Urological Oncology
EFFECTS OF LEUPROLIDE AND GOSERELIN FOR SUPPRESSING SERUM TESTOSTERONE IN PROSTATE CANCER
FUJII
et al.
Equivalent and sufficient effects of leuprolide acetate and
goserelin acetate to suppress serum testosterone levels in
patients with prostate cancer
Yasuhisa Fujii, Junji Yonese, Satoru Kawakami, Shinya Yamamoto, Yuhei Okubo and
Iwao Fukui
Department of Urology, Cancer Institute Hospital, Japanese Foundation of Cancer Research, Tokyo, Japan
Accepted for publication 28 September 2007
Study Type – Therapy (case series)
Level of Evidence 4
OBJECTIVE
To compare the effects of leuprolide acetate
and goserelin acetate for suppressing serum
testosterone levels in Japanese patients with
prostate cancer, as several recent studies
suggested that serum testosterone is not
always suppressed below the upper limit of
the castration range in patients using
luteinizing hormone-releasing hormone
(LH-RH) agonists, especially leuprolide
acetate.
PATIENTS AND METHODS
In all, 232 patients with prostate cancer,
whose serum testosterone levels were
measured before and during treatment using
INTRODUCTION
Treatment with an LHRH agonist is a standard
alternative to surgical castration for patients
with prostate cancer and metastases. LHRH
agonists are currently increasingly used as a
treatment option in a neoadjuvant and/or
adjuvant setting for patients with localized or
locally advanced disease before external beam
radiation therapy or radical prostatectomy, or
in case of biological and clinical failure after
these treatments. The serum testosterone
level is generally kept at castrate levels
continuously during LHRH agonist therapy.
LHRH agonists are available in most countries
as 1- and 3-monthly formulations. The main
LHRH agonists used in prostate cancer are
leuprolide, goserelin, buserelin and triptorelin.
In Japan, leuprolide acetate (Leuplin, Takeda)
and goserelin acetate (Zoladex, Astra Zeneca)
1096
a 1- or 3-monthly formulation of leuprolide
or goserelin, were enrolled in a retrospective
study. The mean age of the patients was
69.8 years and the mean testosterone level
before the LHRH treatment was 4.54 ng/mL.
The patients had their testosterone levels
assessed a mean (range) of 5.4 (1–35) times
during the LHRH treatment. A castrate
serum testosterone level was defined as
≤0.5 ng/mL.
RESULTS
The mean maximum testosterone level during
1-monthly leuprolide (40 patients), 3-
monthly leuprolide (68), 1-monthly goserelin
(50), or 3-monthly goserelin (74) treatment
was 0.22, 0.20, 0.19 and 0.20 ng/mL,
respectively (not significant). Four patients,
including two treated with 1-monthly
leuprolide, one with 3-monthly leuprolide and
one with 3-monthly goserelin, had serum
are on the market for 1-monthly (3.75 mg for
leuprolide, 3.6 mg for goserelin) and 3-
monthly (11.25 mg for leuprolide, 10.8 mg for
goserelin) use.
All LHRH agonists have been shown to be as
effective as surgical castration, and the 3-
monthly formulations are considered to be as
effective as the 1-monthly formulations. In a
meta-analysis that included 12 trials
comparing LHRH agonist monotherapy with
orchidectomy or diethylstilbestrol, the overall
hazard ratio for survival with LHRH agonists
relative to orchidectomy suggested that LHRH
agonists are essentially equivalent to
orchidectomy in terms of survival [1].
Although none of these trials directly
compared the three LHRH agonists, an
indirect comparison of seven studies of
goserelin (1137 men), four of buserelin (308
JOURNAL COMPILATION © 2 0 0 8 B J U I N T E R N A T I O N A L | 1 0 1 , 1 0 9 6 – 11 0 0 | doi:10.1111/j.1464-410X.2007.07374.x
testosterone above the castrate level, with a
maximum of 0.5–0.65 ng/mL. Three of these
patients had elevated testosterone only once
or twice during the follow-up, and the
remaining patient had serum testosterone
fluctuating at 0.4–0.6 ng/mL throughout the
follow-up.
