W~Id Journal ~

World J Urol (1989) 6:209-214

Ul"olo
© Springer-Verlag1989

Nonsurgical treatment of benign prostatic hypertrophy

P. Ekman
Department of Urology, Karolinska Hospital, Box 60500, S-10401 Stockholm, Sweden

Summary. Drug therapy has never been widely used in be- viewpoint, these drugs have little relevance and their effi-
nign prostatic hypertrophy (BPH), partly because the in- cacy is purely empirical.
troduction of safe and radical surgical techniques provid- Drug therapy derived from scientific observation and
es rapid improvement of symptoms of outflow obstruc- experience can be grouped under three major headings:
tion. However, some patients hesitate to undergo surgical (1) endocrine manipulations; (2) urodynamic manipula-
intervention, and others are in poor condition, making tions; and (3) others, e.g., cholesterol-lowering agents. Of
them less than ideal candidates for surgery. A conserva- these, endocrine manipulations have been particular in-
tive means by which outflow problems could be relieved terest and will therefore constitute the major part of this
should be of benefit for a significant number of patients. report.
Drugs from primitive cultures, usually herbal, have been
reported to be of benefit; however, in double-blind con- Castration
trolled studies none seems to be superior to placebo.
Credit for the discovery of the endocrine dependency of
t~l-Blockers do not influence prostate size but may still
the prostate gland has been given to John Hunter [22],
be of value in patients with dysuria, bladder neck sclero-
who described the atrophy of the seminal vesicles and
sis, and mild prostatic enlargement. Endocrine therapy
prostate in bulls following castration in the late eight-
appears to be effective in reducing prostate size and hence
teenth century. One hundred years later White [59] and
improving urinary outflow. The most promising agents
Cabot [5] independently reported that castration was a
thus far used include progestational antiandrogens and
means by which outflow obstruction could be relieved.
LHRH agonists as an alternative to pure castration. The
However, castration for benign prostatic hypertrophy
drugs must be provided for the patient's lifetime, since
(BPH) never became widely used, partly due to the simul-
the prostate rapidly regains its enlarged size following ter-
taneous introduction of safe surgical procedures. Treat-
mination of the treatment. A combination of progesta-
ment of BPH by medical or surgical castration has re-
tional antiandrogens and antiprolactin seems to be an ef-
cently again drawn particular attention [13, 39, 46].
ficient remedy for symptoms of prostatism when surgery
is not applicable or wanted. Recent research has intro-
Sex hormones
duced new drugs with endocrine effects such as aromatiz-
ing inhibitors and 5 t~-reductase inhibitors; their efficacy In the late 1920s and during the 1930s, when sex hor-
has not as yet been confirmed in randomized clinical tri- mones became available in pure form, several investiga-
als. tors confirmed the sensitivity of the prostate gland to an-
drogen and estrogen administration [20, 31, 34]. Differ-
ent endocrine regimens were tried on prostatic hyperpla-
sia, however, with conflicting results [20 25, 42]. Contrib-
Introduction uting to this confusion were difficulties in recruiting a
fairly nonselected group of patients, since surgery is pre-
Enlargement of the prostate gland, described since early ferred by the vast majority of patients, and in defining
civilization as a torment for the aging male, has become objective means by which to evaluate the effect of the
an important sociopathological problem during the last treatment [4]. Most reports have been neither random-
150 years as a consequence of man's increasing life span. ized, double-blind, nor placebo-controlled. The untoward
In all cultures, primitive as well as civilized, numerous side effects of most endocrine regimens has also been a
drugs have been used that claim a beneficial effect in re- major disadvantage.
