Tibolone: a review

Maturitas 30 (1998) 295 – 305

Tibolone: a review Paola Albertazzi *, Raffaele Di Micco, Ettore Zanardi Centro di Fisiopatologia della Menopausa, Ospedale Maggiore Sezione D’Azeglio (Ospedale Maternita`), Via d’Azeglio 56, 40123 Bologna, Italy Received 24 February 1998; received in revised form 17 June 1998; accepted 6 July 1998

Abstract Tibolone appears to be at least as efficacious as other forms of hormonal replacement therapy (HRT) on climacteric symptoms. It does not cause withdrawal bleeding when used in women with at least 1 year of amenorrhea. It is, therefore, not indicated in perimenopause because it may cause irregular bleeding. The androgenic action of tibolone may have a two-fold benefit: on the one hand, it may help depression and libido more than other forms of HRT, while, on the other hand, it may improve some lipid parameters such as Lp(a), and triglycerides. However, this androgenic action, may also be responsible for the reduction of HDL cholesterol, that may thus reduce the beneficial effect of tibolone on lipids. It is estimated that only 30% of cardiovascular risk protection of HRT is due to improvement of classical lipids parameters while a great role is played by the direct effect of estrogen on vessels. Tibolone, as well as estrogen, has been shown to induce peripheral vasodilatation and also has a direct effect on vascular reactivity thus increasing peripheral blood flow with no changes in blood pressure or cardiac output. Tibolone seems to exert a similar effect as other forms of HRT on markers of bone metabolism and bone mass, but no data is yet available on fracture prevention. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Tibolone; Livial; Osteoporosis; Lipids; Climacteric symptoms

1. Introduction For a long time estrogens have been prescribed with the recommendation to begin at the time of menopause. This recommendation was aimed not

* Corresponding author. Tel.: +39 51 582158; fax +39 51 584346.

only at climacteric symptoms relief but above all at osteoporosis prevention. However, recent evidence has suggested that estrogen begun after age 60 and continued later in life appears to be equally effective in preventing osteoporotic fractures [1]. Moreover, concern about breast cancer and other possible risks associated with long term estrogen use contributed to the idea that starting treatment later in life would be particularly costeffective [2]. Older women are very sensitive to

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P. Albertazzi et al. / Maturitas 30 (1998) 295–305

side effect of hormonal replacement therapy (HRT) such as breast tenderness and do not tolerate well monthly bleeding. Very recently many efforts have been placed in researching the ideal combination of low dose estrogen and progestogens that could exert a bone sparing effect and improve genitourinary atrophy without producing withdrawal bleeding [3]. Tibolone has an interesting combination of both week estrogenic and progestogenic action. In this paper we have reviewed the evidence on the efficacy of tibolone on both osteoporosis and cardiovascular disease prevention as well as its effects on mood, sexuality and genito-urinary system. Tibolone has been on the market for many years, and now it could prove to be particularly suitable for the growing population of women in the older age group requiring HRT.

1.1. General information and pharmacology Tibolone ((7(),17()-17-hydroxy-7methil-19norpregn-5 (10)-en-20yn-3-one) (Livial-Organon) is a synthetic steroid structurally related to norethynodrel. Tibolone possesses weak estrogenic, progestational and androgenic properties. Comparative animal studies have demonstrated that the estrogenic potency of tibolone is about 1/50 that of ethinyl estradiol, its progestogenic potency is 1/8 that of norethisterone [4]. The dose, a single 2.5 mg tablet daily need not be accompanied by progestagen so that restoration of period does not occur. An oral dose of the drug is rapidly absorbed, appearing in the plasma within 30 min and peaking in 4 h. Metabolism is mainly in the liver and excretion occurs in the urine and faeces. The elimination half-life is about 45 h [5]. In the product monograph the manufacturer states that tibolone is indicated in women ‘who are at least 1 year after the menopause’ when endogenous estrogen effects have subsided and treatment is less likely to be complicated by bleeding. To minimise irregular bleedings, the data sheet also recommends to add progestin for 10 days at least every 3 months of treatment if the patient has recently switched from a different form of HRT.

2. Effects of tibolone on climacteric symptoms

2.1. Hot flushes Tibolone has been shown to be significantly more effective than placebo in reducing hot flushes and sweating in randomised, double-blind, placebo-controlled non cross-over [6–8] and cross over studies [9,10] which lasted from 6 weeks to over 2 years. In other randomised, double-blind, cross-over [11] and non cross-over [12] studies which compared tibolone with other forms of HRT using self-scoring measures, tibolone was found to be as clinically effective in controlling vasomotor symptoms as a daily dose of 2 mg estradiol valerate [11,12] or 0.625 mg of conjugated estrogen [12]. Questionably, in some of these studies, the method by which symptoms are measured is not given [7] whilst in others, non-standardised measures were used. Features that rose doubts about the validity and reliability of results (see Table 1) [13].

