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00/0 The Journal of Clinical Endocrinology & Metabolism 87(1):16 –23

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CLINICAL REVIEW 140

Tibolone for Postmenopausal Women: Systematic Review
of Randomized Trials
KATHARINA MODELSKA AND STEVEN CUMMINGS
University of California Coordinating Center, Department of Medicine, Prevention Sciences Group, University of California,
San Francisco, California 94105

Tibolone (Livial, Org OD 14), produced by Organon (West Materials and Methods
Orange, NJ), is a synthetic steroid that has estrogenic, A computerized search of the published literature in diverse elec-
androgenic and progestagenic properties. It has been used in tronic databases, including MEDLINE, Gallen II, EMBASE, and Co-
Europe for almost 2 decades, primarily for the prevention of chrane library, was conducted. We did not restrict our search to English
language literature. Keywords used in our search included: tibolone,
postmenopausal osteoporosis and treatment of climacteric
Livial, postmenopausal women, hormonal replacement therapy, climac-
symptoms. Research about tibolone as well as reviews of teric symptoms, sexual function, osteoporosis, breast cancer, lipid me-
clinical studies have been conducted and published, mainly tabolism, and cardiovascular effects. Journal articles published from
in Europe (1–3). The FDA has not yet approved tibolone, and January 1981 to August 2001 were retrieved and reviewed for content,
and their references were used to identify other articles of interest.
therefore information about tibolone is less easily accessible Additionally, we manually searched conference proceedings and bib-
to clinicians and postmenopausal women in the United liographies of published articles. Finally, articles in press were obtained
States. from Organon, the manufacturer of tibolone.
Tibolone itself has no biological activity; its effects are the From over 390 clinical reports we have found 21 unique RCTs that
assessed the clinical effects of tibolone (2.5 mg/d) in postmenopausal
results of the activity of its metabolites on various tissues (4). women. Summaries of the study design, duration of the trials, partici-
After administration, tibolone is quickly metabolized into pant demographics, and different outcomes are presented in Tables 1– 4.
3␣-hydroxytibolone (3␣-OH-tibolone) and 3␤-OH-tibolone If a trial measured many different effects of tibolone in postmenopausal
compounds, which are also present in an inactive, sulfated women, we presented the results of this 1 trial in more than 1 table.
Selection criteria and characteristics of the study participants are de-
form (4) (Fig. 1). A third compound, the ⌬4-isomer, is formed scribed in the body of this review. Because the aim of this review is to
from tibolone directly or from the 3␤-OH-metabolites. The summarize tibolone’s effects on postmenopausal women, we excluded
3␣- and 3␤-OH-metabolites bind solely to the ER, whereas trials involving premenopausal women. We also excluded retrospective
the ⌬4-isomer has affinity for PR and AR, but not ER. analyses, nonrandomized and open label studies, and trials in which the
use of a placebo was not specifically stated.
The concentrations of tibolone metabolites and the meta-
bolic regulation of hormonal activities vary depending on
tissue type (4 – 6) (Fig. 1). Tibolone has estrogenic effects on Results
bone and vaginal tissue. In endometrial tissue the ⌬4-isomer Tibolone and its effects on climacteric symptoms
functions as a progestagen, whereas in the brain and liver it Menopause-associated symptoms impair quality of life for
has androgenic effects. In breast tissue, the main actions of many women. More than 75% of postmenopausal women
tibolone are strong inhibition of sulfatase activity and weak experience hot flushes and sweating. Other symptoms, such
inhibition of 17␤-hydroxysteroid dehydrogenase activity, as insomnia, headache, or fatigue, as well as changes in mood
which result in blocking the conversion of estrone sulfate to E2. and libido may result directly from menopause or indirectly,
Tibolone given orally is rapidly absorbed, appearing in the such as effects of hot flushes on sleep. We found eight unique
plasma within 30 min and peaking in 4 h. Tibolone is me- RCTs that assessed the effects of tibolone on climacteric
tabolized mainly in the liver and is excreted in the urine and symptoms (Table 1). In the first five RCTs (7–11) the effects
feces. The elimination half-life is approximately 45 h. of tibolone on climacteric symptoms were compared with
In this review we will discuss the results from the ran- those of placebo. In addition, one trial compared tibolone to
domized, controlled, and double blind trials (RCTs) of tibo- E2 valerate (12), and two unique RCTs compared tibolone to
lone, with respect to its effects on climacteric symptoms, the combination of E2 and noresthisterone acetate (E2/
sexual function, endometrial and breast tissue, lipid metab- NETA) (13, 14). The results of the first combination trial with
olism, and bone mineral density (BMD). E2/NETA were presented in two different publications by
Nathorst-Böös (13) and Hammar (15), and the results of the
second trial were presented recently by Dören (14).
Abbreviations: BMD, Bone mineral density; DXA, dual-energy x-ray
absorptiometry; HDL-C, high density lipoprotein cholesterol; LDL-C, The selection criteria for all subjects involved in the RCTs
low density lipoprotein cholesterol; NETA, noresthisterone acetate; OH, were hot flushes, sweating, and other postmenopausal-
hydroxy; RCT, randomized, controlled, and double blind trial. related symptoms, such as fatigue, headaches, changes in

