Selective Tissue Estrogenic Activity Regulator Research Articles

Tibolone and Breast Cancer.

Tibolone, a selective tissue estrogenic activity regulator, is a synthetic steroid with distinct pharmacological and clinical characteristics in contrast to conventional menopausal hormone therapy. Tibolone induces estrogenic activity in the brain, vagina, and bone but remains inactive in the endometrium and breast. In particular, several studies have investigated whether tibolone usage increases the risk of breast cancer. This study aims to determine the effects of tibolone on the breast by focusing on the relation between tibolone use and breast cancer. Our investigation emphasizes recent studies, particularly those based on Asian populations.

A Review of Analytical Methods for the Determination of Tibolone: Pharmacokinetics and Pharmaceutical Formulations Analysis and Application in Doping Control

Background:: Tibolone is a synthetic steroid commercialized by Organon under the brand name Livial (Org OD14), which is used in hormone therapy for menopause management and treatment of postmenopausal osteoporosis. Tibolone is defined as a selective tissue estrogenic activity regulator (STEAR) demonstrating tissue-specific effects on several organs such as brain, breast, urogenital tract, endometrium, bone and cardiovascular system. Aims:: This work aims to (1) present an overview of important published literature on existing methods for the analysis of tibolone and/or its metabolites in pharmaceutical formulations and biological fluids and (2) to conduct a critical comparison of the analytical methods used in doping control, pharmacokinetics and pharmaceutical formulations analysis of tibolone and its metabolites. Results and conclusions: : The major analytical method described for the analysis of tibolone in pharmaceutical formulations is High Pressure Liquid Chromatography (HPLC) coupled with ultraviolet (UV) detection, while Liquid Chromatography (LC) or Gas Chromatography (GC) used in combination with Mass Spectrometry (MS) or tandem mass spectrometry (MS/MS) is employed for the analysis of tibolone and/or its metabolites in biological fluids.

Tibolone Effects on Human Glioblastoma Cell Lines

Ovarian steroid hormones are involved in modulating the growth of glioblastomas (the most common, aggressive, and lethal brain tumor) through the interaction with their intracellular receptors. Activation of sex hormone receptors is involved in glioblastomas progression. Tibolone (TIB) is a selective tissue estrogenic activity regulator widely prescribed to treat menopausal symptoms and to prevent bone lost. The effects of TIB on the growth of glioblastoma are unknown. To evaluate the effects of TIB on cell number, migration, and invasion of two derived human glioblastoma cell lines (U251MG and U87), as well as the role of this steroid in estrogen and progesterone receptors activity and content. U251-MG and U87 human glioblastoma cell lines were grown with different doses of TIB. The number of cells was determined and migration and invasion tests were carried out. Protein expression was performed by Western blot. We observed that TIB (10nM) increased the number of cells by inducing proliferation with no effects on cell migration or invasion. The increase in cell proliferation induced by TIB was blocked by estrogen (ERs) or progesterone receptor (PRs) antagonists, ICI 182, 780 and RU 486, suggesting that these receptors mediate proliferating actions of TIB; TIB also modified the content of ERs and PRs by increasing ER-α, ER-β, and PR-B, while decreased PR-A. Our results suggest that TIB increases cell number and proliferation of human glioblastoma cells through the regulation of ERs and PRs actions and content.

Tibolone improves depression in women through the menopause transition: A double-blind randomized controlled trial of adjunctive tibolone

BackgroundMany women with no past psychiatric history experience severe mood symptoms for the first time in their life during the menopausal transition, with debilitating long-term consequences. Women with a history of depression can experience a relapse or worsening of symptoms during the menopause transition. Traditional antidepressants, SSRIs or SNRIs, are commonly prescribed as the first line response. However, such treatment has shown only small improvements with side effects. Hormone therapies directly targeting the perimenopausal fluctuations in reproductive hormonal systems such as tibolone, have significant potential to treat perimenopausal depression. Our study investigated the use of adjunctive tibolone, selective tissue estrogenic activity regulator, to treat de-novo or relapsing depression occurring during the menopause transition period. MethodsWomen who were going through the menopause transition with depressive symptoms were invited to participate in a double-blind, 12 week randomized control trial with two arms: tibolone (2.5 mg oral/day) or oral placebo (NCT01470092). Forty-four women met inclusion/exclusion criteria; 22 were randomized to tibolone and 22 were randomized to oral placebo. Symptoms were measured with the ‘Montgomery- Asberg depression rating scale’ (MADRS) as the primary outcome measure. Latent growth curve analysis was used to assess the MADRS scores change over time. ResultsParticipants in the tibolone group demonstrated a significant improvement in depression scores, as compared to the placebo group, without any significant side effects. LimitationsThis trial only monitored tibolone's effects over 12 weeks. Future research should be conducted over an extended timeframe and explore whether the benefits of tibolone extend to other symptoms of perimenopausal depression. ConclusionsThe use of hormone therapies such as tibolone provide exciting innovations for the treatment of depression during the menopause transition.

