FERTILITY AND STERILITY~ Vol. 67, No. 1.

January 1997
Copyright ~ 1997 American Society for Reproductive Medicine Printed on acid.free paper in U. S, A.

Effectiveness of tibolone on hypoestrogenic symptoms induced by

goserelin treatment in patients with endometriosis*

Omur Taskin, M.D.t Ismail Uryan, M.D.

A. Ihsan Yalcinoglu, M.D. Ali Buhur, M.D.
Senol Kucuk, M.D. Feza Burak, M.D.

Division of Reprod,lctive Endocrinology, Department of Obstetrics and Gynecology, Inonu Universi(y School of Medicine,
Malatya, Turkey

Objective: To investigate the efficacy and safety of tibolone on hypoestrogenic vasomotor

symptoms and bone parameters in patients treated with goserelin acetate.
Design: Prospective, randomized placebo controlled double-blind study.
Setting: Human volunteers in a university-based fertility clinic.
Patient{s): Twenty-nine women of mean age 29.2 __+4.8 years with mild to severe endometrio-
sis undergoing 6 months of treatment with 3.6 mg goserelin acetate in an SC depot formulation
were studied.
Intervention{s): The patients were allocated randomly to either 2.5 mg/d tibolone (n = 15)
or an iron pill (n = 14) in a double-blinded fashion beginning in the third cycle.
Main O u t c o m e Measure(s): Frequency and severity of hot flushes, sweating, irritability,
loss of libido, nervousness, and sleeplessness were assessed by the patients using 0 to 6 point
scoring system and compared. Samples of urine were obtained for calcium and creatinine (Ca:Cr)
ratios at the start of treatment and monthly there after. The vasomotor scoring for each symptom
and Ca:Cr ratios before the treatment and at the end of 6th month were analyzed by parametric
and nonparametric tests.
Result(s): The mean age, weight, vasomotor scores, pelvic scores, and urine Ca:Cr ratios
were similar in both placebo and tibolone group (28.7 +_ 4.8 versus 27.6 _+ 6.3 years, 50.9 ___5.3
versus 53.1 +_ 7.1 kg, 4.7 _+ 1.1 versus 4.2 _+ 0.8, and 0.056 _ 0.008 versus 0.059 _+ 0.006,
respectively). The decreases in vasomotor scoring as regards to hot flushing, sweating, and other
associated symptoms were statistically significant in tibolone group compared with placebo
(10.4 _+ 1.6 versus 24.6 _+ 4.9). During the study significant reductions in urine Ca:Cr ratio was
obtained in the tibolone patients compared with placebo (0.031 ___0.006 versus 0.0055 _+ 0.007).
The incidence of side effects (weight change, vaginal bleeding) was low and did not differ from
the placebo group.
Conclusion(s): Considering the beneficial effects of tibolone on vasomotor symptoms and
bone loss, our data suggest that this synthetic steroid is an effective and safe option in relieving
symptoms induced by GnRH-analogue. Fertil Steril ® 1997;67:40-5

Key Words: GnRH-a, tibolone, hypoestrogenism, endometriosis, add-back therapy

One of the most recent and promising a p p r o a c h e s G n R H receptors, with r e s u l t a n t reduction in s e r u m

has been the introduction of G n R H agonists (GnRH-
a) to reproductive endocrinology. C o n t i n u e d admin-
istration of G n R H - a results in desensitization of
Received April 26, 1996; revised and accepted July 29, 1996.
* Presented in part at the 51st Annual Meeting of the American
Society for Reproductive Medicine, Seattle, Washington, October
7 to 12, 1995.
t Reprint requests: Omur Taskin, M.D., Inonu University
School of Medicine, Malatya, Turkey {FAX:90-422-324-6821}.
g o n a d o t r o p i n and o v a r i a n steroid levels, c a u s i n g a
reversible state of h y p o e s t r o g e n i s m (1). This poten-
tial reversible h y p o g o n a d o t r o p i c h y p o g o n a d i s m h a s
m a d e these a g e n t s to be used effectively in endome-
triosis, u t e r i n e fibroids, assisted reproductive tech-
nology, the p r e m e n s t r u a l s y n d r o m e , a n d precocious
puberty.
Endometriosis is characterized with the ectopic
presence of endometrial tissue and stroma. It has
been estimated t h a t it affects 7% of reproductive age