lieving outflow obstruction. Even today, new drugs, usu- Modern research has improved our insight into the
ally derived from herbal extracts, are introduced accom- etiology and pathogenesis of BPH. Similar to the normal
panied by promising reports as to their efficacy in reduc- prostate, the hypertrophic gland is dependent on the an-
ing micturition problems [36, 44, 54]. From the scientific drogen supply to maintain its size and epithelial height
210

[39, 48]. In experimental animals, benign enlargement urinary retention could void spontaneously within 2
can be induced by androgens; however, the effect is more months of treatment. At histologic examination follow-
pronounced when these are combined with estrogens ing surgery, it was noted that the epithelial cells were
[56]. In contrast to that of the canine prostate, the human cuboidal and the nuclei had a midzonal position contrast-
BPH is primarily a stromal disease [2, 35], but the stroma ing with the normal BPH pattern. In 1979, Geller et al.
also appears to be under endocrine influence, perhaps in [17] reported the results of a double-blind trial using
particular by estrogens [32, 33]. Aromatization of andro- megestrol acetate (120 mg/day) in 28 patients compared
gens to estrogens described in human prostate stroma has with 30 patients in the placebo group; improvement in
been thought to be of crucial etiological importance [19, micturition was noted in 20/28 and 19/30, respectively.
47]. Urodynamic evaluation revealed an improved flow of
Endocrine treatment of BPH can be based on one or 30070 in the megestrol group, whereas that of the control
several of the following pathways: (a) blocking lutinizing group remained unchanged.
hormone (LH) production and thereby testosterone secre-
tion (LHRH agonists, estrogens); (b) reducing circulating Bromocriptine
androgens (castration, estrogen or progestin administra- Prolactin has been reported to stimulate the uptake of
tion, LHRH agonist administration); (c) preventing tes- testosterone into the prostate cells [27, 30]. In 1976 Farrar
tosterone conversion to 5a-DHT, the active metabolite and Pryor [11] reported on the effect of the antiprolactin
(5¢t-reductase inhibitor); (d) binding to the androgen re- bromocriptine in BPH: nine patients received a daily dose
ceptor in the prostate cells (progestational agents, flutam- of 2.5 mg bromocriptine for 8 weeks in a double-blind,
ide spironolactone); and (e) inhibiting the aromatization crossover study; the patients served as their own controls.
of androgens to estrogens. Six of the patients noted improved urinary stream; four
could be taken off the waiting list for surgery. No reduc-
Progestational agents. Estrogens were soon abandoned as
tion in prostate size could be noted. It was concluded that
an alternative to castration because of their lack of effi-
the improvement was due to a symptomatic reduction in
cacy [20, 25], which should be clear from their dual role
frequency, nocturia, and urgency, indicating a modifica-
in stimulating the development of benign enlargement.
tion of detrusor instability rather than improved urinary
Instead, endocrine manipulations have focused on pro-
outflow. Similar conclusions were drawn by Rolland and
gestational agents, since they may both reduce circulating
co-workers [43], who gave bromocriptine at a daily dose
androgens and bind to the androgen receptor. The sur-
of 15 mg for 10 days and achieved improved micturition
prising discovery of large amounts of progestin receptors
in 75°70 of the patients. Again, the size of the prostate was
in the human prostate [8, 18] has been difficult to under-
not altered.
stand; it has been suggested that the progestin-receptor
complex may inhibit androgen stimulation of the prostate
cells [10].
Other antiandrogens
Geller and co-workers [14] were the first to carry out Theoretically, flutamide appears to possess several advan-
a clinical trial using progestational agents against BPH. tages in drug therapy against BPH. Flutamide is a non-
They used hydroxyprogesterone caproate and registered steroidal antiandrogen, which binds to the androgen re-
an improvement of symptoms in all of ten patients; two ceptor in the prostate and blocks androgen action in the
had their indwelling catheters removed. No control group target organ. The cardiovascular side effects are minimal,
was included. In a later study comprising 20 patients with and the preparation does not substantially decrease
indwelling catheters, half were given hydroxyprogesterone potency or libido [50]. Clinical trials have demonstrated
caproate while awaiting surgery [15]. In the drug-treated an effect on the size of the prostate gland; however, com-
group, the catheter could be removed in 6/10 compared pared to placebo, the effect on other outflow obstruction
with 3/10 in the control group; however, the control criteria (flow rate, residual urine) was not significantly
group was not given placebo. superior [3]. Clinical trials with the drug have been
Simultaneously, Scott and Wade [48] reported on the sporadic, perhaps because of the reported incidence of
use of cyproterone acetate, a progestational antian- hepatic toxicity from the drug [12].