16

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Modelska and Cummings • Clinical Review J Clin Endocrinol Metab, January 2002, 87(1):16 –23 17

FIG. 1. Tissue-specific effects of tibolone’s

metabolites. (⫹), Stimulatory effect of tibo-
lone on the receptor; (-), suppressive effect of
tibolone on the receptor; (?), unknown effect of
tibolone in postmenopausal women.

mood, insomnia, and decrease in libido. All subjects selected placebo group in these trials, the magnitude of improvement
for these RCTs had been postmenopausal for at least 12 of hot flushes and sweating could not be ascertained.
months and free of any treatment for at least 3 months.
Women after surgical menopause were included in two trials
Effects of tibolone on other postmenopausal symptoms
(12, 16). Excluded were patients who received any hormonal
or psychotropic therapy in the 6 –12 wk before the trials Many trials reported a beneficial effect of tibolone on fa-
started and patients with a previous history of gynecological tigability, frequency of headaches, psychological instability,
or malignant disease (7, 10, 11, 17). Also excluded were and insomnia (7, 10, 11). Genazzani (9) found that the relief
patients with hypertension (12, 14); as well as patients with of hot flushes from the second month of treatment was as-
any cardiovascular or cerebrovascular disease, thrombo- sociated with improvement of both mood and insomnia. The
embolic disorder (18 –20), history of renal or liver disease reported changes in postmenopausal symptoms varied
(14, 20); and patients who were treated with medication among the trials, which may be due to variations in study
known to affect coagulation, fibrinolysis, or lipid or bone duration, social differences in multicultural samples, and
metabolism (21, 22). Women who smoked cigarettes were different scoring systems used. Two of the trials were very
excluded in several trials (23, 24). In addition, tobacco use short (8, 9), and two trials did not describe clearly the meth-
equivalent to more than five cigarettes per d was an exclusion ods by which the symptoms were measured (9, 12).
criteria in one trial (25).
Effects of tibolone on mood
Effects of tibolone on hot flushes and sweating In one small trial of young women who had undergone
Compared with placebo, most RCTs reported a significant oophorectomy and hysterectomy, Crona et al. (12) found
reduction in hot flushes and sweating in women taking ti- that tibolone and E2 valerate reduced hot flushes and
bolone (Table 1). However, the magnitude of changes was improved mood to a similar degree. In another trial,
not reported in all of the publications. When the effects of Genazzani (9) found that tibolone increased the concen-
tibolone on hot flushes were compared with the effects of tration of ␤-endorphins and proposed that this might con-
hormonal replacement therapy, a similar reduction of hot tribute to the improved mood in postmenopausal women.
flushes was seen with both therapies. Because there was no However, mood was not directly assessed in this trial.