40 Taskin et al. GnRH.a and tibolone Fertility and Sterility ~

women (2). Endometriosis generally is accepted to be
an estrogen-dependent disorder. Amelioration of pre-
existing endometl-iosis after surgical and natural
menopause and further demonstration of stimulated
endometrial tissue growth on estrogen therapy in ani-
mals may support the above pathophysiology. The
suppression of sex steroids is the rationale of pharma-
cologic therapy used to manage endometriosis.
Gonadotropin-releasing hormone agonists have
been used widely in medical t r e a t m e n t of endometri-
osis by causing ovarian suppression. The resulting
fall of estrogen levels into the postmenopausal range
showed significant improvement in stage and symp-
toms of endometriosis (3, 4). Gonadotropin-releasing
hormone agonists frequently are associated with hy-
poestrogenic side effects, such as hot flushes, head-
ache, depression, emotional lability, and vaginal
atrophic changes. Besides, an important consider-
ation in the use of GnRH-a is the change in bone
density, which may not recover after the t r e a t m e n t
(57. Moreover, Barbieri (6) has proposed t h a t the
above hypoestogenic side effects can be alleviated by
addition of sex steroids to GnRH-a t r e a t m e n t with-
out any reduction in efficacy. The present study is
designed to investigate the efficacy and safety of ti-
bolone, a synthetic weak estrogenic steroid on hypo-
estrogenic side effects in patients treated with goser-
elin acetate.
MATERIALS AND M E T H O D S
Twenty-nine women of mean age 29.2 _+ 4.8 years
with mild to severe endometriosis undergoing 6
months of t r e a t m e n t with 3.6 mg goserelin acetate
in an SC depot formulation were studied. The study
was approved by the Investigation Review Board
and the patients were consented. All the patients
were diagnosed by laparoscopy and revised Ameri-
can Fertility Society (AFS7 score (77 used to classify
the lesions. No operative interventions were per-
formed during the initial laparoscopy. The patients
had regular menstrual cycles and have not received
any medical therapy before diagnosis. The patients
used condom as a barrier contraception for the dura-
tion of the GnRH-a t r e a t m e n t period. Second-look
laparoscopy was performed within 1 month after the
last injection of goserelin acetate.
Before the randomization, the patients were as-
sessed for pelvic symptoms such as dysmenorrhea,
pelvic pain, and dyspareunia and pelvic tenderness
and induration on vaginal examination. The severity
of above symptoms scored on a scale of 0 to 3 (absent,
mild, moderate, and severe). All these scores were
assessed monthly throughout the t r e a t m e n t period.
All the patients received 3.6 mg SC depot injection
Vol. 67. No. 1, January 1997
of goserelin acetate every 4 weeks for 6 months
within 7 days from the commencement of menstrua-
tion. The patients were allocated randomly to either
2.5 mg/d tibolone in = 15) or an iron pill (n = 14)
in a double-blinded fashion beginning in the third
cycle.
Patients were questioned at each visit and com-
pleted a chart throughout the study to assess the
frequency and severity of hypoestrogenic side ef-
fects. Frequency and severity of hot flushes, sweat-
ing, irritability, loss of libido, nervousness, and
sleeplessness were assessed by the patients using 0
to 6 point scoring system and compared monthly.
Samples of urine were obtained for calcium and cre-
atinine (Ca:Cr7 ratios at the start of t r e a t m e n t and
monthly there after.
Serum LH, FSH, and E._,levels were measured just
before the first goserelin acetate injection and
monthly thereafter within 3 days of GnRH-a admin-
istration. The LH and FSH levels were assayed us-
ing immunoradiometric assay. Serum E2 was mea-
sured by RIA. Fasting blood samples were collected
simultaneously to measure the concentrations of se-
rum cholesterol, triglyceride, high-density lipopro-
tein (HDLT, and low-density lipoprotein (LDL7
throughout the study period.
The pelvic scores, serum LH, FSH, E2, vasomotor
scoring for each symptom and Ca:Cr ratios before
the t r e a t m e n t and at the end of 6th month were
analyzed with and within the groups by parametric,
nonparametric tests, analysis of variance. A P value
< 0.05 denoted statistical significance.
RESULTS
Of the 29 women studied, all except 7 underwent
second-look laparoscopy, but all have completed the
clinical and hormonal assessments. The baseline
features of the women included in the study are de-
picted in Table 1. There were no differences observed
among the t r e a t m e n t groups regarding age, weight,
pelvic scores, vasomotor scores, and the hormonal
profile (P > 0.05). No pregnancies occurred during
treatment. Twenty-two patients had second-look
laparoscopy (12 in tibolone and 10 in placebo group).
The revised AFS scores were reduced significantly
in both groups compared with baseline, with no sig-
nificant differences between the placebo and tibolone
treatments (26.7 _+ 10.4 and 27.7 _+ 9.3 versus 12.7
_+ 6.5 and 14.3 _ 5.2, respectively; P < 0.05). The
mean reduction in AFS scores was >40% in each
group. Based on AFS scores in second-look laparos-
copy, the number of patients showing objective im-
provement were similar in goserelin acetate plus
placebo and goserelin acetate plus tibolone groups
(n = 9 v e r s u s n = 11).
Taskin et al. GnRH-a and tibolone 41
Table 1 Baseline Characteristics of Patients Studied*
30-
Goserelin acetate Goserelin acetate
+ placebo + tibolonet 25-
(n = 14) (n = 15)
==
Age (y) 28.7 ± 4.8 27.6 +_ 6.3 ¢=~ 20-
Weight [kg) 50.9 ± 5.3 53.1 +_ 7.1
Pelvic score 6.5 ± 1.2 7.0 +_ 1.0
15-
Vasomotor score 4.7 ~ 1.1 4.2 ~ 0.8
AFS score 26.7 +_ 10,4 27.7 _+ 9.3
Ca:Cr 0.056 _+ 0.008 0.059 +_ 0.006 10-
FSH (mIU/mL)$ 7.1 ~ 3.2 6.8 + 2.8
LH ( m l U / m L ) - 5.8 _* 1.8 5.6 _+ 2.0
E~ {pg/mL)$ 105 _* 10.5 118.4 + 12.4 5-