Hormone replacement therapy and the prevention of postmenopausal osteoporosis.

Fracture prevention is one of the public health priorities worldwide. Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis, the most common metabolic bone disease. Different effective treatments for osteoporosis are available. Hormone replacement therapy (HRT) at different doses rapidly normalizes turnover, preserves bone mineral density (BMD) at all skeletal sites, leading to a significant, reduction in vertebral and non-vertebral fractures. Tibolone, a selective tissue estrogenic activity regulator (STEAR), is effective in the treatment of vasomotor symptoms, vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT. Selective estrogen receptor modulators (SERMs) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures. The combination of bazedoxifene and conjugated estrogens, defined as tissue selective estrogen complex (TSEC), is able to reduce climacteric symptoms, reduce bone turnover and preserve BMD. In conclusion, osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms. The use of a standard dose of HRT for osteoporosis prevention is based on biology, epidemiology, animal and preclinical data, observational studies and randomized, clinical trials. The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover, with compelling scientific evidence.

Continuing Medical Education: The Use of Estrogen Therapy in Women's Sexual Functioning (CME)

Estrogen is relevant to women's well-being including sexual functioning. Aim. The goal of this Continuing Medical Education article was to provide a comprehensive review of the effect of exogenous estrogen use on women's sexual function. Main Outcome Measures. We present a literature review. The medical literature was accurately searched (1990-2008) with regard to estrogen therapy in menopausal women by using several terms related to and including the terms "estrogen" and "sexual function." A review of the studies most useful to guide menopausal practice. Estrogen decline is one of the key factors contributing to sexual functioning during menopausal transition and beyond. Systemic estrogen treatments are associated with significant benefits in some domains of menopausal sexual function, especially when estradiol is delivered transdermally, whereas local estrogens are effective in preventing urogenital aging. Even tibolone, a selective tissue estrogenic activity regulator, displays positive effects in postmenopausal women with sexual complaints. However, a tailored approach to the individual woman is always needed.

Hormone replacement therapy use and the risk of stroke

ObjectivesRandomised trials reported an increase risk of stroke with an estrogen plus progestogen formulation of hormone replacement therapy (HRT). A recent trial also reported an increased risk with tibolone, a selective tissue estrogenic activity regulator. MethodsWe used the General Practice Research Database to conduct a case–control study within a cohort of women aged 50–79 between January 1987 and October 2006, without history of stroke prior to cohort entry. We identified all cases of stroke occurring during the study period and selected up to four controls matched to each case on age, general practice and year of start in the practice. Information on HRT use during the year preceding the index date was obtained. Conditional logistic regression was used to estimate the rate ratios of stroke associated with current use of the different HRTs. ResultsThe cohort included 870,286 women, of whom 15,710 experienced a stroke during follow-up and were matched to 59,958 controls. The adjusted rate ratio of stroke associated with current use of tibolone relative to non-use of HRT was 1.08 (95% CI: 0.82–1.44). The rate ratios with current use of estrogens alone and estrogen plus progestogen were 1.26 (95% CI: 1.10–1.45) and 1.19 (95% CI: 1.05–1.36) respectively. ConclusionsWe found no evidence of an elevated risk of stroke associated with the use of tibolone, although the low number of subjects using tibolone does not permit to rule out a small risk. The small elevated risk of stroke with estrogens or estrogens plus progestogen is consistent with that reported in randomised trials.

Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women

A randomized trial was conducted in osteopenic postmenopausal women to compare the efficacy of tibolone versus raloxifene on BMD of the lumbar spine and hip. Tibolone increased lumbar spine and total hip BMD to a statistically significantly greater extent than raloxifene after two years of treatment. Both tibolone, a selective tissue estrogenic activity regulator (STEAR), and raloxifene, a selective estrogen receptor modulator (SERM), are known to prevent postmenopausal bone loss. However, no head-to-head studies to compare the efficacy on bone have been performed. A double-blind, randomized trial was conducted in osteopenic postmenopausal women aged 60-79 years to compare the effects of tibolone 1.25 mg/day to raloxifene 60 mg/day on bone mineral density (BMD). Serum osteocalcin and serum type I collagen C-telopeptides were measured as biochemical markers of bone metabolism. Three hundred and eight subjects were allocated to treatment. Both treatments significantly increased lumbar spine BMD, however the increase was significantly larger after tibolone treatment than after raloxifene treatment (at year 1: 2.2% versus 1.2%, p<0.01 and at year 2: 3.8% versus 2.1%, p<0.001). After 2 years of treatment, the increase in total hip BMD in the tibolone group was significantly larger than in the raloxifene group (p<0.05). Both treatments significantly reduced type I collagen C-telopeptides and osteocalcin levels when compared to baseline. Tibolone 1.25 mg/day for 2 years prevents postmenopausal bone loss in older women and results in a larger increase of BMD both at the lumbar spine and hip than raloxifene.