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18 J Clin Endocrinol Metab, January 2002, 87(1):16 –23 Modelska and Cummings • Clinical Review

TABLE 1. Tibolone and climacteric symptoms

Main outcomes and

Ref. Study design N [age (yr)] Duration (wk) Comments
magnitude of effects
Tibolone vs. placebo
Kicovic, 1982, Random, double-blind, 82 16 wk/period On 0 –3 point scale score: 39% Poor description of inclusion
Reproducción cross-over reduction in hot flushes; criteria; no wash-out
24% reduction in sweating; period; 24% drop-out rate
28% reduction in insomnia
(P ⬍ 0.001)
Cittadini, 1982, Random, double-blind 60 6 No significant difference in Drop-out rate not reported
Reproducción perspiration, palpitations,
irritability, backache
compared with placebo
Nevinny-Stickel, Random, double-blind, 35 (48 – 69) 16 wk/period On 0 –3 point scale score: Small sample size; no wash-
1983, cross-over reduction in frequency out period; drop-out rate
Arch Gynecol (P ⬍ 0.003) and severity not reported
(P ⬍ 0.01) of hot flushes;
reduction in sweating
(P ⬍ 0.01); reduction in
headaches (P ⬍ 0.02);
sexual function: no sign of
differences in libido and
mood
Genazzani, 1987, Random, double-blind 30 (36 –59) 24 Increase in plasma levels of Poor description of study
Maturitas ␤-EP and ␤-lipoprotein design; broad spectrum in
age; no meaningful
statistics for hot flushes
and other symptoms
Bedenk-Jaszman, Random, double-blind 60 (44 – 61) 48 On 0 –3 point scale score: Short wash-out period
1987, significant reduction in hot
Maturitas flushes (P ⬍ 0.001),
sweating (P ⬍ 0.01) and
fatigue (P ⬍ 0.05)
Laan, 2001, Random, double-blind 38 (⬎65) 12 Significant reduction in hot Very small sample size for
Climacteric flushes (P ⬍ 0.0005); no comparisons between the
changes in severity of night subgroups
sweats and quality of sleep;
sexual function: significant
increase in vaginal pulse
amplitude levels (P ⬍
0.001); arousability (P ⬍
0.01), sexual fantasies (P ⬍
0.03), sexual desire (P ⫽
0.08), vaginal lubrication (P
⬍ 0.001) with tibolone vs.
placebo; no change in
frequency of sexual activity
in both groups
Tibolone vs. E2V
Crona, 1988, Random, double-blind, 20 (27–37), all ppts 18 On 0 –3 point scale score: No wash-out period; drop-
Maturitas cross-over after oophorectomy mood: tibolone and E2V out rate not reported
equally improved
climacteric symptoms and
ratings in mood (95% CI)
Tibolone vs. E2/NETA
Nathorst, 1997, Random, double-blind 437 (⬎53) 48 Sexual function: Swedish No placebo group; 28%
Maturitas version of McCoy’s Sex drop-out rate; no data of
Scale Questionnaire: socio-economic or
significant improvement in educational milieu of
frequency, satisfaction ⫹ subjects involved
enjoyment vs. E2/NETA
Hammar, 1998, Random, double-blind 437 (⬎53) 48 On a 0 –5 point scale score: 25% drop-out rate
Br J Obstet both therapies reduced hot
Gynaecol flushes, sweating ⫹ vaginal
dryness; significant
reduction in bleeding with
tibolone compared with E2/
NETA (P ⬍ 0.0001)
Dören, 2001, Random, double-blind, 100 (⬎45) 48 Sexual function: in contrast to No placebo group; no
Fertil Steril prospective E ⫹ NA, tibolone doubled assessments of sexual
free T levels and decreased function
SHBG levels

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Modelska and Cummings • Clinical Review J Clin Endocrinol Metab, January 2002, 87(1):16 –23 19