* Values are m e a n s ÷ SD.

t Significantly different, P > 0.05.
$ Conversion factors to SI units are as follows: E~, 3.671; LH
and FSH, 1.00.
Both groups showed significant subjective im-
provement in pelvic symptoms compared with pre-
treatment (Fig. 1). The pelvic scores decreased from
5.8 and 6.1 in placebo and tibolone group to 1.4 and
1.5 after 6 months, respectively (P < 0.05). There
was no difference between the goserelin acetate plus
placebo and goserelin acetate plus tibolone groups,
denoting similar efficacy (P > 0.05).
After 3 months of goserelin acetate treatment,
both groups reported similar frequency of increased
vasomotor symptoms, whereas addition of tibolone
to goserelin acetate significantly reduced the inci-
dence and severity of vasomotor symptoms (P
fro5
,Y.,
_=
Month 0 Month 3 Month 6
F i g u r e 1 The pelvic scores as regards to d y s m e n o r r h e a , dyspa-
reunia, pelvic pain, induration, and pelvic t e n d e r n e s s before and
d u r i n g t r e a t m e n t with goserelin acetate plus placebo and gosere-
lin acetate plus OD 14 (mean _+ SD). I , goserelin acetate + pla-
cebo; [:::], goserelin acetate + OD 14. *P < 0.05 compared with
pretreatment.
0 I I I I I I I
0 1 2 3 4 5 6
Months
F i g u r e 2 The vasomotor scores as r e g a r d s to fl'equency and
severity of hot flushes, sweating, irritability, loss of libido, ner-
vousness, and sleeplessness t h a t were a s s e s s e d by the p a t i e n t s
using 0 to 6 point scoring s y s t e m d u r i n g t r e a t m e n t period between
the groups. - - [] - - , goserelin acetate + placebo; - - • - - , goser-
elin + OD 14. *P < 0.05.
< 0.051. Figure 2 shows the changes in vasomotor
scores. The improvement was significant in the gos-
erelin acetate plus tibolone group compared with
goserelin acetate plus placebo, which was consistent
with the above data reporting reduced incidence and
severity of vasomotor symptoms.
The adverse effects of hypoestrogenism on bone
metabolism have been followed and quantified by
measuring urinary Ca:Cr ratio. The urinary Ca:Cr
ratio increased during goserelin acetate treatment.
During the study, significant reductions in urine
Ca:Cr ratio was obtained in the tibolone patients
compared with placebo (0.031 +_ 0.006 versus 0.0055
+_ 0.007).
Both treatment groups showed suppressed LH,
FSH, and E2 levels with goserelin acetate (Fig. 3).
The trend was similar in both groups as regards to
FSH and LH levels. The differences observed be-
tween groups was not significant (P > 0.05). Serum
E., levels suppressed significantly with goserelin ace-
tate alone, beginning at the end of 1st treatment
month. This suppression was reversed after addition
of tibolone to goserelin acetate at the 3rd month of
treatment. Although it remained <45 pg/mL, the
E.~ levels were significantly higher in the patients
treated with goserelin acetate plus tibolone than in
those with goserelin acetate plus placebo at 4, 5, and
6 months (P < 0.05).
There were no changes in the concentrations of
serum cholesterol, triglyceride, HDL, and LDL
throughout the study period. Although there was a