CONCLUSIONS
One- and 3-monthly formulations of
leuprolide and goserelin have equivalent
and sufficient effects to suppress serum
testosterone levels in men with prostate
cancer. There were testosterone levels just
outside the castrate range in a few patients
during treatment.
KEYWORDS
prostate cancer, LHRH agonist, testosterone
levels
men), and one of leuprolide (94 men) found
that the hazard ratios for survival with the
individual agents relative to orchidectomy
were similar.
Several recent studies suggested that serum
testosterone levels are not always suppressed
below the upper limit of the castration range
in patients using LHRH agonists, especially
leuprolide acetate [2–4]. Yri et al. [4] reported
that four (10%) of 40 patients treated with
a 3-monthly formulation (11.25 mg) of
leuprolide acetate failed to reach the castrate
level of serum testosterone (<0.81 ng/mL), but
all 25 treated with a 3-monthly formulation
(10.8 mg) of goserelin acetate achieved the
castration level. Oefelein and Cornum [2]
showed that the nadir serum testosterone
level was >0.2 ng/mL in five (13%) and
>0.5 ng/mL in two (5%) of 38 American
© 2008 THE AUTHORS
 EFFECTS OF LEUPROLIDE AND GOSERELIN FOR SUPPRESSING SERUM TESTOSTERONE IN PROSTATE CANCER
TABLE 1 The clinical profile of patients treated with the 1- or 3- monthly formulation of leuprolide or goserelin
Leuprolide
1-monthly
No. of patients 40
At start of LHRH agonist
Mean (median, range)
Age, years 70 (72, 55–83)
Testosterone, ng/mL 4.79
(4.43, 1.71–10.3)
PSA level, ng/mL 197 (13, 0.13–2900)
Non-metastatic/metastatic 30/10
During LHRH treatment
Mean (median, range) no. of 7.1 (5, 1–26)
testosterone tests
patients treated with a 3-month depot of
LHRH agonists. LHRH agonist therapy
consisted of 22.5 mg leuprolide acetate in 37
cases and 10.8 mg goserelin acetate in the
remaining one. Of 37 German patients treated
with a long-term 3-month (11.25 mg) depot of
leuprolide acetate, four (11%) had serum
testosterone levels of >0.5 mg/mL with a
maximum level of 0.5–1.06 ng/mL [5]. By
contrast with these studies, in an open, non-
comparative phase I study, 11.25 mg leuprolide
acetate achieved effective suppression of
serum testosterone levels to the castrate range
(<1.74 nmol/L, corresponding to <0.5 ng/mL)
in all 24 enrolled patients at 4 weeks [6]. The
results of these studies were based on few
patients and testosterone samples, e.g. the first
study analysed serum testosterone only once
for each patient [4].
There have been few studies directly
comparing LHRH agonists; Heyns et al. [7]
compared the efficacy of a monthly
administration of triptorelin pamoate and
leuprolide acetate, and reported that the
former reduced testosterone concentrations
less rapidly, but maintained castrate levels as
effectively as the latter. At our hospital, serum
testosterone was principally measured before
the start of hormonal treatment and at least
once during treatment. Here we compare the
effects of leuprolide acetate and goserelin
acetate for suppressing serum testosterone
levels in Japanese patients, in a retrospective
and unrandomized study of an intermediate
scale.
PATIENTS AND METHODS
From our database of patients with prostate
cancer we identified 232 men treated with
© 2008 THE AUTHORS
JOURNAL COMPILATION © 2008 BJU INTERNATIONAL
Goserelin
3-monthly 1-monthly
68 50
70 (70, 50–88) 69 (69, 52–86)
4.40 4.30
(4.07, 1.31–12.5) (4.26, 1.52–7.45)
211 (20, 0.10–4928) 178 (20, 1.6–3052)
49/19 32/18
4.1 (3, 1–12) 8.1 (4, 1–35)
LHRH agonists from 1997 to 2006, and in
whom the serum testosterone level was
recorded before and during treatment, and
enrolled them in the present retrospective
study. The LHRH agonists used were 1-
monthly (3.75 mg for leuprolide and 3.6 mg
for goserelin) or 3-monthly (11.25 mg and
10.8 mg, respectively) formulation of
leuprolide acetate or goserelin acetate. The
patients had their testosterone levels assessed
a mean (range) of 5.4 (1–35) times during
treatment, using the the Elecsys 1010/
2010 testosterone assay (Roche, Basel,
Switzerland), an electrochemiluminescence
immunoassay. The normal range for serum
testosterone (total) is 2.07–7.61 ng/mL, and a
castrate serum testosterone level was defined
as ≤0.5 ng/mL.