drogen, in a group of patients with BPH. A daily dose of An untoward side effect of the antihypertensive drug
50 mg was given to 13 patients, 11 of whom were judged spironolactone has also been reported: gynecomastia and
to experience subjective improvement. Flow rate was in- loss of libido. It was found that the serum content of
creased in nine patients and residual urine decreased in testosterone was markedly decreased [55] while pro-
eight; reduction in the size of the gland as estimated by gesterone increased [51]. The effect is probably due to
rectal examination was noted in seven patients. Punch competitive binding to the androgen receptor. The drug
needle biopsies from 11 patients disclosed a marked re- has been tried against BPH [7] but never tested on a
duction in epithelial height as compared with the large-scale basis, probably due to the untoward side ef-
pretreatment pattern. No control group was included. fects.
In 1975 Geller and co-workers [16] reported on the ef- A less conventional way of reducing androgen activity
fect of cyproterone acetate given at a daily dose of 250 mg was tried by Wei and Zhou [57], who used 5-fluorouracil
to five patients prior to surgery. Three of four patients in (5-FU) at 250 mg/day for 1 week in 43 Chinese men with
 211

B P H a n d u r i n a r y retention. I n all, 70070 o f t h e p a t i e n t s Table 1. Results of drug therapy in BPH, subjective and objective
were relieved o f their catheters, with n o relapses w i t h i n 6 improvement
m o n t h s . T h e d r u g was c o n s i d e r e d to b e effective p r i m a r i -
Placebo Candicidin Endocrine therapy
ly in t h e p r o s t a t i c epithelium; t h e s t r o m a l c o m p a r t m e n t s
were o n l y little influenced. T h e exact m e c h a n i s m b y Improved urinary flow 2/8 0/12 18/20
w h i c h 5 - F U exerted its effect was n o t k n o w n . Decreased residual urine 1/8 1/12 13/20
Decreased volume (PR) 2/8 2/12 15/20
Subjective improvement 3/8 4/12 13/20
Adrenergic antagonists Judged as improved 2/8 2/12 15/20
C a i n e et al. [6] were t h e first to d e m o n s t r a t e t h a t t h e a d -
m i n i s t r a t i o n o f a - b l o c k i n g agents c o u l d relieve o b s t r u c -
Before the onset of therapy and at 3 and 6 months follow-up,
tive uropathy. H e d l u n d a n d colleagues [21] later showed uroflowmetry was carried out, residual urine was measured, and the size
t h a t this was p r i m a r i l y d u e to a n a l - r e c e p t o r of the gland was evaluated by computerized axial tomography (CAT)
o v e r s t i m u l a t i o n . By using specific a l - b l o c k e r s , a n effi- [38], whereby the radiologist was unaware of which drug the patient had
cient relief o f o u t f l o w o b s t r u c t i o n p r o b l e m s c o u l d o f t e n been given.
