Tibolone: a review

doi:10.1016/S0378-5122(98)00059-0

Maturitas

Volume 30, Issue 3, 16 November 1998, Pages 295-305

https://doi.org/10.1016/S0378-5122(98)00059-0 Get rights and content

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.

Introduction

For a long time estrogens have been prescribed with the recommendation to begin at the time of menopause. This recommendation was aimed not 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 cost-effective [2]. Older women are very sensitive to 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.

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.

Section snippets

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, 7, 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

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].

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

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

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, 35, 36, 37, 38, 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

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].

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].

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,

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

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The effect of tibolone treatment on lipid profile in women: A systematic review and dose-response meta-analysis of randomized controlled trials
2021, Pharmacological Research
Citation Excerpt :
One HRT agent is tibolone, a synthetic steroid with progestogenic, estrogenic, and androgenic activity depending on the target tissue [2]. It is used in the treatment of postmenopausal osteoporosis, endometriosis, and in menopausal hormone therapy [3]. Following oral intake, tibolone is processed into three active metabolites, two responsible for its estrogenic effects (3-β-hydroxytibolone and 3-α-hydroxytibolone) and one for its androgenic and progestogenic actions (Δ-4-tibolone) [4].
Inconsistencies exist with regard to influence of tibolone treatment on the lipid profile. The reasons for these inconsistencies might derive from several factors, i.e., differences in baseline variables, intervention duration, participants’ health status or baseline body mass index (BMI). To address these inconsistencies, based on a systematic search in Scopus, PubMed/Medline, Web of Science, and Embase for papers published until 21 December 2020, we conducted the current dose-response meta-analysis of randomized controlled trials (RCTs) to determine the impact of tibolone treatment on the lipid profile. The overall findings were derived from 26 RCTs. Tibolone administration decreased total cholesterol (TC) (weighted mean difference, WMD: −18.55 mg/dL, CI: −25.95 to −11.16, P < 0.001), high-density lipoprotein-cholesterol (HDL-C) (WMD: −9.42 mg/dL, CI: −11.83 to −7.01, P < 0.001) and triglyceride (TG) (WMD: −21.43 mg/dL, CI: −27.15 to −15.70, P < 0.001) levels. A significant reduction in LDL-C occurred when tibolone was prescribed for ≤ 26 weeks (WMD: −7.64 mg/dL, 95% CI: −14.58 to −0.70, P = 0.031) versus > 26 weeks (WMD: −8.84 mg/dL, 95% CI: −29.98, 12.29, P = 0.412). The decrease in TG (WMD: −22.64 mg/dL) and TC (−18.55 mg/dL) concentrations was more pronounced in patients with BMI ≥ 25 kg/m² versus BMI < 25 kg/m². This systematic review and meta-analysis discovered that tibolone decreases TC, HDL-C and TG levels. LDL-C concentrations are significantly reduced when tibolone administration lasts for ≤ 26 weeks.
Neuroactive steroids, neurosteroidogenesis and sex
2019, Progress in Neurobiology
Citation Excerpt :
The presence of tibolone hydroxymetabolites in the brain of these monkeys may explain the effect of tibolone on cerebral functions as associated with mood and libido. On the other hand, the activity of tibolone metabolites depends on the enzymes sulfatases and sulfotransferases present in the various tissues, since sulfation interferes with the interaction of steroids with nuclear receptors (Albertazzi et al., 1998; Berning et al., 2001; Colombo et al., 2008; de Gooyer et al., 2001). In this same way, the sulfotransferase activity promotes estrogenic stimulation in tissues (de Gooyer et al., 2001).
The nervous system is a target and a source of steroids. Neuroactive steroids are steroids that target neurons and glial cells. They include hormonal steroids originated in the peripheral glands, steroids locally synthesized by the neurons and glial cells (neurosteroids) and synthetic steroids, some of them used in clinical practice. Here we review the mechanisms of synthesis, metabolism and action of neuroactive steroids, including the role of epigenetic modifications and the mitochondria in their sex specific actions. We examine sex differences in neuroactive steroid levels under physiological conditions and their role in the establishment of sex dimorphic structures in the nervous system and sex differences in its function. In addition, particular attention is paid to neuroactive steroids under pathological conditions, analyzing how pathology alters their levels and their role as neuroprotective factors, considering the influence of sex in both cases.
Effects of tibolone on fibrinogen and antithrombin III: A systematic review and meta-analysis of controlled trials
2017, Pharmacological Research
