Pharmacological properties of the drug Tibolone
A drug for the treatment of menopausal syndrome that does not cause regular withdrawal bleeding. Stabilizes the functioning of the hypothalamic-pituitary system during menopause, which is achieved due to the estrogenic, progestogenic and weak androgenic properties of tibolone. Tibolone is rapidly metabolized to form three compounds that provide its pharmacotherapeutic effect. Two metabolites, 3α-OH-tibolone and 3β-OH-tibolone, have predominantly estrogenic activity, and the third, the delta-4 isomer, has progestogenic and weak androgenic activity. After oral administration, tibolone is quickly and completely absorbed. Due to rapid metabolism, tibolone plasma levels are very low. Maximum plasma concentrations of tibolone metabolites are achieved 1–1.5 hours after administration. Excretion of tibolone occurs mainly in the form of metabolites. A small amount is excreted in urine, and most is excreted in bile and feces. The half-life of metabolites is approximately 7 hours without subsequent accumulation.
Hormone replacement therapy (HRT) has become widespread over the past decades, especially abroad. For example, in the USA, about 6 million women currently receive it [1]. This is due to the fact that certain menopausal symptoms occur in more than 75% of postmenopausal women, and in approximately 25% of them they are assessed as severe [2]. Along with the positive effects, HRT is not without a number of disadvantages, so the search for effective and safe alternatives continues. One of them is tibolone, a synthetic steroid with androgenic, progestogenic and estrogenic properties [3]. The drug has been on the global pharmaceutical market for more than two decades and is registered in approximately 70 countries. It was developed specifically for the treatment of osteoporosis, however, due to its unique pharmacological properties, it was soon also registered for the treatment of menopausal syndrome and the prevention of osteoporosis.
The pharmacological effects of tibolone are mainly due to its metabolites, which affect various organs and tissues [4]. Tibolone is a synthetic steroid; when ingested, it is metabolized to form three metabolites: 3alpha-OH-tibolone, 3beta-OH-tibolone and 4sigma isomer, which have different affinities for steroid receptors. In vitro studies
showed that tibolone hydroxymetabolites have a high affinity for estrogen receptors (mainly a-receptors), and the 4-sigma isomer has a high affinity for progesterone receptors and weak affinity for androgen receptors [5]. The concentration of various tibolone metabolites varies in different organs and tissues [4], and therefore the drug exhibits a tissue-selective effect [7]. Tibolone has an estrogenic effect on bone tissue and the vagina. In the endometrium, the gestagenic effect of the 4-sigma isomer is manifested, and in the brain and liver this isomer has androgenic effects. In the mammary gland, tibolone causes potent inhibition of sulfatase and inhibition of 17beta-hydroxysteroid dehydrogenase (type I), which leads to blockade of the conversion of estrone sulfate to estrone and then to estradiol.
By exerting selective hormonal effects on different target organs, tibolone causes various effects in postmenopausal women, which have been studied in more than 20 randomized, controlled, double-blind studies [8].
Due to its unique mechanism of action, tibolone is classified into a separate class of therapy - STEAR (selective tissue estrogenic activity regulator; tissue-selective regulator of estrogenic activity). The official presentation of tibolone as a new class of therapy took place in May 2003 at the Sixth European Congress on Menopause.
Currently, taking into account non-randomized and open studies, as well as clinical trials and retrospective analyses, more than 400 studies have been devoted to the study of tibolone in women [8].
The effect of tibolone on menopausal symptoms and quality of life in postmenopausal women
The effect of tibolone on menopausal symptoms has been studied in at least 8 randomized, double-blind clinical trials, 4 of which were placebo-controlled [9–13]. One study compared tibolone with estradiol valerate [13], another with a combination of conjugated estrogens and medroxprogesterone acetate [14], and two with a combination of estradiol and norethisterone acetate [15,16].
These studies showed that tibolone 2.5 mg was as effective as standard HRT regimens in reducing hot flashes. The drug is also effective in the treatment of hot flashes that develop during therapy with gonadotropin-releasing hormone agonists [17].
Many studies have demonstrated beneficial effects of tibolone on other menopausal symptoms, including fatigue, psychological instability, headaches and insomnia [9,12,14].
In the work of Genazzani et al. It has been shown that reduction of hot flashes during treatment with tibolone is associated with improved sleep and mood [11]. Researchers have suggested that the latter effect is due to beta-endorphins, the concentration of which increases under the influence of tibolone. In a small study of young women with uterus and ovaries removed, tibolone was equally effective as estradiol valerate in reducing hot flashes and improving mood [13].