b e o b t a i n e d with l i m i t e d risk o f h y p o t e n s i o n a n d o t h e r
side effects c o m m o n l y seen with o t h e r a - b l o c k e r s [23, 26,
29, 41]. a-Blockers have b e e n r e p o r t e d to b e effective in Results
relieving o u t f l o w p r o b l e m s d u e to b l a d d e r neck sclerosis
a n d m i l d p r o s t a t i c h y p e r t r o p h y as a n alternative to b l a d - I n this s t u d y c a n d i c i d i n a p p e a r e d to have n o a d v a n t a g e
d e r n e c k incision [41]. N o r e d u c t i o n o f the e n l a r g e d g l a n d over placebo. A p p r o x i m a t e l y 20070 o f the p a t i e n t s in b o t h
was observed; therefore, t h e value o f a - b l o c k e r s seems g r o u p s i m p r o v e d (17070 a n d 25070, respectively) as m e a -
l i m i t e d in p a t i e n t s with m a r k e d p r o s t a t i c h y p e r t r o p h y sured b y objective m e a n s (Table 1). I n contrast, 75070 o f
[29]. t h e p a t i e n t s t r e a t e d b y e n d o c r i n e m a n i p u l a t i o n s were
c o n s i d e r e d to be o b j e c t i v e l y i m p r o v e d . Five o f seven p a -
tients i m p r o v e d w h e n s w i t c h e d f r o m c a n d i c i d i n / p l a c e b o
Cholesterol-lowering agents to e n d o c r i n e t h e r a p y ; n o n e o f t h e six p a t i e n t s s w i t c h e d
A s a side effect o f t o x i c o l o g i c studies in dogs, a p e r o r a l from placebo to candicidin improved. The mean improve-
p r e p a r a t i o n o f t h e p o l y e n e m a c r o l i d e c a n d i c i d i n achieved m e n t in u r i n a r y flow was 60070 in t h e e n d o c r i n e - t r e a t e d
a r e d u c t i o n in the size o f t h e p r o s t a t e [45]. C a n d i c i d i n is g r o u p as c o m p a r e d with 0070 a n d 5070, respectively, in the
n o t a b s o r b e d in t h e intestinal t r a c t b u t exerts a n a b i l i t y c a n d i c i d i n a n d p l a c e b o - t r e a t e d groups. R e s i d u a l u r i n e de-
t o b i n d cholesterol, t h e r e b y r e d u c i n g t h e s e r u m a n d tissue creased b y 35°70 in t h e g r o u p o f p a t i e n t s t r e a t e d w i t h h o r -
levels o f cholesterol. Since cholesterol is s y n t h e s i z e d in m o n e s b u t r e m a i n e d u n c h a n g e d in t h e o t h e r two g r o u p s
excessive a m o u n t s in t h e h y p e r p l a s t i c prostate, this indi- [9].
rect d e p l e t i o n o f cholesterol was t h o u g h t to e x p l a i n the P r o s t a t e size as e s t i m a t e d by C A T scan d e c r e a s e d in
s h r i n k a g e o f t h e p r o s t a t e gland. P r e l i m i n a r y clinical trials 12 o f 17 fully evaluated p a t i e n t s in t h e h o r m o n e - t r e a t e d
i n d i c a t e d t h a t this d r u g was also effective in t h e t r e a t m e n t g r o u p as c o m p a r e d with 6 o f 9 given c a n d i c i d i n a n d 2 o f
o f B P H in m a n [1, 28]. 5 fully evaluated p l a c e b o p a t i e n t s (Table 2). T h e reduc-
We r e p o r t o u r experiences u s i n g a c o m b i n a t i o n o f t i o n in size was m u c h m o r e m a r k e d in t h e g r o u p s u b j e c t e d
c y p r o t e r o n e acetate a n d b r o m o c r i p t i n e vs. c a n d i c i d i n , vs. t o h o r m o n a l m a n i p u l a t i o n s (mean, 23070, 32070 w h e n t h e
p l a c e b o in a r a n d o m i z e d s t u d y in m e n suffering f r o m p a t i e n t s n o t r e s p o n d i n g to t r e a t m e n t are excluded, c o m -
B P H [9]. p a r e d with 4070 a n d 2070 in t h e c a n d i c i d i n a n d p l a c e b o
groups, respectively [9].