2.2. Other climacteric symptoms 2.2.1. Headache Headache was found to be reduced by tibolone when compared to placebo in three studies [6,9,10]. Its effect were similar to that of conjugated estrogen but better than that of estradiol valerate [12]. Tibolone did not seem to affect headache in one study [7]. 2.2.2. Insomnia Insomnia appeared to improved by tibolone in five studies as compared to placebo [6,9–12]. One study did not show any difference with placebo [7]. 2.2.3. Backache Backache appeared reduced with tibolone in three studies [11,12,14] but tibolone had no effect over placebo in two further studies [9,10]. Two studies showed similar beneficial effects of tibolone, estradiol valerate and conjugated estrogens on this symptom [11,12]. De Aloysio et al. did not find any effect of tibolone on arthralgia [7].

P. Albertazzi et al. / Maturitas 30 (1998) 295–305

297

Table 1 Description of some of the studies on climacteric symptoms Number of patients Tibolone vs placebo [6] Tibolone vs placebo and no treatment [7] Tibolone vs placebo [9]

Type of patients

Study design

Problems with study design

60

N/S

Symptoms self scored

168

N/S

Random, double blind, non-cross-over Random, non crossover Random, double blind cross-over Random, double blind, cross-over Random, double blind, cross-over Random, non cross over

82

N

Tibolone vs placebo [10]

35

N

Tibolone vs placebo and estradiol valerate [11] Tibolone vs placebo, E2 and CE [12]

20

N/S

113

N/S

Tibolone vs placebo [14]

60

Not stated

Random, double blind, non cross-over

Tibolone vs placebo [16]

30

N/S

Non cross-over

Tibolone vs CE [17]

44

N/S

Non cross-over

129

N

Randomised

301

N/S

Observational study

Tibolone vs continuous CE+ sequential colprone [15] Tibolone [32]

Not stated how symptoms were measured Symptoms self scored, no washout period Symptoms self scored, no washout period Symptoms scored 0–3, no washout period Symptoms scored 0–3. Blinding and statistical significance not stated. Not stated how symptoms were measured and statistical significance. Symptoms self scored. Randomisation, blinding, and statistical significance not stated Symptoms self scored. Randomisation, blinding, and statistical significance not stated No blinding No control group, no blinding, symptoms self scored.

E2, estradiol valerate; CE, conjugated estrogen; N, natural menopause; S, surgical menopause.

2.2.4. Fatigue Fatigue was significantly reduced as compared to placebo in four studies [6,9 – 11] but the effect of tibolone was similar to placebo and no treatment in one [7]. Crona et al. showed similar beneficial effect of tibolone and estradiol valerate [11]. 2.2.5. Dizziness Dizziness improved with tibolone over placebo in two studies [9,11] but was the same in three studies [6,7,10]. Tibolone was compared with other forms of HRT in two studies: one did not show any difference between tibolone and estradiol valerate [11], while the other found tibolone more effective than continuos combined sequential conjugated estrogens 0.625 mg and progestogens [15].

2.2.6. Palpitations Palpitations were improved by tibolone over placebo [9,14] in two studies, but were not in a further two [7,10]. 2.2.7. Breathlessness This improved over placebo in two studies, [6,11] but did not in three [7,9,10]. 2.2.8. Mood/depression Mood/depression improved over placebo in five studies [6,11,12,16,17] but did not in two orther studies [7,10]. When compared with other forms of HRT, the action of tibolone was found similar to that of estradiol valerate in two studies [12,17] and better than continuos conjugated estrogens 0.625 mg combined with sequential medrogestone in one [15].

NS, not stated.