Due to the presence of estrogenic action, tibolone normalizes the maturation of vaginal cells, reduces dryness and dyspareunia in menopausal women [18,19]. According to a number of studies, it is not inferior to estrogens in eliminating these symptoms. Moreover, prospective randomized studies have shown that the sexuality of women when using tibolone increases to a greater extent than when using estrogens or their combinations with progestins [15,20-24].
Placebo-controlled studies have shown that tibolone increases libido and sexual activity [25]. Under the influence of the drug, sexual fantasies, sexual arousal and orgasm were especially intensified. An open-label, multicenter study of 184 women receiving tibolone for the first time for 4 months demonstrated a significant increase in their satisfaction with various aspects of sexual life [25]. These effects are based on 2 mechanisms: the direct androgenic effect of the 4-sigma isomer and an increase in the circulation of free testosterone. Under the influence of tibolone, the amount of circulating hormone-binding globulin is reduced by approximately 50% [26,27]. As a result, the concentration of total testosterone decreases, but the level of its free active fraction increases significantly. The changes in hormone levels caused by tibolone compare favorably with those caused by estrogen (increased levels of hormone binding globulin and decreased levels of total and free testosterone). The weak androgen-like effect when taking tibolone clinically determines mainly an improvement in the quality of life, in the form of a beneficial effect on mood and improved libido. Some authors even recommend the use of tibolone to enhance sexual desire in women with persistent, despite adequate combined HRT, decreased libido [30]. It is important that tibolone does not cause androgenic side effects, such as acne and hirsutism [3].
Unlike estrogens, tibolone does not have an estrogenic effect on the myometrium; on the contrary, its 4-sigma isomer causes a gestagenic effect. As a result, when using tibolone, there is no stimulation of the endometrium and, accordingly, there is no need for additional administration of gestagen to protect the myometrium [7,28,29].
In comparative studies with a combination of estradiol and norethisterone acetate, the number of episodes of vaginal bleeding in women receiving tibolone was approximately 2 times less than in women receiving combination therapy [31,32]. According to the results of a double-blind multicenter European study, tibolone caused bleeding significantly less frequently than when using combined monophasic therapy (conjugated estrogens with medroxyprogesterone acetate) [23]. In another randomized trial, oral tibolone (2.5 mg/day) was associated with lower bleeding rates than cyclic transdermal combination therapy (17beta-estradiol patch 50 mcg/day for 14 days, then 17beta-estradiol patch 50 mcg/day). day + norethisterone acetate 0.25 mg/day for the next 14 days) [33]. Bleeding caused by tibolone is more often observed in the early postmenopausal period, and therefore the drug is currently recommended for women who have been menopausal for at least 1 year [3].
In general, the weakening of menopausal and urogenital symptoms under the influence of tibolone is associated with an improvement in the quality of life of women [36].
The effect of tibolone on the neuropsychic state and cognitive functions
Tibolone has a moderate positive effect on mood [27,31]. In a small open-label study, long-term use of tibolone (10 years) resulted in a decrease in nervousness in response to mild stress [35]. These data were confirmed in another randomized trial [36].
The effects of the drug on cognitive functions have not been sufficiently studied, which is due to the complexity of conducting such studies, which require matching the main and control groups according to many parameters (intelligence level, age, education, position, mental status, etc.), and the lack of standardized definitions of a number of concepts and standardized methods for their measurement. A small study suggests that when used short-term (3–6 months), tibolone may help preserve cognitive function in postmenopausal women [37]. However, all these data require confirmation in well-designed large studies.
The effect of tibolone on risk factors for cardiovascular diseases
Under the influence of tibolone, changes in blood lipid concentrations occur that differ from traditional HRT (pure estrogens and combined estrogen-progestogen combinations). The effect of tibolone on the lipid profile and coagulation factors was studied in 7 placebo-controlled, double-blind studies and 2 comparative double-blind studies with a combination of estradiol and norethisterone acetate. In short-term studies, tibolone 2.5 mg/day reduced high-density lipoprotein (HDL) cholesterol by approximately 20%, total cholesterol by 10%, and triglycerides by 20%. It also caused little or no effect on low-density lipoprotein (LDL) cholesterol concentrations [25,26,32,38]. In other placebo-controlled studies, the reduction in HDL cholesterol and triglyceride levels was more pronounced under the influence of the drug, but the concentrations of LDL cholesterol and lipoprotein (alpha) were not changed [11,28,29]. In some studies, the decrease in HDL levels under the influence of tibolone was unreliable [40,41].
The reduction in HDL cholesterol with tibolone was associated with an increase in hepatic lipase activity (androgenic effect), but the study showed that the ability of the patients' plasma to release cholesterol from the arterial walls remained unchanged [42]. In a study in monkeys, a significant decrease in HDL cholesterol levels was not accompanied by an exacerbation of iliac artery atherosclerosis, which is associated with a beneficial effect of the drug on vascular function or hepatic metabolism [43].