Side effects were m o r e p r o n o u n c e d a f t e r e n d o c r i n e
Materials and m e t h o d s therapy, p a r t i c u l a r l y vertigo, fatigue, shivering, a n d cardi-
Thirty patients aged 54-88 years (mean, 70 years) were enrolled in a ac d y s f u n c t i o n . Surprisingly, a loss o f p o t e n c y was n o t e d
randomized protocol and given either 50 mg/day cyproterone acetate in in o n l y 25070 o f the patients. T h e t r e a t m e n t h a d to b e
combination with bromocriptine, 1.25 mg twice daily, or candicidin, s t o p p e d in two p a t i e n t s d u e to E C G changes in o n e a n d
100 mg thrice daily, or placebo. The candicidin/placebo arms were run loss o f p o t e n c y in t h e other. T h e side effects o f c a n d i c i d i n
double-blind, whereas the endocrine arm was an open trial. The effect
was finally evaluated after 6 months. Patients in the placebo arm were
switched to active drug; those not responding to candicidin were
switched to the endocrine arm. A total of 20 patients were given endo- Table 2. Results of volume measurements of the prostate gland by
crine therapy (of whom 7 had first been given candicidin and/or place- CAT-scan before and after 6 months of therapy
bo); 12 were given candicidin (of whom 6 were first given placebo); and
the placebo group comprised 8 patients A lag period of 1-2 months Placebo Candicidin Endocrine therapy
preceded the start of therapy to allow the temporary worsening of symp-
toms to subside The patients were checked before the lag period, before Decreased size of gland 2/5 6/9 12/17
the onset of therapy, after 3 weeks as well as 2, 4, and 6 months of treat- Mean reduction in size 2°7o 407o 23070
ment, and then at 3 and 6 months following the termination of treat- Mean corrected a - 6070 32070
ment. At each control, routine blood samples were drawn for hormone
analyses, rectal palpation was carried out, and an ECG was registered. a Excluding patients with no improvement
212
were similar to those o f placebo: fatigue, vertigo, and against thromoboembolic complications following estro-
nausea [9]. gen therapy [51].

Case report. One patient (E. L.) aged 81 commenced the

Discussion trial with an indwelling catheter and a prostatic enlarge-
ment of grade 3 - 4 (on a 4-graded scale). He was first en-
A review of the current literature on drug therapy against tered into the placebo arm, then switched to candicidin
B P H clearly emphasizes the importance o f including with no effect on the symptoms. After 3 months of endo-
double-blind, randomized control groups before any con- crine therapy, his prostate volume was reduced by 20°/o
clusions regarding the efficacy o f a drug can be drawn. and his catheter could be removed. At the termination of
The response rate in the placebo groups varies between the 6-month endocrine treatment, he wished to continue
20°7o and 50o70, depending on evaluation criteria [9, 40, taking the drugs. After 4 years o f continuous treatment,
41]. It is not u n c o m m o n that "all" patients, included in his prostate was down to normal size or, rather, atrophic.
a trial on outflow problems, in poor risk groups experi- He died at the age of 86 of an intercurrent disease.
ence a feeling o f well-being, possibly as a psychological Unfortunately, the present study did not answer the
phenomenon due to the attention drawn to their prob- question as to whether or not combination treatment is
lems [41]. Our experience and that of others has been necessary to obtain the results reported above, or whether
that patients often report an improvement, perhaps so as cyproterone acetate alone could be expected to provide
not to disappoint the doctor and risk exclusion from the the same result. Therefore, a four-armed double-blind,
trial. In reviewing the charts, one can often find that the placebo-controlled study was started. The study has not
conditions are actually unchanged. been terminated since the recruitment of patients has
Even uroflowmetry and the measurement of residual been extremely difficult. Informed about the risks of re-
urine may be subject to irrelevant variations. The old pa- ceiving placebo only, the patients almost exclusively pre-
tient may be confused by the test situation; later he is ferred to take both pills in an open trial and risking tak-
more "at home" and can produce a far better test result. ing one pill that might have little effect on their problems.