42 T a s k i n e t al. GnRH.a arid tibololze Fertility and Sterility '~'

 slight decrease in HDL cholesterol in the goserelin
3 .-K- A acetate plus tibolone group at months 5 and 6, the
difference was not statistically significant (data not
shown).

DISCUSSION

-!
u_
Tibolone is a synthetic steroid t h a t d e m o n s t r a t e s
simultaneous weak estrogenic, androgenic, and pro-
gestational activity (8). It is effective against climac-
teric vasomotor symptoms and has positive influ-
ences on mood and libido. Tibolone has been used
successfully to prevent and t r e a t postmenopausal
problems for longer t han a decade in Europe (8, 9).
Estrogen and/or progestogen is the most widely
used and established component of hormone replace-
ment therapy (HRT) in the t r e a t m e n t of climacteric
and postmenopausal symptoms. There are extensive
data in the literature devoted to the risks and benefits
balance of the above agents (10). This established role
a ** B in postmenopausal symptoms has extended HRT use
in preventing hypoestrogenic complications of GnRH-
a (11-13). Despite its efficacy in relieving hypoestro-
genic problems, the main concern has been focused on
stimulation of endometrium. Because endometriosis
has been accepted as an estrogen-dependent disorder
t hat resolves on withdrawal of sex hormones, induced
..J hypoestrogenism is the basis of presumed mode of
available medical intel-centions such as GnRH-a,
2-
which is associated with serious side effects limiting
their use to 6 months. The concept of add-back HRT
to prevent hypoestrogenic effects of GnRH-a was ex-
0 ¢ l I I l I !
plored since the late 1980s. The first studies reported
o 1 2 3 4 5 6
partial relief by combining GnRH-a with progestins
(14). Gangar et al. (15) used goserelin acetate and
estrogen-progestogen HRT to t reat pelvic pain and
reported abolished hypoestrogenic side effects with-
140
C out prominent endometrial stimulation, thus sup-
120 porting its use in endometriosis. Moreover, Barbieri
100
(6,) has suggested that GnRH-a side effects can be
reduced or inhibited by adding estrogen-progestogen
80 without any loss in efficacy.
With increased use of laparoscopic interventions,
long-term randomized studies have been published
investigating the use of steroid add-back with
20 GnRH-a in endometriosis (11, 16-18). All these
studies have reported diminished postmenopausal-
0 ! | ! i i ! i
0 1 2 3 4 5 6 type symptoms without adversely affecting GnRH-a
Treatment Months
efficacy in t reat i ng endometriosis.
To our knowledge, the present study is the only
one using tibolone as add-back regimen to GnRH-a
Figure 3 Endocrine responses showing serum levels of FSH, t reat m ent . Our results are consistent with the above
LH, and E., before, during, and after treatment with goserelin studies using estrogen-progestogen HRT. Tibolone
acetate plus placebo and goserelin acetate plus OD 14. -- [] --
goserelin acetate + placebo; -- • --, goserelin acetate + OD 14. did not reduce the efficacy of GnRH-a t h e r a p y as
*P > 0.05; **P < 0.05. assessed by laparoscopy and effectively diminished