A randomized clinical trial showed that a significant decrease in HDL levels (by an average of 27%) during treatment with tibolone was due to its effect on only one subclass of HDL, and therefore antiatherogenic functions (reverse cholesterol transport and inhibition of LDL oxidation) remained unchanged [43 ]. The disadvantage of this study is its short duration (12 weeks), but the results obtained are completely consistent with data from 2-year experimental studies on monkeys. They were confirmed in another randomized, placebo-controlled study that lasted 3 months [44].
The potential adverse effects associated with lowering HDL cholesterol are counterbalanced by tibolone's effects on endothelin and lipoprotein (alpha), anti-ischemic effects found in women with angina, and increased insulin sensitivity [45–49]. In long-term studies, HDL cholesterol levels returned to baseline after 3 years of treatment with this drug [46–49]. Recently, tibolone has been shown to reduce thromboxane B2 concentrations, which may lead to improved prostaglandin metabolism and reduce the risk of cardiovascular disease [50].
Unlike estrogens, tibolone does not have a pronounced effect on increasing blood clotting, but stimulates fibrinolytic activity. Placebo-controlled studies have shown that long-term use of tibolone leads to increased levels of hemoglobin, antithrombin III, plasminogen and platelet count [51,52]. A multicenter, randomized, double-blind study failed to reveal a significant effect of the drug on blood clotting [32].
According to the researchers, the clinical significance of tibolone's effects on lipid metabolism and hemostasis remains unclear and requires further study.
When treated with tibolone, a 3-4-fold increase in C-reactive protein levels was observed, which is comparable to that with standard HRT [53]. However, the significance of changes in C-reactive protein levels for the clinical manifestations of cardiovascular diseases in menopausal women remains unclear [8]. Tibolone does not affect levels of homocysteine, another substance associated with the risk of coronary disease [54].
Tibolone reduces the level of free fatty acids in the blood plasma, which leads to normalization of the ratio of sympathetic and parasympathetic effects on the heart and, according to researchers, can help prevent myocardial infarction and heart failure [55]. Another beneficial effect of tibolone on the cardiovascular system is its direct effect on endothelial cells, causing a decrease in the adhesion of leukocytes to the endothelium [56].
No thromboembolic complications were observed in clinical studies of the drug [57]. An increased risk of venous thromboembolism could not be identified based on the results of the widespread medical use of tibolone for more than 15 years in many countries around the world [3]. Data obtained from 4537 women participating in phase III and IV clinical trials of tibolone showed that the relative risk for all cardiovascular diseases was RR=0.58 (0.31-1.10).
Data from experimental studies in monkeys suggest that tibolone does not have a significant effect on the cardiovascular system, presumably because its negative effects are balanced by positive ones. Long-term (on average 7.5 years) observation of women receiving tibolone also did not reveal an increase in the thickness of the carotid artery intima and an increase in the number of atherosclerotic plaques [58]. However, the final question of the safety of tibolone in relation to the cardiovascular system can only be resolved in well-designed large-scale clinical trials.
The effect of tibolone on bone tissue
The effect of tibolone on bone tissue is a consequence of its estrogenic activity [8]. It was studied in 8 randomized, double-blind studies, 7 of which were placebo-controlled and one was comparative with estrogens [59-66]. All studies demonstrated significant increases in bone mineral density at the lumbar spine and femoral neck with tibolone compared with placebo [67]. The most pronounced beneficial effect of tibolone on bone tissue was in women with osteoporosis. It manifested itself even with short-term use of the drug (3 months) [65] and persisted with long-term use (10 years) [68].
In clinical studies, tibolone was not inferior to estrogens and combined HRT in terms of its effectiveness in preventing bone loss in postmenopausal women [41,59,69,70]. The similar effectiveness of tibolone and estrogens was confirmed by the results of a meta-analysis that included 39 randomized controlled 2-year studies [71]. The advantage of tibolone over standard HRT is its better tolerability, which allows its use for a long time (10 years or more) [68,72]. The drug also prevents bone loss caused by gonadotropin-releasing hormone agonists [73].
BMD measurements with tibolone suggest a protective effect against osteoporotic fractures, but this needs to be confirmed in targeted clinical trials.
The effect of tibolone on the endometrium
Despite isolated reports of endometrial proliferation in women treated with tibolone [74,75], long-term (up to 8 years) studies have shown that the drug has a protective effect on the endometrium [29,76-78]. It is due to the fact that the predominant (if not the only) metabolite of tibolone in the endometrium is the 4-sigma isomer, which binds to the progesterone receptor and, thus, protects it from the agonistic effects of two metabolites with estrogenic activity [79]. Data obtained from phase III and IV clinical trials of tibolone showed that the relative risk of endometrial cancer was RR=0.37 (0.03-0.59).