Therefore, we always include a lag period of 2 months be- In recent years, numerous patients have started on this
fore starting any trial, allowing the patient to produce drug regimen with continuously good results and few side
two separate flowmetries and measurements of residual effects. However, these results have little relevance, since
volume. In the meantime, contributing diseases such as the drugs have been provided in a less than scientific
subclinical prostatitis should also be treated. Measure- manner.
ments o f prostatic size by ultrasonography or CAT scan It has been our experience, later confirmed by other
should be mandatory before any conclusions regarding workers [39], that any reduction in prostatic size due to
the efficacy o f a drug can be drawn. endocrine manipulations is of short duration once the
The present study, which was terminated in 1980, therapy is discontinued. In our own study, some patients
seemed to confirm that endocrine therapy can efficiently were subjected to surgery within 1 - 2 years; others pre-
improve the symptoms o f prostatism, not only by means ferred to have a second session with the drugs. As report-
of subjective well-being but also by objective criteria. The ed by Peters and Walsh [39], reductions in prostate size to
improved urinary flow and reduced residual urine could 75.8% following 6 months of L H R H agonist therapy re-
be attributed to a reduction in the size o f the gland as es- versed to pretreatment volumes within another 6 months.
timated by CAT scan examinations. A similar reduction These authors concluded that drug therapy had to be life-
in size has recently been reported by Schr6der et al. [46] long to provide anything but temporary relief of symp-
in five patients 3 months following castration (31o70), by toms. Hence, considering the costs o f L H R H agonists, as
Peters and Walsh [39] in nine patients 6 months following in prostatic carcinoma, bilateral orchidectomy must still
the administration L H R H agoinsts (24%), and by remain the first alternative when choosing between medi-
Gabrilove et al. [13] in three patients also given the latter cal or surgical castration.
(58o/o reduction after 6 months). The reduction in size Much attention has recently focused on the value o f
was most prominent during the first 3 months of therapy; al-blockers in the treatment o f outflow obstruction.
further reduction usually occurred between 3 and 6 Apart from the prostate's being a heterogeneous gland
months; however, if no change was noted after 3 months, comprised of epithelial elements as well as stroma with
the prostate size remained unchanged, even after 6 possibly highly variable sensitivity to external influence,
months. the phenomenon of prostatism is not a clear-cut entity.
The side effects o f the treatment were tolerable. No se- Prostatism may be ascribed to the outflow obstruction
rious cardiovascular problems or thromboembolism were due to the enlarged gland, the poor function of a "slow"
noted. Loss o f potency was surprisingly low; however, detrusor, and/or to contractability in the bladder neck
these data were based on patient inquiries only. Possibly due to hyperactivity in ~t-adrenergic receptors. It seems
the combination of an antiandrogen and an antiprolactin clear that al-blockers have no effect on the prostate
balanced some of the expected side effects; bromocrip- gland per se, apart from a theoretical effect on the
tine has been widely used on an empirical basis to im- smooth muscles of the stroma; rather, they exert their ef-
prove potency and has been reported to be "protective" fect by relaxing the smooth muscles controlling the ten-
 213
sion of the bladder neck and possibly the tensile strength components but may act beneficially on pure
of the prostate capsule. Bromocriptine has also been at- psychological grounds.