Effects of tibolone on sexual function another placebo-controlled trial with a larger sample size. If
It is believed that tibolone may improve sexual function. tibolone improves sexual function, it will be important to
This is plausible because T has been shown to increase libido determine whether it does so by increasing free T in women
and frequency of sexual activities (26, 27), and tibolone has with very low T concentrations or in all women regardless
androgenic activity (4). Specifically, as noted earlier, the ⌬4- of androgen levels.
isomer of tibolone stimulates AR. In addition, tibolone may
act indirectly to decrease SHBG concentrations and thereby Tibolone and its effects on vaginal bleeding
increase the availability of T. Postmenopausal women have, and endometrium
on the average, 30% lower circulating T levels than those
measured in premenopausal women (26, 27). In one recent In the endometrium, tibolone is transformed into the ⌬4-
trial, Dören and colleagues (14) found that women treated isomer by 3␤-hydroxysteroid dehydrogenase isomerase.
with tibolone had higher free T levels and lower SHBG levels This metabolite does not have estrogenic activity, but does
than women treated with E2/NETA. However, sexual func- have intrinsic progestagenic activity; therefore, it does not
tion was not assessed in this trial. stimulate the endometrial tissue (4, 5). Thus, therapy with
Two randomized and double-blind trials assessed the ef- tibolone may not require the addition of progestagen to
fects of tibolone on sexual function compared with placebo protect the endometrium (16).
(10, 28). In the first trial by Nevinny-Stickel (10), performed Only 1 trial with a total of 94 women has assessed the
almost 20 yr ago, there was no significant improvement in effects of tibolone on vaginal bleeding compared with pla-
regard to libido in women taking tibolone. On the contrary, cebo (Table 2). In this trial, Berning (24) reported that 51% of
the recent double blind and placebo-controlled trial by Laan women taking tibolone and 22% of women taking placebo
(28) has shown that treatment with tibolone significantly had incidences of vaginal bleeding during 96 wk of treat-
improved the physiological aspects of sexual function in ment. He concluded that early postmenopausal women who
postmenopausal women, such as vaginal blood flow and took tibolone were 2–2.5 times more likely to sustain vaginal
vaginal lubrication, and subjective measures, such as sexual bleeding compared with women taking placebo. In this trial
desire and arousability, but there was no difference in the endometrial morphology assessed by curettage showed no
frequency of sexual intercourse, nonpenetrative sexual ac- evidence of endometrial stimulation in women with bleed-
tivity, or initiation and rejection of sexual activity between ing. However, hysteroscopy was not performed in the pa-
women who were taking tibolone vs. those receiving placebo tients who bled, and therefore precise information about
(28). However, the small sample size in the subgroups may intrauterine abnormalities could not be collected. Berning
have diminished the power to detect statistical differences also investigated the relationship among E2 levels, endome-
between these variables. trial morphology, and vaginal bleeding among his study
In two other trials, tibolone was compared with the com- subjects. Interestingly, there was no relationship between E2
bination of E2/NETA (13, 14). In the first trial by Nathorst- levels and the occurrence of bleeding in women who were
Böös (13), the improvement of sexual function with regard to taking tibolone.
frequency, satisfaction, and enjoyment was measured in Two other trials have compared the effects of tibolone with
women taking tibolone vs. those taking E2/NETA. However, those of E2/NETA on vaginal bleeding (15, 29) (Table 2). The
almost 30% of the subjects dropped out, and the reasons for results showed that the combination of E2/NETA caused
discontinuation were not reported. In the second trial by approximately twice as many episodes of bleeding as tibo-
Dören (14), tibolone decreased SHBG and increased free T, lone. Women who bled while taking tibolone were younger
as mentioned previously. The problem with the interpreta- at menopause or were recently menopausal and therefore
tion of both trials by Nathorst-Böös and Dören was that E2 may have had higher remaining endogenous estrogen pro-
increases SHBG levels and there were no placebo-control duction than women who did not bleed. For this reason,
groups used. tibolone is currently recommended only for women who are
Thus, although Laan and colleagues (28) have shown that at least 1 yr postmenopausal.
tibolone increased sexual interest and desire in postmeno- In summary, treatment with tibolone caused significantly
pausal women compared with the effects of placebo, tibo- more vaginal bleeding than placebo, but about half as much
lone’s ability to increase sexual activity among postmeno- vaginal bleeding as E2/NETA. The endometrial effects of
pausal women remains unclear and needs to be answered by tibolone need to be assessed in larger trials.