The clinical characteristics of the patients are
summarized in Table 1; the mean age of the
patients was 69.8 years and the mean
testosterone level before LHRH treatment was
4.54 ng/mL. At the start of LHRH agonist
treatment, the mean (median, range) PSA
level was 201 (18, 0.10–4928) ng/mL. Seventy
patients (30%) had metastatic disease and
the remaining 162 with non-metastatic
disease (70%) had LHRH treatment in the
neoadjuvant setting before radiation
treatment or radical prostatectomy, or when
these local treatments failed. In the present
study, 40, 68, 50 and 74 patients received 1-
monthly leuprolide, 3-monthly leuprolide, 1-
monthly goserelin, or 3-monthly goserelin,
respectively. Age, serum testosterone levels
and PSA levels before treatment, presence or
absence of metastases, and the number of
testosterone assessments during LHRH
treatment were all equivalent among the
study groups.
3-monthly Total
74 232
70 (72, 47–86) 70 (71, 47–88)
4.59 4.54
(4.37, 0.95–9.88) (4.33, 0.95–12.5)
208 (19, 0.17–4100) 201 (18, 0.10–4928)
51/23 162/70
4.0 (3, 1–15) 5.4 (3, 1–35)
Non-steroidal antiandrogen, bicalutamide
80 mg once daily or flutamide 125 mg two or
three times daily, or steroidal antiandrogen
chlormadinone acetate 100 mg daily, was
combined with the LHRH agonists in 184,
three and five patients, respectively. Data on
the combined antiandrogen in the remaining
patient were lost.
The testosterone data of the groups was
analysed statistically using ANOVA, with
P < 0.05 considered to indicate statistical
significance.
RESULTS
The mean maximum testosterone levels
during 1-monthly leuprolide (40 men), 3-
monthly leuprolide (68), 1-monthly goserelin
(50) and 3-monthly goserelin (74) treatment
were 0.22, 0.20, 0.19 and 0.20 ng/mL,
respectively (P = 0.659) (Fig. 1A). Four
patients, including two treated with 1-
monthly leuprolide, one with 3-monthly
leuprolide, and one with 3-monthly goserelin,
had serum testosterone levels above
the castrate level, with a maximum of
0.5–0.65 ng/mL (Table 2). Three of these
patients had elevated testosterone only once
or twice. The remaining patient had serum
testosterone fluctuating at 0.4–0.6 ng/mL
throughout the 1-monthly leuprolide
treatment. Interestingly, his serum
testosterone levels remained unchanged even
after 1-monthly leuprolide was changed to 3-
monthly leuprolide, and thereafter to 3-
monthly goserelin. Of these four patients, one
was classified as overweight (body mass
index, BMI, 25–30 kg/m2). The mean minimum
testosterone levels during the four treatments
were 0.11, 0.12, 0.10 and 0.12 ng/mL,
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TABLE 2 Details of the four patients who failed to achieve castrate levels of testosterone during LHRH agonist treatment

Patient
Variable 1 2 3 4
LHRH agonist 1-m leuprolide 3-m leuprolide 3-m goserelin 1, 3-m leuprolide, 3-m goserelin
Body mass index, kg/m2 22.7 22.1 25.9 24.1
No. of testosterone assays 5 9 8 4, 5, 3
Period, month 7 20 19 9, 12, 9
No. of testosterone levels > castrate 1 1 2 4, 2, 2
Testosterone level > castrate 0.51 0.59 0.51, 0.65 0.50–0.60, 0.51 + 0.55, 0.51 + 0.52

respectively (P = 0.51; Fig. 1B). Levels of
testosterone were castrate in all patients at
some time during the LHRH agonist
treatment. The mean maximum testosterone
levels in 37 patients with LHRH agonist
escape [9]; the present results support these
studies.
