Prospective double-blind randomized controlled trial of terazosin, finasteride and allylestrenol in the management of benign prostatic hyperplasia

Madhu S Agrawal; Monish Aron

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ORIGINAL ARTICLE

Year : 2001 \| Volume : 17 \| Issue : 2 \| Page : 132-140

Prospective double-blind randomized controlled trial of terazosin, finasteride and allylestrenol in the management of benign prostatic hyperplasia

Madhu S Agrawal, Monish Aron
Departments of Urology, S. N. Medical College, Agra, and All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Madhu S Agrawal
4/18-C, Bagh Farzana, Civil Lines, Agra- 282002
India

Source of Support: None, Conflict of Interest: None

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Abstract

Medical management is rapidly becoming a very important part of the armamentarium of the urologist involved in the treatment of benign prostatic hyperplasia. The commonest options for medical management include alpha-blockers, 5-alpha reductase inhibitors, and progestational anti-androgens. We present a double-blind randomized controlled trial evaluating the safety and efficacy of terazosin, finasteride and allylestrenol, the prototype drugs in each of these respective categories. A total of 140 patients who satisfied the inclusion and exclusion criteria were inducted into the trial after an informed consent. They were randomized into 4 groups, which received placebo, terazosin, finasteride and allylestrenol respectively for 6 months. Since 29 patients did not complete 6 months of therapy, there were 111 evaluable patients at the end of the study. We found that these 3 drugs produce comparable improvement in symptom score (-40%), flow rates (-60%) and PVR (-50%) which is significantly better than that in the placebo group. Both allylestrenol and finasteride bring about a comparable reduction in prostate volume (-23%), which is statistically significant as compared to the placebo and terazosin groups. Terazosin in doses of I and 2 mg/ day was, found to be effiective and well-tolerated in the vast majority of our cases. No adverse effects were seen in the placebo and finasteride groups, while 9.6% in the terazosin group had postural hypotension and 10.7% in the allylestrenol group had some loss of libido, problems which were reversible upon cessation of therapy.

Keywords: Medical Management; Benign Prostatic Hyperplasia; Terazosin; Allylestrenol; Finasteride.

How to cite this article:
Agrawal MS, Aron M. Prospective double-blind randomized controlled trial of terazosin, finasteride and allylestrenol in the management of benign prostatic hyperplasia. Indian J Urol 2001;17:132-40

How to cite this URL:
Agrawal MS, Aron M. Prospective double-blind randomized controlled trial of terazosin, finasteride and allylestrenol in the management of benign prostatic hyperplasia. Indian J Urol [serial online] 2001 [cited 2023 Jan 28];17:132-40. Available from: https://www.indianjurol.com/text.asp?2001/17/2/132/21043

Introduction

Benign prostatic hyperplasia (BPH) is found in about 50% of the male population in their fifth decade and shows a tendency to increase to 80% in men over 80 years of age.^[1] Based upon data from the normative aging study, the cumulative incidence of BPH, judged by physical findings or symptoms for a 40-year old man surviving to age 80, is 78% and that of a prostatectomy is 29%.^[2] Transurethral resection of the prostate (TURP) is the gold standard in the management of these cases but its complications, hospital stay, anesthesia and cost necessitate a constant search for an alternative treatment. A recent survey of the U.S. Medicare database revealed that the absolute number of prostatectomies decreased over 30% despite the progressively increasing number of males enrolled in the Medicare program.^[3] This decrease in the number of prostatectomies coincides with the evolution and acceptance of medical therapy. In patients in whom there is no absolute indication for prostatectomy or those who are unfit or waiting for surgery, several drugs have been tried, the most common of which are terazosin (an alpha blocker), finasteride (a 5-alpha reductase inhibitor), and allylestrenol (a progestational agent). Although several studies on terazosin and finasteride are available from Europe and the United States, the literature on allylestrenol appears principally from Japan. However, very little data is available from Indian subcontinent on the comparative safety and efficacy of these drugs. We present the results of a prospective double-blind randomized trial conducted to determine the efficacy and safety of the 3 most commonly used agents in the medical management of BPH.