In an open prospective multicenter study, there was no stimulating effect of tibolone on the endometrium after 12 and 24 months of treatment, respectively, in 98.2% and 91.9% of the women examined [81].
The incidence of breakthrough bleeding with tibolone is significantly lower than with combined HRT [20,26,31,81]. Amenorrhea when taking tibolone is achieved faster: in 90% of women it occurs within 6 months of treatment [31,74,75]. Bleeding is less common in older women [82]. A 3-year follow-up of women with uterine fibroids treated with tibolone did not detect fibroid growth [83].
Tibolone and breast cancer
The effect of tibolone on breast cells has been studied especially carefully. In breast tissue, tibolone and its metabolites have an inhibitory effect on enzymes that promote local synthesis of estradiol (sulfatase and 17sigma-hydroxysteroid dehydrogenase (type I)) and, on the contrary, activate enzymes (sulfotransferase and 17sigma-hydroxysteroid dehydrogenase (type II)) that convert active estradiol into less active estrone and inactive sulfated forms, which are excreted from the body in the urine. Thus, tibolone has a unique mechanism of action, which determines not only the lack of stimulation of estrogen receptors in the mammary gland by estrogenic metabolites of tibolone, but also, due to specific “enzyme regulation,” helps to reduce the local concentration of active estradiol [84]. In addition, in vitro studies revealed tibolone to have antiproliferative activity, the ability to enhance cell differentiation and induce apoptosis of breast cancer cells [85].
Clinical studies have proven that tibolone is significantly less likely to increase breast density on mammography and less likely to cause mastalgia than estrogens and combined HRT [31,85-87]. The positive effects of tibolone are associated with its effect on enzymes involved in the local production of estrogens in breast tissue. In phase III and IV clinical trials of the drug involving 4,537 women, the documented incidence of breast cancer was 1.59 per 1,000 person-years in the study group versus 3.15 in the placebo group. The relative risk of breast cancer when taking tibolone was: RR=0.50 (0.11-2.54) [80].
The above allowed us to suggest that tibolone has a protective effect against breast cancer [3].
Tibolone and diabetes mellitus
In elderly women with type 2 diabetes mellitus, no significant changes in the lipid profile were detected when using tibolone at a dose of 2.5 mg/day [88]. The drug increased insulin sensitivity in cases of hormone resistance [88]. It did not have a negative effect on blood pressure in women with diabetes mellitus and hypertension [38]. The above effects allow us to recommend tibolone for use in postmenopausal diabetic patients [38,89].
Conclusion
Today, tibolone can be considered as a worthy alternative to standard HRT for most postmenopausal women [89]. Tibolone exhibits similar clinical efficacy to estrogens for symptoms of menopause, such as hot flashes and various urogenital disorders, but is superior to the latter in its effect on sexuality. Its safety on the endometrium and ability to prevent bone loss is comparable to that of combined HRT, but tibolone is less likely to cause breakthrough bleeding. The overall effect of tibolone and its metabolites on the cardiovascular system is currently considered to be neutral. Further randomized studies will allow definitive conclusions to be drawn. The presence of tibolone's protective effect against breast cancer also requires confirmation.
This kind of research has already begun. These are large multicenter randomized, blind, placebo-controlled studies:
- the LIFT study (Long-term Interventional Fracture study in osteoporotic patients), aimed at identifying the incidence of fractures;
- the OPAL (Osteoporosis Prevention and Antiatherosclerosis effects of TiboLone) study, evaluating the effect of the drug on bone tissue and the cardiovascular system;
- the LIBERATE (Livial Intervention Following Breast Cancer; Efficacy, Recurrence, and Tolerance Endpoints) study, which examined the safety of tibolone in the breast;
- The THEBES (Tibolone Histology of the Endometrium and Breast Endpoints Study) study assessing the response of the endometrium to treatment [21].
The results of these studies will allow us to finally determine the place of tibolone in the treatment and prevention of postmenopausal disorders.
Special instructions for the use of Tibolone
Tibolone is not a contraceptive. Tibolone should be prescribed immediately after surgical menopause and no earlier than 1 year after natural menopause (last menstruation). It is not recommended to exceed the recommended daily dose due to the possibility of bleeding from the vagina. While taking tibolone, it is necessary to exercise medical supervision over the condition of patients with migraine, epilepsy, diabetes mellitus, impaired renal function and hypercholesterolemia, as well as a history of these diseases.