TABLE 2. Tibolone and vaginal bleeding

Ref. Study design N [age (yr)] Duration (wk) Vaginal bleeding

Tibolone vs. placebo
Berning, 2000, Random, double-blind 94 (⬎50) 96 51% participants on tibolone; 22% participants
Maturitas on placebo (P ⬍ 0.05)
Tibolone vs. E2/NETA
Hammar, 1998, Random, double-blind 195 (⬎53) 48 34% participants on tibolone; 58% participants
Br J Obstet Gynaecol on E2/NETA (P ⬍ 0.0001)
Winkler, 2000, Random, double-blind 60 (45–70) 24 25% participants on tibolone; 50% participants
Fertil Steril on E2/NETA

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20 J Clin Endocrinol Metab, January 2002, 87(1):16 –23 Modelska and Cummings • Clinical Review

Tibolone and its effects on lipids (18, 19, 21, 29). Compared with placebo, tibolone caused
In postmenopausal women, there is typically an increase increases in hemoglobin, antithrombin III, plasminogen, and
in total cholesterol and triglycerides, mostly due to an in- platelet count (18, 19, 30). However, the number of serum
crease in low density lipoprotein cholesterol (LDL-C), parameters measured in these trials was limited. Therefore,
whereas high density lipoprotein cholesterol (HDL-C) re- the clinical implication of the effects on lipid metabolism and
mains unchanged. Seven trials assessed the effects of tibolone hemostasis, as reported in these trials, is not clear. Definite
on lipids and the clotting factors compared with those of conclusions with regard to risks for cardiovascular disease or
placebo, and two other trials assessed these effects compared venous thromboembolism cannot be drawn from these trials.
with those of E2/NETA (Table 3). Compared with placebo,
Tibolone and osteoporosis
tibolone reduced HDL-C by approximately 34% (11, 21, 22)
and decreased triglycerides by approximately 25%, but had Postmenopausal bone loss results from an increase in bone
no effect on LDL-C and lipoprotein(a) (9, 17, 20, 21). These resorption after menopause. Tibolone’s action on bone is
effects distinguish tibolone from estrogens, which decrease mediated via stimulation of ER (4, 23, 25, 31, 32). Six trials
LDL-C and lipoprotein(a) and increase HDL-C. The reduc- have assessed the effects of tibolone on bone mass in post-
tion in HDL-C by tibolone may be due to an androgenic effect menopausal women vs. placebo (23, 25, 31, 33–35), and one
of the compound ⌬4-isomer on hepatic lipase. trial evaluated the effects of tibolone vs. estrogens (36) (Table
The androgenic effects of tibolone caused a decrease in 4). In early postmenopausal women who took tibolone vs.
SHBG concentrations and an increase in fibrinolytic activities placebo, a 15% net increase in lumbar BMD was measured