Patients and Methods

Between January and December 1997, a total of 140 patients were enrolled into the study after an informed consent. The inclusion criteria were:

a) age 45-80 years

b) symptoms of prostatism (Boyarsky symptom score >8)

c) maximum flow rate (MFR) <15 ml/s

d) prostatic enlargement

The exclusion criteria were:

a) prostate cancer

b) complicated BPH (acute or chronic retention, recurrent urinary infection, hematuria, upper tract changes and bladder calculi)

c) patients with other causes for poor flow (stricture urethra, neurogenic bladder)

d) significant co-morbid illnesses

e) history of intake of drugs that affect voiding

f) prior surgery on the prostate or bladder neck

These patients were randomized, in a prospective manner, into 4 groups, of 35 patients each using computer generated random numbers. Patients in group I received a placebo tablet once daily, group 11 received terazosin 1-10 mg daily, group Ill received finasteride 5 mg daily and group IV received allylestrenol 25 mg twice daily. All patients underwent a baseline evaluation prior to starting the drug, which included a detailed history and examination, including blood pressure measurement and digital rectal examination (DRE), electrocardiogram, hemogram, blood chemistry, urinalysis, urine culture and serum PSA. The parameters for comparison between each drug were recorded at this evaluation and at subsequent visits. These were:

1. Symptom score (Boyarsky et al)^[4]

2. Prostate volume (as determined by transrectal ultrasound) in ml

3. Maximum flow rate (MFR) in mi/s

4. Post-void residual urine (PVR) in ml (as determined by abdominal ultrasound)

The dosage remained constant in all groups except group II where terazosin was used in a dose escalation schedule, beginning with 1 mg daily at bedtime and increasing to 2mg, 5 mg, and 10 mg at weekly intervals, up to the maximum tolerated dose. Only 7 patients in this study went up to or beyond 5 mg/day, with only 2 patients receiving 10 mg/day on a regular basis. All patients were called for follow-up, fortnightly for the first 2 months and then monthly for another 4 months. The same parameters were recorded again at the visit at 1 month, 3 months and 6 months. Any adverse effects including the effects on blood pressure and libido were noted. In order to eliminate observer bias, the study was conducted in completely double-blind fashion so that the person recording the parameters was not aware of the drug the patient was taking. The data in terms of the observed parameters was statistically analyzed using the student's t-test. A p value <0.05 was considered significant.

Results

29 patients did not complete 6 months of medical therapy and hence we had Ill evaluable patients, on whom the final analyses were made. Of the 29 patients who did not complete 6 months, 14 failed to present themselves for regular follow-ups, 9 patients in group I, and 2 patients each in group III and IV underwent TURP, while 2 patients in group II dropped out because of adverse effects. Thus there were 25 evaluable patients in group I, 31 in group II, 27 in group III, and 28 in group IV.

The 4 groups were comparable in terms of the observed parameters since there was no significant difference among them at initial evaluation, confirmation that adequate randomization had been achieved. Subsequently, the patients in groups II (terazosin), III (finasteride), and IV (allylestrenol) showed significant improvement in symptom score, PVR, and MFR, while a reduction in prostate size was noted only in groups Ill (finasteride) and IV (allylestrenol) [Table - 1],[Figure - 1],[Figure - 2],[Figure - 3],[Figure - 4]. As many as 90% of evaluable patients in groups II, III, and IV showed improvement in symptom score, PVR, and MFR by 1 month. However, the earliest response was noticed in group II (terazosin), where 76% patients showed improvement by 2 weeks. At 6 months the mean improvement in these parameters in these 3 groups was comparable, and significantly better than the controls (group I). Similarly the mean reduction in prostate volume by 6 months, seen in approximately 90% of evaluable patients in groups III (finasteride) and IV (allylestrenol), was also comparable (22% and 23.5% respectively) and significantly better than that in groups I (control) and II (terazosin).

No adverse effects were noted in groups I (control) and III (finasteride). Three patients (9.6%) in group H (terazosin) developed persistent postural hypotension. These were the only 7 patients in whom terazosin was used in doses of 5 mg or more. Once the dose was scaled down the postural hypotension resolved. Thus 24 of 31 patients in group II settled on 21mg/day of terazosin and only 2 patients received 10 mg/day. If the 2 patients from group II, who dropped out of the study because of hypotension and related side effects are included, the incidence of adverse effects in this group is 14.2%. 3 patients (10.7%) in group IV (allylestrenol) developed loss of libido and 1 developed fluid retention and pedal edema. However, these adverse events reversed in all 4 patients within 8 weeks of cessation of therapy.

Discussion

The prostate is a glandular organ with a fibro-muscular stroma. BPH comprises hypertrophy and hyperplasia of prostatic stromal and glandular components. Bartsch et al reported that the stromal-to-epithelial ratio in a normal prostate was 2:1 compared to 5:1 in BPH.^[5] Prostatic smooth muscle accounts for 51% of the total stromal volume in BPH.^[6] The prostatic smooth muscle contains alpha, adrenoceptors that mediate its contraction. The mechanism of bladder outlet obstruction in men with BPH has been attributed to static and dynamic factors,^[7] the dynamic component being due to the tone of the prostatic smooth muscle and the static component due to the anatomic enlargement encroaching upon the bladder outlet. This concept forms the basis for the two main arms of pharmacotherapy for BPH, namely, alpha, receptor blockade to control the dynamic component, and hormonal manipulafion for the static component.