Vol. 67, No. 1, January 1997 Taskin et al. GnRH-a and tibolone 43
hypoestrogenic symptoms. Although we have not
studied bone density, Ca:Cr ratio as a biochemical
marker revealed decreased loss in urine with tibo-
lone add-back. Our findings in conjunction with
those of Lindsay et al. (19) and Fogelman et al. (20)
are consistent with tibolone having a protective ef-
fect on cortical bone similar to the estrogen-proges-
tin add-back regimens. Besides, tibolone effects on
mood and libido are additive to the above findings.
Lack of endometrial stimulation seen with tibo-
lone may increase further its superiority over es-
trogen-progestogen add-back, although there is a
questionable relationship between maintenance of
endometriotic lesions and circulating ovarian ste-
roids (17, 21, 22). This provides increased flexibility
and safety with tibolone add-back compared with
estrogen-progestogen HRT without concerning the
dose and duration of therapy that may exacerbate
the endometriotic lesions reducing the efficacy of
GnRH-a. Although the mean E2 levels were higher
in the tibolone add-back group, it remained <45 pg/
mL, without any significant effect on endometriosis
scores. The above relatively higher E,~ levels in the
tibolone group may reflect its weak estrogenic effect.
The only adverse effect observed in our study, al-
though not significant, was the reduced HDL-choles-
terol levels. This finding is consistent with the re-
ported studies on tibolone (23, 24). Haenggi et al.
(25) have found that tibolone is at present the only
postmenopausal HRT that shows a significant inhib-
iting influence on serum levels of lipoprotein(a). Its
effect on lipoprotein(a) might counterbalance, at
least to some extent, the theoretical adverse effect on
the other lipoprotein risk factors, such as decreased
HDL-cholesterol levels.
In conclusion, our study demonstrates the efficacy
of tibolone in relieving hypoestrogenic side effects
and preventing bone loss seen with GnRH-a therapy.
The above effects are achieved without adversely af-
fecting efficacy of goserelin acetate treatment in
endometriosis. Tibolone may be used as an safe al-
ternative to estrogen-progestogen add-back in estro-
gen-dependent gynecologic problems treated with
GnRH-a and extend their role without restricting
the duration of therapy. Considering the above bene-
ficial effects of tibolone, our data suggest that this
synthetic steroid is an effective and safe add-back
option to GnRH-a and may provide a new strategy
of prolonged medical treatment for women with en-
dometriosis as an alternative to surgery.
Acknowledgments. We acknowledge Organon, Ttirkiye's techni-
cal support, in preparation of this manuscript.
44 T a s k i n e t al. GnRH-a and tibolone
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