocht~tn MI)I t;iol

*ilh

JF, C~ormlc\ of finastcrtclc

benign

the North American Am 20: 627-636, Henderwn

(,J. \tc)ncr on 40 un~ PV.

prosiaitc

Phaw 1993

D. Hahcnicht

pt-
c.lint(.dl

trtal

UF{ Ntshttto

rc\ult\ Ltol

\. .tncl

antI

I’oncct~-

h) pt~r-plasia

III

37:

(Iltn

El L:trch)

MT: Esrrogens and hentgn prostattc h) pet pla\ia the b,ist\ aromalax inhthitor therapy. Stercltds 50: 219 -2 i 3. 1YSi. 50. Scha.eikcrt HII. Turin L’M: tlabcntcht L -1: Arnold Scnge T. Schulze Horntger LV. and on human benign

\ec,rerion clocrtnol

and Mclah

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53. mones

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H. Schroder FH. Blom JH Fnncrnoser 0. Bartsch G, Effects of c
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in

R. Dhonr M. c.t‘ll functton

and tn

\‘crdonc

m,itc. 1972.

Deslypcre

lc\to\tvronc

\c~rrnculcn old ,tg:c PI)

1 Ctn

Vcrmeulcri

A

Fn-

A I urthct stud/ ( itn l~nticicrtnol

Kt.ptocluc ttvl’ 111 ‘WA sl<,rotds

an d I.eydtg cclt r-cyp(‘nsc J Clin Enclocrtnc~l 11t~tah

JP. and

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h L

wnw‘ctlct

I97+. SM. and lsitouras mtn. I. Measurement

hormone. gotiadolroptn.

I c\,c!tg

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in

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3X Lt’chcr IP Ocsrcrllng Jt, Peters (‘A. Partm :\\i’, Ghan IIL1: and \Z’al~h P<: The tnflucncc of revcrsthlr Jndrogen ilcpt-tvatioti on wrum prrwatc-specific antigen Icvels in men \vith I YW

48. itucss Oestcrling JE:

i2 Ruhens IL>\ on Leydtg

Gonadotroptn-rrleas-

N Engl

Fl-1, Uesterhof

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Disorders JD, Foster

mono \ttmulation ot lurcinizing rr~ccptor--c,ffcc Ior tiic)clel. Proc 7307-731 I, IWL Benign prostatic, ILHRfi analoguc 31%321.198h

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Mol

33. Grtlfin Jl:. and Wilson ID: malt rqx~tdu~tt\~v IKICL tn Wtlson hor)l: ttj tttdtrc 1985. pp ?iY-

1

tn hyprr-

ptwtatc

I’(:,

47. Finasrertdc tatlc hypcrpla\ia 2Y I -2w 194 3.

Treat-

1895. srudic\ 01 prosand of csrrogen tn-

Icc( ton (It1 the‘ normal and on the hyperpla\tic of dogs. J F%p Mcd 72: 71-7-761) 1940.

Walsh

46. Qorter F! The tnhibilor. ftnastertde. 375-378. lYY(1.

ahlatton (HlFlJ).

caslraiton

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10

C:

prostatic

IWI

45. Imprrato-Mc(;inlc~.). JIL and Peterwn RF: Steroid

rptrhcliaL hypcrplasta:

prelirntn,lr\ trc~ul~s. J Androl 12: 423-428, 1991, 18 ‘Llxhcrg:er M. Madersbacher S. and Kratz~k

benign

wl~tl

LIonaid PC-‘. and Wilson ID. pseudoherrnaphrodi[istn, type leronc formation in pseudovagtnal dias. N F:ngl ] Mcd 291: 94-VYtY,

the Ireatmcnt 1 Llrol 147:

2T ~~cstvrltng JE: .A pcrmanen(, self-expandtrtg izing slcnt lot- chc trealmcnt of hentgn pros[actc

tattc

In tllc’tl 376-380.

Dixon CM and Lcpor H: Laser ahlatton 01 the prostate. L rol 10: 273-277, 1YY2. I)cvonec M. Bcrgcr N. and Perrtn P: rransurcthral m-

cn)\\a\ c heattng of the thcrmotlicral,\: J Fndourol

mcnt with I’rol

J L;rol

f?K,

Schulze

KH,

and

Junghlut

P\1’

Estt-ogcti

and andragen receptor tn human pt-wtatc .tn,l prwtattc tumor tissue. Acra Endocrinol (SuppI) 193: i2. 1075 57 Ehman TV Barrack ER, Grctnc (;I-. ]enst~n EL and Walsh PC. Estrogen receptor5 m human prcl\tatlcvidcnce for multiple binding 166-176. I983

\ite\

] Cltn

L!ndocrttlc~l

Mctahl

57:

58. Stow NN. Fair WR. and Ft,,hman ] F ~~ro~cn forma[ton tn human prostactc tissue front pattcnt5 wtth and jvtthout bcntgn hyprrplasta. Prostate 9: 3 1 I- 3 18, I W6 59. Pcrel E. and Ktlltngcr DW The tnctaholt\m 01 androstcnedlone and testwteronc to C. 1Y mrtalx)lt te\ tn normal breast. breast carctnoma and hentgn prostattc. I-I\ pertr<~phy ttscuc. J Steroid Bttrchetn 19: 1135-l 139. 10113. 60 Hahentcht L-‘-F Turin UW. \engc 1 5~ ht-oder FH. Schwetkerr ot hcntgn aromatasc

HII. Bartsch G. and El Elrchv Lff~ Management prostattc hyperplasta u’tth parttcular cntphasis on tnhthitors. J .Sterotd Btochcm Mel Viol 44:

557-563. lYY3. 61. Schweikert HU, and Tunn UW: Effects of the aromatase inhibttor testolactone on human benign prostatic hyperplasia. Steroids 50: 19 l-200, 1987. 62. El Etreby MF: Atamestane: an aromatase inhtbttor for the treatment of benign prostatic hyperplasia: a short review J Steroid Biochem Mel Bio144: 565-572, 1993. 63. El Etreby MF, Habenicht UF, Henderson D, et al:

16

SUPPLEMENT

Atamestune: A New Aromutasc Inhibitor Berlin, Dicsbach Verlag, 1991, pp 49-51. 64. Oesterling JE: LHRH agonists: a nonsurgical trcatment for benign prostatic hyperplasia. J Androl 12: 381-388. 1991. 65. Monda JM, and Oesterling JE: Medical and minimally invasive treatments for benign prostatic hypcrplasia. Curr Prob Urol2: 99-142, 1992.

TO UROLOGY

/ FFHRI;,U).

1994 / i’o~ ~‘hjr 4.3. h’rmrH

2