Berning et al., 1996 [31] Tibolone 2.5 mg Tibolone 1.25 mg Placebo

Rymer et al., 1994 [28] Tibolone 2.5 mg No-treatment

Ginsburg et al., 1996 [29] Tibolone 2.5 mg

Bjarnason et al., 1996 [30] Tibolone 2.5mg Tibolone 1.25 mg Placebo

51.6 92.9 52.99 3.1 51.99 2.5

35 36 23

24

1.9

1 (2.7)

0

5 (12)

45

1.75

52 (11)

1 (5)

4 (11)

7 (20)

9 (19)

49.5 9 4.2

63 911.3

20.0

19.6

17.5

Amenorrhea be- No. of patients fore starting bleeding (%) treatment (years)

46

24

35.29 1.3

68.4

20 434

66.4

36

Average age (years)

65.5

24

Duration of study (months)

35

No. of patients

Table 2 Effects of tibolone on bleeding in long term studies

NS

5

9

27

NS

No. of causes found

NS

2

NS

Endometrial cancer

NS

Fibroids = 7, simple hyperplasia =2

Polip= 11

NS

Others

298 P. Albertazzi et al. / Maturitas 30 (1998) 295–305

39 ¡12

¡2

¡17 ¡8

=

=

¡18

¡28

¡5  14

=

=

¡7

¡14

¡27 ¡17

=

¡26

¡11

¡19

¡21

 15*

HDL2/HDL3 (%)

¡21

 6

¡33  

¡

¡27

 9

 11

 31*

=

TRIG (%)

¡39

¡46

¡43 ¡45

¡

 12

=

¡30*

¡36*

Lp(a) (%)

¡7

¡33 ¡1

=

=

=

 10*

¡18*

Apo A1 (%)

¡1

¡26 ¡11

=

=

=

¡5*

 15*

Apo B (%)

CEE, conjugated estrogens 0.625 mg; PO 2 mg E2, oral estradiol; Dyd10, dydrogesterone 10 mg daily for 14 days; TTS 50 mg E2, transdermal estradiol. Bold indicates statistically significant changes with baseline within-group. * indicates statistical significant changes between-groups.

Farish et al., 1995 [36] Open study no controls

+ norgestrel No-treat50 ment 6

24

Milner et al., 1996 [34] Tibolone CEE 32 31

6

11

¡5

 3

35 3

¡3

¡7

=

35 ¡2

¡13*

 7*

¡3

35

 7

LDL (%)

¡26*

HDL (%)

=

Total CHOL (%)

35

24

Duration (months)

Rosati et al., 1997 [39] Tibolone vs 8 no-treatment

Cagnacci et al., 1997 [38] Open study no controls

Hanggi et al., 1997 [37] Tibolone 2.5 mg PO 2 mg E2+Dyd 10 TTS 50 mg E2+Dyd 10 No treatment

No. of patients

Table 3 Effects of tibolone on lipids

P. Albertazzi et al. / Maturitas 30 (1998) 295–305 299

300

P. Albertazzi et al. / Maturitas 30 (1998) 295–305

2.2.9. Libido Androgens are have been reported to improve libido in women [18]. Tibolone has a mild androgenic effect, it is therefore conceivable it has a favourable effect on this symptom. There are two studies that found libido improved by tibolone versus placebo [9] and no treatment [19], although another study reported no effect [10]. Four studies compared tibolone with other forms of HRT on libido. Tibolone was found to be better than conjugated estrogens 0.625 mg continuously and sequential medrogestone in 129 women [15]. Volpe et al. [12] did not find it any more effective than conjugated oral estrogen and Crona et al. [11] found the effects of tibolone similar to estradiol valerate on libido. One further study compared tibolone with continuous estradiol –norethisterone on 437 postmenopausal women. Both treatments improved sexual life, however, tibolone was found superior to the other preparation especially with respect to the frequency of sexual activity satisfaction and enjoyment [20]. 2.2.10. Effect on the 6agina Vaginal dryness was improved over placebo [21] and no treatment [19] and tibolone was found to be as effective as conjugated estrogens in restoring/maintaining a healthy vaginal environment [12]. These effects are present despite the fact that the mixed hormonal profile of tibolone does not stimulate the endometrium demonstrating a tissue specific effects of this compound.

3. Effect on the uterus The endometrium was not stimulated despite of the estrogenic effect of tibolone on the central nervous system, bone and vaginal epithelium [22,23]. Genazzani et al. [22] in a review of six studies on the effect of tibolone on 168 women treated up to 2 years showed no change during treatment in the endometrial histology of 90% of patients. Fifteen patients (8.9%) showed a slight proliferative endometrial pattern. This picture was similar to that of untreated normal postmenopausal patients [22].

Von Dadelszen et al. [24] reported three cases of endometrial carcinoma, one case of atypical hyperplasia and two cases of simple hyperplasia on patients taking tibolone for an average of 12.3 months (range 7–18). These were the only six cases known to have occurred in an estimated population of 1732 women taking tibolone in the UK at the time. Tibolone thus shows to be extremely safe and, in fact, to reduce the risk of endometrial cancer since 16 cases of endometrial carcinoma were expected if tibolone was just neutral over the development of this tumour [24].