The pathogenesis of BPH has been reviewed in detail by Walsh^[8] and Wilson.^[9] Development of the disease clearly requires a combination of testicular androgens and aging. Since the recognition that BPH is an androgen dependent process, numerous treatment strategies to inhibit androgen production or action in the prostate have been devised and tested. Indeed, both approaches, namely, alpha-blockade and androgen deprivation, appear to have value in the management of these patients. However, in evaluation of these agents, it must be recognized that a strong placebo effect is associated with the management of BPH, and that for any trial to be meaningful, it needs to be properly controlled.

The proposed mechanism for the efficacy of alpha₁ blockade in BPH is via relaxation of prostatic smooth muscle, which lowers outflow resistance without impairing detrusor contractility. Alpha-blockers used in the studies on the medical management of BPH can be sub-grouped according to their receptor selectivity and their elimination half-life.^[10] The most extensively studied agent in this category is terazosin, which is a long-acting selective alpha, blocker.

The primary advantage of the selective alpha₁ blockers is that the incidence and severity of side effects is considerably less than the nonselective alpha-blockers. The advantages of selective long-acting (once-a-day) alpha-blockers are related to compliance and tolerance. The most common adverse effects related to alpha, blockers include dizziness, light-headedness, asthenia and postural hypotension. The administration of long-acting, once-a-day formulations at bedtime reduce the incidence and severity of these adverse effects.^[10] Terazosin is the most commonly used alpha, blocker in clinical practice and has been shown to be safe and effective over the long-term.^[11]

Hormonal treatment of BPH can be given using several options,^[12] including inhibiting pituitary LH secretion (GnRH agonists, like busrelin), androgen receptor inhibition (true anti-androgens like flutamide), inhibiting conversion of testosterone to dihydrotestosterone (5α-reductase inhibitors like finasteride), and progestational antiandrogens (e.g. hydroxyprogesterone caproate, allylestrenol, and cyproterone acetate).

Of these multiple options the most successful in clinical practice are the use of 5α -reductase inhibitors and progestogens. 5α -reductase inhibitors act by inhibiting conversion of testosterone to DHT, resulting in decreased levels of serum and prostatic DHT. Finasteride has been shown to reduce mean serum PSA levels by approximately 50%,^[13] even though the effect on each individual patient is highly variable. The implications of the PSA-altering effect of finasteride, on the detection of prostate cancer, are as yet unresolved.^[14] Finasteride has a very agreeable adverse event profile. Impotence and decreased ejaculate volume are the primary treatment-related side effects. However, in a recent multicenter study of 1229 patients with BPH, Lepor et al,^[11] demonstrated no advantage of finasteride over placebo. A subset analysis of this study revealed that modest efficacy was seen only in patients with prostates larger than 50 cm³ .

Interest in progestins for the management of BPH began in 1965 with the report by Geller and associates that hydroxyprogesterone caproate results in prostatic regression.^[15] Progestational agents such as allylestrenol act not only by reducing the pituitary release of gonadotrophins, but also produce an androgen receptor blockade in the prostate. They also partly inhibit the enzyme 5α -reductase responsible for the synthesis of DHT. The biggest drawback with these agents is the loss of sexual function they produce by virtue of the reduction in pituitary gonadotrophin secretion.^[16] The present study was designed to determine the efficacy and adverse effect profile of these three agents in the medical management of BPH. We found that all 3 agents bring about subjective and objective improvement in patients with BPH. These 3 drugs show comparable improvement in symptom score (-40%), flow rates (-60%) and PVR (-50%) which is significantly better than that in controls. It is interesting to note that nearly 15% subjective improvement was observed in the placebo group as well. Both allylestrenol and finasteride bring about a comparable reduction in prostate volume (-23%), although allylestrenol tends to cause a reversible loss of libido in about 10% of patients.

Contrary to reports from western literature, we found that 2 mg/day dose of terazosin is sufficient in the vast majority of our cases. Terazosin is well tolerated in doses up to 2 mg daily, although a 5 mg dose led to postural hypotension in several of our patients, and only 7 patients received doses of 5 mg or above in the present study. The first benefit from terazosin was noted as early as 2 weeks, while that with finasteride and allylestrenol appeared at 4 weeks, somewhat earlier than what has been described in the literature.