Tibolone is a synthetic steroid with estrogenic, androgenic and progestogenic activity, but the evidence regarding its effects on fibrinogen and antithrombin III (ATIII) has not been conclusive. We assessed the impact of tibolone on fibrinogen and ATIII through a systematic review and meta-analysis of available randomized controlled trials (RCTs). The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2016) to identify controlled clinical studies investigating the effects of oral tibolone treatment on fibrinogen and ATIII. Overall, the impact of tibolone on plasma fibrinogen concentrations was reported in 10 trials comprising 11 treatment arms. Meta-analysis did not suggest a significant reduction of fibrinogen levels following treatment with tibolone (WMD: −5.38%, 95% CI: −11.92, +1.16, p = 0.107). This result was robust in the sensitivity analysis and not influenced after omitting each of the included studies from meta-analysis. When the studies were categorized according to the duration of treatment, there was no effect in the subsets of trials lasting either <12 months (WMD: −7.64%, 95% CI: −16.58, +1.29, p = 0.094) or ≥12 months (WMD: −0.62%, 95% CI: −8.40, +7.17, p = 0.876). With regard to ATIII, there was no change following treatment with tibolone (WMD: +0.74%, 95% CI: −1.44, +2.93, p = 0.505) and this effect was robust in sensitivity analysis. There was no differential effect of tibolone on plasma ATIII concentrations in trials with either <12 months (WMD: +2.26%, 95% CI: −3.14, +7.66, p = 0.411) or ≥ 12 months (WMD: +0.06%, 95% CI: −1.16, +1.28, p = 0.926) duration. Consistent with the results of subgroup analysis, meta-regression did not suggest any significant association between the changes in plasma concentrations of fibrinogen (slope: +0.40; 95% CI: −0.39, +1.19; p = 0.317) and ATIII (slope: −0.17; 95% CI: −0.54, +0.20; p = 0.374) with duration of treatment. In conclusion, meta-analysis did not suggest a significant reduction of fibrinogen and ATIII levels following treatment with tibolone.
Tibolone decreases Lipoprotein(a) levels in postmenopausal women: A systematic review and meta-analysis of 12 studies with 1009 patients
2015, Atherosclerosis
Circulating lipoprotein (a) (Lp(a)) is a recognized risk factor for cardiovascular disease (CVD). Tibolone, a synthetic steroid, may lower Lp(a) levels; however, evidence of the effects of tibolone on Lp(a) still remain to be defined. Therefore, we investigated the effects of tibolone treatment on circulating Lp(a) levels in postmenopausal women.
The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2015) to identify controlled clinical studies investigating the effects of oral tibolone treatment on Lp(a) levels in postmenopausal women. Random-effects meta-regression was performed using unrestricted maximum likelihood method for the association between calculated weighted mean difference (WMD) and potential moderators.
Meta-analysis of data from 12 trials (16 treatment arms) suggested a significant reduction of Lp(a) levels following tibolone treatment (WMD: −25.28%, 95% confidence interval [CI]: −36.50, −14.06; p < 0.001). This result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. When the studies were categorized according to the tibolone dose, there were consistent significant reductions of Lp(a) in the subsets of studies with doses <2.5 mg/day (WMD: −17.00%, 95%CI: −30.22, −3.77; p < 0.012) and 2.5 mg/day (WMD: −29.18%, 95%CI: −45.02, −13.33; p < 0.001). Likewise, there were similar reductions in the subsets of trials with follow-up either <24 months (WMD: −26.79%, 95%CI: −38.40, −15.17; p < 0.001) or ≥24 months (WMD: −23.10%, 95%CI: −40.17, −6.03; p = 0.008).
This meta-analysis shows that oral tibolone treatment significantly lowers circulating Lp(a) levels in postmenopausal women. Further studies are warranted to explore the mechanism of this effect and the potential value and place of tibolone or its analogues in the treatment of elevated Lp(a) in individuals at risk of CVD.
Neuroprotection by Exogenous Estrogenic Compounds Following Traumatic Brain Injury
2015, Estrogen Effects on Traumatic Brain Injury: Mechanisms of Neuroprotection and Repair
Traumatic brain injury (TBI) is the leading cause of death and disability in young and adult people. Since TBI is a lesion characterized by its heterogeneity and complexity, many clinical and pharmacological approaches have been unsuccessful. The current understanding of the physiopathology of TBI indicates that it is imperative to focus on a multifactorial therapy. Endogenous hormones have pleiotropic neuroprotective effects that can be used for a therapeutic approach in TBI. However, these neurosteroids have secondary effects depending on the target tissue. In this concern, the development of more specific estrogenic-progestogenic-androgenic like compounds and the advances in elucidating their protective role in TBI has led to the use of SERMs and STEARs. In vitro and in vivo models have shown promising results in elucidating the role of neurosteroids and how they may be considered as a potential therapy aimed at improving the outcome in TBI.
Application of UPLC-MS/MS for separation and quantification of 3α-Hydroxy Tibolone and comparative bioavailability of two Tibolone formulations in healthy volunteers
2013, Journal of Pharmaceutical Analysis
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Tibolone substitutes for the loss of estrogen production in post-menopausal women and alleviates menopausal symptoms [1,2].
A novel, fast, sensitive and robust method based on ultra-performance liquid chromatography coupled to atmospheric pressure electrospray ionization tandem mass spectrometry (UPLC–ESI-MS/MS) has been developed to separate two Tibolone stereoisomers i.e., 3α-Hydroxy Tibolone and 3β-Hydroxy Tibolone and to quantify 3α-Hydroxy Tibolone using p-toulenesulfonyl isocyanate (PTSI) as a derivatizing reagent in human plasma. 3α-Hydroxy Tibolone-¹³CD₃ was used as an internal standard (IS). The analyte and IS were extracted from human plasma by liquid–liquid extraction using ethyl acetate. Extracted samples were analyzed by UPLC–ESI-MS/MS. Chromatography was performed using binary gradient on UPLC analytical column. A linear calibration curve over the range of 0.100–35.000 ng/mL was obtained and lower limit of quantification (LLOQ) was 0.100 ng/mL demonstrating acceptable accuracy and precision. This method was successfully applied to a pharmacokinetic study in order to compare a test Tibolone 2.5 mg formulation vs. a reference 2.5 mg Tibolone tablet formulation in 50 post-menopausal/surgical menopause female human volunteers under fasting conditions. It is concluded that test formulation of Tibolone is bioequivalent to reference formulation of Tibolone.

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Tibolone: a review

Abstract

Introduction

Section snippets

Hot flushes

Effect on the uterus

Effect on the breast

Compliance

Lipid profile effect

Blood clotting

Effects on bone

Conclusions

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Lancet

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