3.0.1. Endometrial thickness This did not increase over 6 months of treatment with tibolone while continuos conjugated estrogen (0.625 mg) combined with sequential medrogestone increase it significantly [15]. No increase of endometrial thickness was also found after 6 months treatment with either tibolone or 0.625 mg of conjugated estrogen given vaginally [25]. 3.0.2. Fibroids Fibroids did not increase in 20 women after 6 months treatment with tibolone over 20 untreated controls [26]. This is in keeping with the evidence that progestogen rather than estrogen affects fibroid size and particularly important seems to be the progestogen dose [27]. Tibolone has a weak progestogenic action, one, therefore, should not expect it would have any influence on fibroids. 3.0.3. Bleeding This occurs in 11–20% of the patients (Table 2) [28–31] The number of months of amenorrhea before starting treatment was stated by several authors to be inversely related to bleeding while on tibolone [28,29]. However, at least two studies seem to refute this hypothesis. Women participating to the Bjarnason et al. [30] trial had an average of over 15 years of amenorrhea before starting treatment and yet 20% of patients on 2.5 mg tibolone bled similarly to what occurred to the patients of the study by Rymer et al. [28] where women had only an average of 1.7 years of amenorrhea before enrolment. Bjarnason et al. [30] experimented in the same study with a lower dose

1.75

51.8 49.5 94.2

35

 3.1 ¡1.7

 4.0 ¡6.4

52.9 93.1 51.99 2.5

36 23

 5.5

 9.1

RAD

51.6 92.9

CT

BMD phalangeal (%)

35

1.9

¡3.7

¡2.9

45 24

 3.5

 2.5

¡1.6

¡3.4

46

 2.8

=

DEXA

3

 2.8

 2.4

DEXA

24

2

53.0

35

2

52.1

35

 2.8

¡2.1

 0.4

 2

 2.2

 5.9

DEXA

 1.9

 5.1

BMD femoral neck (%)

DEXA

SPA

BMD forearm (%)

DEXA

BMD spine (%)

DEXA, dual-energy X-ray absorbiometry; STA, single photon absorbiometry; Ct, Sigle energy quantitative computerised tomography; RAD, radiographic absorption densitometry.

Berning et al., 1996 [31] Tibolone 2.5 mg Tibolone 1.25 mg Placebo

Rymer et al., 1994 [51] Tibolone 2.5 mg No-treatment

20.0

68.4

3

19.6

66.4

51.8

24

Lippuner et al., 1997 [56] Tibolone 2.5 mg PO 2 mg E2+Dyd 10 TTS 50 mgE2+Dyd 10 No treatment

17.5

Amenorrhea (years)

65.5

Age (years)

35

24

Duration of study (months)

Bjarnason et al., 1996 [30] Tibolone 2.5 35 mg Tibolone 1.25 36 mg Placebo 20

No. of patients

Table 4 Effects of tibolone on bone

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P. Albertazzi et al. / Maturitas 30 (1998) 295–305

of tibolone (1.25 mg) and found that only 11% of women bled on this dose, bleeding seems thus to be dose related. However, Ginsburg and Prelevic [29] in the largest follow up study so far performed (434 patients), report 11% of bleeding with 2.5 mg dose of tibolone. Furthermore, Berning et al. reported only one woman dropping out of the study because of bleeding and she was in the 1.25 mg of tibolone group [31]. On the whole, the majority of patients on tibolone who bled did so in the first 4 – 6 months of treatment [28,29] and in more than half of women (51%) in one study [29] and in all the women in the other [28], no cause could be found. Two endometrial carcinoma in situ were found in women who bled after 1 year of treatment [29] suggesting the need for investigation of all bleeding occurring after 6 – 12 months of treatment.

5. Compliance and side effects

5.1. Compliance Compliance seems to be high in all the studies examined. Ginsburg et al. reported an overwhelming satisfaction with therapy in 301 women started on tibolone with an overall compliance of up to 80% on women followed up to 8 years [32]. It is conceivable, however, that in the majority of the studies the drug was supplied free of charge. No study has so far quantified the effect of the cost of the drug on compliance. In Italy for instance this is roughly three time that of most conventional oral HRT regimen and contrary to other forms of HRT it is not subsidised by the national health system.