The reason for insufficient androgen
deprivation during LHRH treatment is not
FIG. 1. The maximum (A) and minimum (B)
testosterone levels during treatment with 1- or 3-
monthly leuprolide or goserelin.
A

Testosterone level (ng/ml)

monotherapy and 184 with combined understood. An association with obesity was 0.7
androgen blockade using bicalutamide 80 mg reported; Oefelein and Cornum [2] showed 0.6
were 0.21 and 0.20 ng/mL (not significant), that the nadir serum testosterone level was 0.5
respectively. >0.2 ng/mL in five (13%) of 38 patients 0.4
treated with leuprolide acetate 3-month 0.3
0.2
DISCUSSION depot. The BMI was >30 kg/m2 (classified
0.1
as obese) in four of the five patients, and 0
This study shows that 1-monthly and 3- 25–30 kg/m2 (classified as overweight) in the
Formulation 1M 3M 1M 3M
monthly formulations of leuprolide and remaining patient. In the present study, one of LH-RH Leuprolide Goserelin
goserelin have equivalent and sufficient the four patients whose testosterone levels
effects in suppressing serum testosterone exceeded the castrate range at least once was B

Testosterone level (ng/ml)

levels in Japanese patients with prostate
cancer. Testosterone levels were just outside
the castrate range in a few patients, most of
which were temporary, during the LHRH
agonist treatment. In a European prospective,
1:2 randomized, phase II multicentre study,
237 patients with advanced or metastatic
prostate cancer were treated with the 1-
monthly (3.75 mg, 80) or 3-monthly
(11.75 mg, 157) of leuprolide acetate for
9 months [8]. The two formulations produced
virtually identical effects, with a pronounced
decrease in testosterone and gonadotrophin
serum levels. Based on all 649 (1-monthly)
and 1203 (3-monthly) serum samples
analysed during treatment, a castrate
testosterone level (<0.5 ng/mL) was verified in
96% and 97%, respectively. Temporary
testosterone levels just outside the castrate
range were found in a few serum samples. In
an another open-label, multicentre study to
evaluate the effects of a 3-monthly depot
formulation of leuprolide acetate (22.5 mg),
there was onset of castrate levels (<0.5 ng/
mL) of testosterone within 30 days of the
initial depot injection in 87 (95%) of the 92
men with metastatic prostate cancer, and by
28 weeks in the remaining five. Two patients
had a transient escape (testosterone >0.5 ng/
mL), with values mostly <1 ng/mL during the
classified as overweight. Smith [10] evaluated
the effects of obesity on sex steroid levels
during treatment with leuprolide 3-month
(22.5 mg) depot in men with prostate cancer,
reporting that obese (BMI > 30 kg/m2) men
had higher total and free testosterone levels
during the treatment than men with a normal
BMI, despite lower pretreatment serum
testosterone levels. Obese men had total and
free testosterone levels 1.8 and 2.3 times
greater than in normal men after 48 weeks of
treatment.
Obesity is an epidemic in the USA; currently,
>30% of men aged >60 years are classified as
obese [11]. Japanese men are typically smaller
and thinner than American men, and this
might be why only a few patients did not
achieve castrate levels of testosterone in the
present study. Indeed, the recommended
monthly dose of leuprolide depot for prostate
cancer is 3.75 mg, which is half the dose
approved to treat men with prostate cancer in
the USA. Possibly other racial factors, rather
than just obesity, in Japanese men are
possible causes for the results, as compared
with Americans. LHRH agonists might be
more effective in suppressing serum
testosterone levels in Asian men than in
Caucasian and African men.
0.4
0.3
0.2
0.1
Formulation 1M 3M 1M 3M
LH-RH Leuprolide Goserelin
A skin reaction has also been proposed as the
cause of hormonal escape. To achieve
continuous release, leuprolide acetate is
coupled to biodegradable microcapsules
made from lactic acid polymers or a
copolymer of lactic and glycolic acids, which
could induce reactions at the drug-injection
site. Koupparis [12] reported that two of
several patients who developed apparent
hormone-escaped disease while receiving
leuprolide acetate for metastatic prostate
cancer developed inflamed nodules at the
injection sites. In the present study, some
patients using leuprolide had a skin reaction,
but there was no association between skin
reaction and testosterone levels outside the
castrate range (data not shown).