TABLE 3. Tibolone and lipid metabolism

Ref. Study design N [age (yr)] Duration (wk) Lipids Clotting

Tibolone vs. placebo
Walker, 1985, Random, 27 (38 – 67) 12 34% decrease in Tibolone: increase in Hb,
Thromb Haemost double-blind HDL-C; no effect antithrombin III and
on LDL-C plasminogen
Bedenek-Jaszman, 1987, Random, 60 (44 – 61) 52 35% decrease in Not determined
Maturitas double-blind HDL-C; 40%
decrease in
triglycerides; no
change in total
cholesterol
Genazzani, 1987, Random, 30 (36 –59) 24 11% decrease in Not determined
Maturitas double-blind HDL-C; 14%
decrease in
triglycerides; no
effects on LDL-C
Cortes-Prieto, 1987, Br J Random, 60 (47–55) 12 Not determined Tibolone: significant increase
Obstet Gynaecol double-blind in plasminogen,
antithrombin III, Hb, Htc,
and platelet count;
increase in fibriolytic
activity
Parkin, 1987, Random, 98 (mean age, 50) 104 Not determined Tibolone: significant increase
Maturitas double-blind in antithrombin III
Bjarnason, 1997, Random, 91 (mean age, 66) 104 30% decrease in Tibolone: significant increase
J Clin Endocrinol Metab double-blind HDL-C; 15% in plasminogen; no
decrease in total changes in antithrombin
cholesterol and III
triglycerides
Lloyd, 2000, Random, 30 (mean age, 60) 24 22% decrease in Nonsignificant reduction in
J Hum Hypertens double-blind HDL-C; 33% fibrinogen levels
decrease in
triglycerides; no
effect on LDL-C
and Lp(a)
Tibolone vs. E2/NETA
Dören, 2000, Random, 100 (mean age, 56) 48 Tibolone group: 17% Tibolone: no change in
Am J Obstet Gynecol double-blind decrease in HDL- vascular resistance in
C; 16% decrease uterine arteries as
in triglycerides; measured by Doppler USG
no change in
LDL-C and Lp(a)
Windler, 2000, Random, 60 (mean age, 54) 24 Not determined Tibolone: significant increase
Fertil Steril double-blind in aPTT, plasminogen and
PAP complexes; reduced
protein S activity

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Modelska and Cummings • Clinical Review J Clin Endocrinol Metab, January 2002, 87(1):16 –23 21

TABLE 4. Tibolone and osteoporosis

Duration Net change in BMD (tibolone

Ref. Study design N [age (yr)] Bone markers
(wk) group vs. placebo)
Tibolone vs. placebo
Lindsay, 1980, Random, double-blind 63 (50) 96 No significant changes in Tibolone: 54% reduction
Br Med J metacarpal bone mineral in urinary calcium
content (photon creatine; 11%
absorptiometry) reduction in
hydroxyproline
creatine
Geusens, 1991, Random, double-blind 38 (68) 96 Net increase of 12% in No changes in serum or
Maturitas lumbar spine BMD urinary calcium,
(photon absorptiometry) serum alkaline
phosphatase, or
hydroxyproline
creatine
Bjarnason, 1997, Random, double-blind 91 (68) 104 Net increase of
J Clin Endocrinol Metab approximately 5% in
lumbar spine BMD
(DXA); net increase of
approximately 4% in
forearm BMD (photon
absorptiometry)
Bjarnason, 1996, Random, double-blind Approximately 30%
Bone reduction of
osteocalcin;
approximately 60%
reduction of urinary
creatine
Bering, 1996, Random, double-blind 94 (52) 96 Net increase of Not done
Bone approximately 15% in
lumbar spine BMD (CT),
net increase of
approximately 7% in
phalanx BMD
(radiographic absorption
absorptiometry)
Gallagher, 2001, Random, double-blind 519 (52) 96 In the group with 2.5 mg Tibolone: approximately
J Clin Endocrinol Metab tibolone/day: net increase 50% reduction in N-
of approximately 2.6% in telopeptides of bone
lumbar spine BMD; net collagen; 25%
increase of reduction in
approximately 2.3% in osteocalcin; 20%
total hip BMD: net reduction in serum
increase of alkaline phosphatase
approximately less than
1% in femoral neck BMD
(DXA)
Tibolone vs. estrogens
Netelenbos, 1991, Random, double-blind 21 (56) 8 Not done Decreases in urinary
Maturitas hydroxyproline
creatine and calcium
creatine; in contrast to
E2, tibolone did not
reduce serum calcium
levels