5.2. Side effects 4. Effect on the breast Benign breast disease in the form of breast tenderness was a symptom reported in 20% of women taking tibolone 2.5 mg and 17% of women taking tibolone 1.25 mg in one study [30]. In the large Ginsburg study, breast tenderness appeared to be significantly less common and it was reported by only 7.52% of the patients [32]. Moreover, 14 women in this study had breast tenderness during previous treatment with estrogen but only one had the same symptoms after she switched to tibolone. Breast cancer has always been, and still is, an absolute contraindication to HRT. Tibolone is not an exception to this, although it has been reported to inhibits the growth of rat mammary tumour cells [33]. Interestingly, Ginsburg et al. [32] report that 11 women were referred specifically for tibolone treatment after they were treated for breast cancer between 3 months to 14 years earlier. Only one women reported breast tenderness while on therapy and five women, in 1995, at the time of the report were still in tibolone (for 1, 1.5, 2, 3, and 4.5 years). Six out of these 11 women stopped tibolone and only one of them because of carcinoma of the controlateral breast.

In the longest study so far reported [32] only 2.6% of patients (8/301) dropped out because of side effects mainly weight gain and bloating (11%). Acne and increased facial hairs have also been described in 3–6% of patients [30,34].

6. Effects on metabolism and vascular reactivity

6.1. Lipid profile effect The majority of studies have shown a statistically significant reduction of high density lipoproteins (HDL) which are negatively correlated with cardiovascular disease (CVD) risk [7,34–39]. Tibolone also appears to alter HDL composition raising HDL2 compared with the HDL3 subfraction [37,40]. This is believed by some [41] but not by others [42] to be most strongly correlated with coronary artery disease. On the side of CVD risk protection, tibolone seems to strongly reduce [34,36,39] the serum lipoprotein (a) [Lp(a)], probably an effect of its androgenicity [43]. This reduction seems to be more marked even than that obtainable with oral estrogen [35]. Tibolone also appears to either decrease [34–36,38] or leave unchanged [37] triglyceride. This is the opposite of what oral and, to a minor degree, transdermal

P. Albertazzi et al. / Maturitas 30 (1998) 295–305

estrogen do. The effect of tibolone on lipids is summarised in Table 3.

6.2. Glucose metabolism and 6ascular reacti6ity Glucose metabolism was not affected in 11 healthy postmenopausal women [44] or in women with non insulin dependent diabetes (NIDDM) taking tibolone [45]. Furthermore, up to 1994 the development of diabetes was reported only in three patients while three other patients worsened their diabetic control. The reported decrease of glucose tolerance with tibolone is comparable with that observed with another form of HRT [47]. Mean systolic blood pressure, diastolic blood pressure and mean pulse rate did not change over 12 months of treatment [45]. Moreover, tibolone, in NIDDM women had a positive inotropic effects parallel to that of estrogen in healthy post menopausal women. It improved cardiac output, stroke volume, ejection fraction, left ventricular systolic and diastolic flow velocity after 6 months treatment [46].

7. Blood clotting Two studies reported no alteration in blood clotting parameters, in a total of 43 healthy women treated with tibolone for 639 – 2437 months compared with untreated controls. However, there are some evidences of increased levels of plasminogen concentration and, therefore, of fibrinolitic activity in women treated with tibolone [48,49]. This beneficial effects could be connected with the androgenic action of the drug on the levels of Lp(a) [50].

8. Effects on bone Tibolone has been shown to reduce the excretion of markers of bone metabolism and increase bone mass density (BMD) (see Table 4) [30,31,51]. Even in women with established osteoporosi [52], tibolone produced an improvement of BMD, similar to that obtained with estrogen, fluoride or biphosfonates [53].

303

The effect of tibolone on bone mass seems to be dose related. Both 2.5 and 1.25 mg [30,31] improve BMD although 2.5 mg seems twice as effective as the other [31]. The 5 mg dose has also been tried, but it increased the frequency of vaginal bleeding considerably [54], while 1.25 mg are insufficient to control climacteric symptoms [55]. The effect of a 2 year treatment with tibolone 2.5 mg on bone has also been compared and found to be similar to that of estrogen either given orally or transdermally in combination with progestogens [56]. However, while long term estrogen intervention in postmenopasual women is associated with significant reduction in the risk of vertebral, hip and wrist fracture [57], the same data are as yet not available on tibolone.

9. Conclusions Tibolone (Livial) is a synthetic steroid that possesses weak estrogenic, progestogenic, and androgenic action. It has positive effects on several lipid parameters and it seems to exert a similar effect as other forms of HRT on markers of bone metabolism and bone mass. Tibolone is easy to use, the incidence of side effects is low and does not produce monthly withdrawal bleeding. This could prove to be particularly useful when hormonal replacement treatment is started in the older age group: a practice now becoming increasingly common.

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