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 EFFECTS OF LEUPROLIDE AND GOSERELIN FOR SUPPRESSING SERUM TESTOSTERONE IN PROSTATE CANCER
Moreover, some patients were reported in
whom serum testosterone was much higher
than the castrate level, and the PSA level did
not respond well despite LHRH agonist
treatment. A case was reported of functional
pituitary adenoma producing LH and FSH,
which could maintain normal testosterone
and LH levels despite the 3-month depot
injection of leuprolide acetate [13]. Smith and
McGovern [3] reported a case in which
leuprolide did not maintain the castrate level
of testosterone, but additional treatment with
goserelin achieved and maintained it. By
contrast, Matsuda et al. [14] reported three
patients who failed to achieve lower serum
testosterone levels (their testosterone levels
were 3.52–6.09 ng/mL) despite treatment
with goserelin acetate. There might be several
explanations, including a change in the LHRH
receptor, and antibodies against the drug. It is
possible that the absorption of LHRH agonists
was blocked, or that administered LHRH
agonists were rapidly metabolized.
What is the optimum level of testosterone
suppression during LHRH agonist treatment?
Most studies, including the present, defined
the ‘castrate range’ for serum testosterone
as <0.5 ng/mL, although some authors
described the expected nadir after bilateral
orchidectomy as <0.1–0.2 ng/mL [15,16]. It
was reported in several studies that when
0.2 ng/mL is used as a definition of optimum
control of testosterone, current LHRH
formulations fail to achieve this threshold
in ≈15% of patients [17]. However, in a
randomized controlled trial, testosterone
suppression was similar for men treated with
goserelin and men who were surgically
castrated [18]. We have no clinical evidence
that this lower level results in improved
survival. Additional studies are needed to
assess the relationship between testosterone
level and survival during LHRH agonist
treatment, and to determine whether
intervention to further decrease sex steroid
levels improves the clinical outcomes.
The present study has some limitations of a
retrospective and unrandomized study. The
assessment times for testosterone during
LHRH treatment were not defined, but the
background of the patients in each group was
comparable, and they had enough sampling
events (mean 5.4) for testosterone analysis
during the treatment. Therefore, we think that
the present results were reliable, at least for
Japanese patients. As noted, Japanese men
are generally smaller and thinner than
© 2008 THE AUTHORS
JOURNAL COMPILATION © 2008 BJU INTERNATIONAL
Caucasian and African men. It might be
possible that the effects of LHRH agonist in
suppressing serum testosterone levels differ
among the races or between obese and other
men. It is known that monotherapy of oral
nonsteroidal antiandrogens leads to elevated
serum testosterone levels. Therefore, there
is the possibility that the nonsteroidal
antiandrogen treatment might have
counteracted the efficacy of LHRH agonists.
However, serum testosterone levels were no
different among the 37 patients treated with
LHRH agonist monotherapy and the 184 on
combined androgen blockade using
bicalutamide. Oefelein [19] also reported that
adding antiandrogen (250 mg flutamide three
times daily) made no significant difference to
serum testosterone levels in patients treated
with LHRH agonists.
The measurement of testosterone has been
recommended as part of clinical practice
when initiating hormonal therapy and
evaluating the effects, because some patients
might fail to reach serum testosterone values
within the castrate range when using LHRH
agonists. No patients should be diagnosed as
androgen-resistant until they have had their
serum testosterone assayed. We agree with
this opinion, but the present study showed
that the incidence of such cases is quite low.
Generally, any of the 1- or 3-monthly
formulations of leuprolide and goserelin can
suppress testosterone levels to the castrate
range in almost all patients.
CONFLICT OF INTEREST
None declared.
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Correspondence: Yasuhisa Fujii, Tokyo
Medical and Dental University, Urology, 1-5-
45 Yushima, Bunkyo-ku Tokyo 113-8519,
Japan.
e-mail: y-fujii.uro@tmd.ac.jp,
yasuhfujii@yahoo.co.jp
Abbreviation: BMI, body mass index.

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