tributed mild tzl-blocking characteristics [49] and may
therefore contribute significantly to the marked efficacy References
of the combined drug regimen reported above: antian-
drogen plus antiprolactin. As a single drug, it has limited 1. Abrams PA (1977) A double-blind trial of the effects of candicidin
on patients with benign prostatic hypertrophy. Br J Urol 49:67-71
value. In a recent study on 32 patients treated with 7.5 mg 2. Bartsch (3, Frick J, Ruegg I, Bueher M, Holliger O, Oberhoizer M,
bromocriptine/day, no advantage over placebo could be Rohr HP (1979) Electron microscopic stereological analysis of the
seen with regard to urinary flow or the amount of residu- normal human prostate and'of benign prostatic hyperplasia. J Urol
al urine [40]. However, the improvement in frequency and 122:481 - 486
3. Bonard M, De Almeida S, Niederhausen W von (1976) Place-
overall efficacy was statistically significantly in favor of
bo-controlled double-blind study in human benign obstructive
bromocriptine. prostatic hypertrophy with flutamide. Eur Urol 2:24-28
The present study failed to demonstrate any advan- 4. Boyarsky S, Jones G, Paulson DF, Prout GR Jr (1977) A new look
tage for active candicidin over placebo. This was believed at bladder neck obstruction by the Food and Drug Administration
to be due to a poor pharmacologic preparation, since the regulators: guidelines for investigation of benign prostatic hypertro-
phy. Trans Am Assoc Genitourin Surg 68:29-32
drug also failed to lower serum cholesterol in hyperchol- 5. Cabot AT (1896) The question of castration for enlarged prostate
esterolemic patients (unpublished observation). However, Ann Surg 24:265-309
a more recent double-blind, placebo-controlled study us- 6. Caine M, Perlberg S, Meretyk S (1978) A placebo controlled double
ing the preparation WA184 (13-sitosteryl 13-D-glucoside) blind study of the effect of phenoxybenzamine in benign prostatic
obstruction. Br J Urol 50:551-554
also failed to show any advantage for the active drug over
7. Castro JE, Griffiths HJL, Edwards DE (1971) A double-blind, con-
placebo [24]. The authors concluded that a cholester- trolled, clinical trial of spironolactone for benign prostatic hyper-
ol-lowering agent should not be expected to be effective trophy. Br J Surg 58:485-489
in a disease which is primarily stromal, not epithelial, in 8. Cowan RA, Cowan SK, Grant JK (1977) Binding of methyltri-
nature. enolone (R1881) to a progesterone receptor-like component of hu-
man prostatic cytosol. J Endocrinol 74:281-289
This report did not deal with the most recent contri- 9. Ekman P, Johansson B, Ohls6n H, Ringertz H (1981) Drug therapy
butions to drug therapy against BPH; aromatizing and in benign prostatic hyperplasia. Stand J Urol Nephrol [Suppl]
5 t~-reductase inhibitors. There have been some clinical 60:77 - 80
studies with promising results [53], but in practice these 10. Ekman P (1983) Treatment with eyproterone acetate and/or bromo-
criptin~ In: Hinman F Jr (ed) Benign prostatic hypertrophy, ch. 25.
still remain in the preclinical laboratories [37, 58]. The ef-
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ficiency of aromatizing inhibitors has thus far not been 11. Farrar DJ, Pryor JS (1976) The effect of bromocriptine in patients
convincing in laboratory animals, since virtually no with benign prostatic hypertrophy. Br J Urol 48:73-75
shrinkage of the enlarged glands was observed [37]. This 12. Fukushima DK, Levin J, Kream J, Freed SZ, Whitmore WF Jr,
can possibly be blamed on the difference in canine and Hellman L, Zumoff B (1978) Effect of flutamide on cortisol
metabolism. J Clin Endocrinol Metab 47:788-791
human BPH, the former being more epithelial, compared 13. Gabrilove JL, Levine AC, Kirschenbaum A, Droller M (1987) Ef-
with the presumely stromal origin of the latter. Aromatiz- fect of a GNRH analogue (leuprolide) on benign prostatic hyper-
ing inhibitors should be of primary value if the theories trophy. J Clin Endocrinol Metab 64:1331-1333
hold true that human BPH occurs due to an estrogen 14. Geller J, Bora R, Roberts T, Newman H, Lin A, Silva R (1965)
Treatment of benign prostatic hypertrophy with hydrox-
hyperstimulation of stromal tissue due to the conversion
yprogesterone caproate: effect on clinical symptoms, morphology,
of androgens to estrogens in the stroma [32]. Conse- and endocrine function. J Am Med Assoc 193:121-128
quently, 5 ~t-reductase inhibitors should be of value pri- 15. Geller J, Angrist A, Nakao K, Newman H (1969) Therapy with pro-
marily in the androgen-dependent epithelium and should gestational agents in advanced prostatic hypertrophy. J Am Med
exhibit little influence on the stroma, the suggested dis- Assoc 210:1421 - 1427
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