Of concern is the fact that as many as 20.7% of patients who were initially enrolled into the study did not complete 6-months' of therapy, and 10% did so because of inability or unwillingness for follow-up. This is an important consideration given the prolonged treatment time and regular follow-up essential for any patient being considered for medical management. Overall, 9.2% of patients developed an indication for TURP during the study. This highlights the need for regular follow-up in these patients, without which they may suffer silent damage to the upper tracts and land up in renal failure.

Conclusions

Terazosin, finasteride and allylestrenol have comparable effects on symptom score, PVR and MFR which are significantly better than placebo. The fastest response is seen with terazosin. Finasteride and allylestrenol produce similar reduction in prostate size and over a similar time frame. Finasteride has the most favorable adverse event profile. The incidence of postural hypotension and related adverse effects with terazosin is dose-dependent and can often be controlled by dose reduction. The adverse effects of allylestrenol are reversible with cessation of therapy, although the -10% incidence of loss of libido may be of concern to sexually active patients.

Although there is little doubt that these drugs are effective treatment options for selected patients with BPH, certain concerns remain. These include the need for prolonged (possibly life-long) therapy, high cost, need for long-term compliance and close follow-up, potential adverse effects and a lack of permanent effect on the primary pathology. Thus the role of medical management for BPH must be continually reassessed in terms of the community at large, keeping in mind the special socio-economic factors in the Indian context. At the present time, with the available drugs, it seems a safe and effective option for the wellinformed and motivated patient, who is willing for close follow-up, and can afford prolonged therapy.

Acknowledgements

We are thankful to M/S Cadila, Cipla, Intas, Infar, and Dr. Reddy's Laboratories for providing us with the various drugs used during this study.

References

1.	Walsh PC. Human benign prostatic hyperplasia: Etiological considerations. In: Kimball AF, Buhl AE, Carter DB (eds.). New approaches to the study of benign prostatic hyperplasia. Liss, New York, 1984: 1.
2.	Glynn RJ, Campion EW. Bouchard GR, Silbert JE. The development of benign prostatic hyperplasia among volunteers in the normative aging study. Am J Epidemiol 1985; 121: 78.
3.	Holtgrewe HL. Economic issues and the management of benign prostatic hyperplasia. Urology 1995; 46 (Suppl 3A): 23-25.
4.	Boyarsky S, Jones G, Paulson DF, Prout GR Jr. A new look at bladder neck obstruction by the Food and Drug administration: Guidelines for investigation of benign prostatic hypertrophy. Trans Am Assoc Genitourin Surg 1977; 68: 29-32.
5.	Bartsch G, Muller HR, Oberholzer M, Rohr HP. Light microscopic stereological analysis of the normal human prostate and of benign prostatic hyperplasia. J Urol 1979; 122: 487-491.
6.	Shapiro E, Hartanto V. Lepor H. Quantifying the smooth muscle content of the prostate using double immuno-enzymatic staining and color assisted image analysis. J Urol 1992: 147: 1167-1170.
7.	Caine M. The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol 1986: 136: 1-4.
8.	Walsh PC. Benign prostatic hyperplasia. In Walsh PC, Gittes RF, Perlmutter AD et al (eds.): Campbell's Urology. 6^th ed., Vol I. Saunders, Philadelphia 1991; 1009.
9.	Wilson JD. The pathogenesis of benign prostatic hyperplasia. Am J Med 1980; 68: 745.
10.	Lepor H. Alpha blockade for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1995; 22: 375.
11.	Lepor H, Williford WO, Barry MJ et al. The efficacy of terazosin, finasteride or both in benign prostatic hyperplasia. N Eng J Med 1996:335:533.
12.	McConnel JD. Benign prostatic hyperplasia: Hormonal treatment. Urol Clin North Am 1995; 22 (2): 387.
13.	Guess HA, Heyse JF. Gor mey GJ. The effect of finasteride on prostate specific antigen in men with benign prostatic hyperplasia. Prostate 1993; 22: 31.
14.	Vaughan ED, Lepor H. Medical management of BPH: Part 1. AUA Update Series 1996: 16: 18.
15.	Geller J, Bora R. Roberts T et al. Treatment of benign prostatic hypertrophy with hydroxyprogesterone caproate. JAMA 1965; 193: 121-128.
16.	Gupta NP, Aron M, Singh KM, Dwivedi RB. Multicenter randomized controlled trial of allylestrenol in the management of benign prostatic hyperplasia. Indian J Urol 1998; 15: 26-29.