with computed tomography (23) and an approximately 3% ever, these trials are small, relatively short in duration (2 yr),
net increase in lumbar BMD was measured with dual-energy and provide no data about the effects of tibolone on fracture
x-ray absorptiometry (DXA) (35). In late postmenopausal risk. Therefore, long-term trials assessing fracture reduction
women, tibolone suppressed bone turnover and prevented with tibolone vs. placebo are required to determine the role of
bone loss, mainly at the lumbar spine, in two trials compared tibolone in the management of postmenopausal osteoporosis.
with placebo (25, 34). Specifically, women with established
osteoporosis who were treated with tibolone had a 12% net
Tibolone and breast cancer
increase in lumbar BMD vs. placebo, measured with dual
photon absorptiometry over 2 yr (34) and a 5% net increase The effect of tibolone on the breast cells has been studied
in lumbar BMD measured with DXA over 2 yr (25). extensively (4, 37– 41). In particular, two studies have shown
In summary, tibolone decreases bone turnover and sig- the effects of tibolone on the hormone-dependent human
nificantly improves BMD, especially trabecular BMD. How- breast cancer cells (37, 39). Chetrite (41) found that the 3␣-

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22 J Clin Endocrinol Metab, January 2002, 87(1):16 –23 Modelska and Cummings • Clinical Review

OH-metabolites of tibolone are strong inhibitors of sulfatase women. It was confirmed that tibolone increases BMD, es-
activity and weak inhibitors of 17␤-hydroxysteroid dehy- pecially in women with established osteoporosis. Tibolone
drogenase activity; therefore, they inhibit the formation of also may have beneficial, androgenic effects on sexual func-
active estrogens in the breast. Gompel (37) found that tibo- tion. However, there have been no placebo-controlled trials
lone has antiproliferative and proapoptotic activities in conducted to determine whether tibolone would improve
breast cancer cells. Thus, in breast cells, tibolone slows down sexual function in postmenopausal women and, if so,
the proliferation rate as well as increases differentiation and whether the effect depends on baseline T levels.
apoptosis. This has led to the view that tibolone might reduce Therefore, we can conclude that tibolone significantly re-
breast cancer risk. duces hot flushes and sweating and increases BMD in post-
One small RCT evaluated the effect of tibolone on mam- menopausal women. Other effects of tibolone in postmeno-
mographic density (42), whereas another assessed the effect pausal women, such as its influence on lipid metabolism,
of tibolone on breast tenderness (15). Colacurci showed that hemostasis, and sexual function, are less certain. In addition,
1 yr of tibolone treatment did not affect breast density in the long-term effects of tibolone, particularly in reducing
postmenopausal women with normal breast tissue com- fractures, breast cancer, and cardiovascular disease are still
pared with a control group and a hormonal replacement unknown.
therapy group (42). However, this trial was very small (n ⫽
44) and may have missed clinically important effects. Ham- Acknowledgments
mar (15) reported that postmenopausal women taking tibo-
lone experienced breast tenderness significantly less fre- We thank Esther Yeung for providing hard copies of the publications,
and Michaela Rahorst for editing the manuscript.
quently than those who were taking E2/NETA, but there was
no placebo control. Tibolone should be tested in large trials Received June 11, 2001. Accepted September 24, 2001.
for its effect in reducing the risk of breast cancer. Address all correspondence and requests for reprints to: Katharina
Modelska, M.D., University of California, 74 New Montgomery Street,
Adverse effects of tibolone Suite 600, San Francisco, California 94105. E-mail: kmodelska@psg.
ucsf.edu.
The adverse effects of tibolone have not been addressed in
placebo-controlled trials. Drop-out rates due to adverse ef- References
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ported adverse effects. However, these trials used estrogen 2. Kimmig R, Hillemanns H 2000 Tibolon: eine Alternative zur Oestrogensub-
as a comparison, which made it impossible to determine the stitution? Gynaekologe 33:408 – 415
3. Moore RA 1999 Livial: a review of clinical studies Br J Obstet Gynaecol
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against placebo should comprehensively report adverse 4. Kloosterboer HJ 2001 Tibolone: a steroid with a tissue-specific mode of action.
events in tibolone and placebo groups. Steroid Biochem Mol Biol 76:231–238
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ysteroid dehydrogenase/isomerase can locally reduce intrinsic estrogenic/
Limitation of this review progestagenic activity ratios of a steroidal drug (Org OD 14). J Steroid Biochem
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