Commentary
Effects of Castration on BPH
FOR the current generation of urologists, the use of
surgical castration for the treatment of benign
prostatic hyperplasia (BPH) as described in this
article by Huggins and Stevens in 19401 must seem
strange, given the well established role of alpha
blockers, 5a-reductase inhibitors, transurethral
resection of the prostate or laser ablation, as well as
a spate of new outpatient procedures such as
RezumÒ and UroLiftÒ, which have the potential to
eliminate the need to ever take a patient with lower
urinary tract symptoms to the operating room.
However, the oldest among us will recall that
modern resectoscopes were not developed until the
1950s and that prior to the development of open and
endoscopic prostatectomy, BPH was not only morbid
but occasionally lethal, owing to renal failure,
infection, strangulated hernias from straining to
void or intraperitoneal bladder rupture.
Prior to this report, there had been several
studies totaling more than 100 patients whose uri-
nary retention and other symptoms were cured by
castration, and the study seems motivated more to
understand the effect of castration on prostate
biology than on promulgating castration as therapy.
At the time there was no direct evidence that an-
drogens affected benign or malignant prostatic
growth, although it would only be a year later when
Huggins and Hodges published their Nobel prize
winning work on the palliative effect of castration
on men with metastatic disease.2 The main finding
of this study was that castration induced atrophy of
the glandular epithelium over time without any ef-
fect on the stroma, clearly supporting the authors’
conclusion that the prostatic epithelium “was under
control of the testes.”1
Observations that men made hypogonadal before
puberty (by dint of testicular trauma, genetics, pi-
tuitary abnormalities or emperors intent on keeping
their harems safe) had rudimentary prostates in
adulthood added to this theory, with ultimate
confirmation of this hypothesis in the 1980s and
1990s through the work of Coffey, Isaacs and others,
demonstrating the ability of prostate epithelium to
regress and regenerate with repeated cycles of
castration and androgen replacement.3 The latter
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observations have suggested the existence of pros-
tatic epithelial stem cells, which may be the cell of
origin of some prostate cancers.4
The recognition of androgen control of prostate
epithelial growth and to avoid undesirable side
effects of castration (chiefly loss of libido, the main
reason early attempts at medical castration using
luteinizing hormone releasing hormone analogues
was abandoned) in otherwise healthy men led
naturally to the search for alternative drugs.
Seminal to this quest was the discovery of a group
of pseudohermaphrodites in the Dominican Re-
public reported in 1974 known as “guevedoces”
(meaning “penis at 12”) or “machihembras”
(meaning “first a woman, then a man”). These
males are born with female external genitalia that
become masculinized at puberty owing to congen-
ital deficiency of 5a-reductase (5AR) leading to
inability to synthesize dihydrotestosterone (DHT),
the latter now proven beyond doubt to be the hor-
monal agent suspected by Huggins and Stevens to
control prostatic epithelium.5
Soon after the guevedoces became known to the
world, big pharma began an intense quest to syn-
thesize a drug that mimicked the effects of 5AR and
DHT deficiency to be used in postpubertal men with
symptomatic BPH to shrink the prostate. Ulti-
mately, Merck developed a 4-aza steroid molecule
that would inhibit 5AR called MK-906 (subse-
quently known as finasteride), and after successful
experiments in animals began human safety and
efficacy trials in 1986, ultimately leading to
approval by the FDA (U.S. Food and Drug Admin-
istration) in 1992.6 In order to prove that use of fi-
nasteride objectively reduced bother and was better
than placebo, Merck also developed and validated a
self-reported symptom checklist,7 serving as a pre-
cursor to the widely used AUA Symptom Score and
the basis for all subsequent BPH related drug and
device trials. Also incidental to the development of
finasteride was a standardized way to measure
prostate volume using transrectal ultrasound,
leading in part to the concept of prostate specific
antigen density (PSAD)8 and the definition of
patients with NCCNÒ (National Comprehensive
http://dx.doi.org/10.1016/j.juro.2016.11.029
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Cancer NetworkÒ) very low risk prostate cancer
who are candidates for active surveillance.
GlaxoSmithKlein subsequently developed dutas-
teride, a similar compound that inhibits both iso-
forms (types I and II) of 5AR and which was
approved by the FDA for treating symptomatic
lower urinary tract symptoms in 2001 based on 3
large phase III trials.9 Although dutasteride results
in greater reduction of serum DHT than finasteride,
the drugs have similar efficacy and toxicity. Given
the observations of Huggins and Stevens on the ef-
fect of castration on prostate cancer, finasteride and
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J Urol 1940; 43: 705.
2. Huggins CV and Hodges CV: Studies on prostatic
cancer. I. The effect of castration, of estrogen and
of androgen injection on serum phosphatase
in metastatic carcinoma of the prostate. Cancer
Res 1941; 1: 293.
3. Juniewicz PE, Berry SJ, Coffey DS et al:
The requirement of the testis in establishing
the sensitivity of the canine prostate to
develop benign prostatic hyperplasia. J Urol
1994; 152: 996.
EFFECTS OF CASTRATION ON BPH S77
dutasteride have also been tried as agents for
treating and preventing cancer, although neither
has gained widespread use for either of these
indications.
It is remarkable that histological observations on
3 patients had such a far reaching effect on men’s
lives.
Eric A. Klein
Glickman Urological and Kidney Institute
Cleveland Clinic
Cleveland, Ohio
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