Effect of Tibolone on Breast Cancer Cell Proliferation in Postmenopausal ER+ Patients: Results from STEM Trial

Tibolone is a selective tissue estrogenic activity regulator, approved for the treatment of vasomotor symptoms in postmenopausal women. We have done an exploratory, double-blind, randomized, placebo-controlled pilot trial to investigate the tissue-specific effects of 2.5 mg tibolone on breast cancer in postmenopausal women, in particular on tissue proliferation (STEM, Study of Tibolone Effects on Mamma carcinoma tissue). Postmenopausal women with initially stage I/II, estrogen receptor-positive (ER+) primary breast cancer, were randomly assigned to 14 days of placebo or 2.5 mg/d tibolone. Core biopsies of the primary tumor were obtained before and after treatment. Ki-67 and apoptosis index were analyzed in baseline and corresponding posttreatment specimen. Of 102 enrolled patients, 95 had evaluable data. Baseline characteristics were comparable between both treatment groups. Breast cancer cases are mainly invasive (99%), stage I or II (42% and 50% respectively), and ER+ (99%). Median intratumoral Ki-67 expression at baseline was 13.0% in the tibolone group and 17.8% in the placebo group, and decreased to 12.0% after 14 days of tibolone while increasing to 19.0% in the placebo group. This change from baseline was not significantly different between tibolone and placebo (Wilcoxon test; P=0.17). A significant difference was observed between the treatment groups when the median change from baseline apoptosis index was compared between the treatment groups (tibolone, 0.0%; placebo, +0.3%; Wilcoxon test; P=0.031). The incidence of adverse effects was comparable. In ER+ breast tumors, 2.5 mg/d tibolone given for 14 days has no significant effect on tumor cell proliferation.

Prescribing of hormone therapy for menopause, tibolone, and bisphosphonates in women in the UK between 1991 and 2005

The purpose of this study was to examine recent trends in the prescribing of hormone therapy for menopause, tibolone, and bisphosphonate preparations for the prevention or treatment of osteoporosis, in the UK in relation to publication of research evidence on the health effects of hormone therapy and subsequent changes in prescribing advice. Individual patient-level data were obtained on the prescribing of hormone therapy, tibolone, and bisphosphonates by general practitioners in the UK between 1991 and 2005 to women aged 40 years and older in the UK General Practice Research Database. Overall and age-specific prescribing prevalence were calculated for each therapy type. Prescribing prevalence was also calculated for subcategories of hormone therapy and bisphosphonates. Prescribing of hormone therapy to women aged 40 years and older increased between 1991 and 1996 and remained fairly stable between 1997 and 2001. Hormone therapy prescribing has fallen by about 50% since 2002. Tibolone, a selective tissue estrogenic activity regulator, is prescribed much less commonly than hormone therapy but shows a similar pattern. Prescribing of bisphosphonates increased rapidly throughout the study period, particularly in women aged 70 years and older, with the pattern of prescribing reflecting to some extent, the availability of new weekly formulations. Trends in the prescribing of hormone therapy in the UK appear to closely reflect new epidemiological evidence and prescribing advice. It is likely that the substantial fall in hormone therapy and tibolone prescribing seen since 2002 is a direct consequence of the publication of Women's Health Initiative trial results and subsequent changes in advice given by the Committee on Safety of Medicines. The 1997 publication of results from the Collaborative Group on Hormonal Factors in Breast Cancer and 2003 publication of the Million Women Study findings may also have impacted on trends, particularly within certain age groups. The substantial and continuing increase in prescribing prevalence of bisphosphonates reinforces the need for research into the long-term risks and benefits of these therapies.

Cardiovascular Effects of Tibolone: A Selective Tissue Estrogenic Activity Regulator

Traditionally, it was accepted that long-term hormone replacement therapy (HRT) has a cardiovascular beneficial effect in postmenopausal women with and without coronary artery disease (CAD). However, randomized trials in postmenopausal women have not shown any benefit in either primary or secondary prevention of cardiovascular events. Therefore, these findings have raised the question of whether traditional HRT (i.e., estrogen and progesterone) has a cardioprotective effect in women at risk for or with established CAD. Concerns about the use of conventional HRT have led to a search for alternatives. Tibolone is a synthetic compound with estrogenic, androgenic, and progestogenic properties that relieves climacteric symptoms and prevents postmenopausal bone loss. Tibolone possesses a tissue-selective mechanism of action that differs from that of estrogen and/or progestogen. Unlike these compounds, tibolone's metabolites play a central role in its mode of action. Tibolone is widely used for HRT. However, its clinical impact on cardiovascular disease is still under study. The current review focuses on the effects of tibolone on the cardiovascular system and discusses clinical investigations with this compound in postmenopausal women.

Selective Tissue Distribution of Tibolone Metabolites in Mature Ovariectomized Female Cynomolgus Monkeys after Multiple Doses of Tibolone

Tibolone is a selective tissue estrogenic activity regulator (STEAR). In postmenopausal women, it acts as an estrogen on brain, vagina, and bone, but not on endometrium and breast. Despite ample supporting in vitro data for tissue-selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we analyzed tibolone and metabolites in plasma and tissues from six ovariectomized cynomolgus monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied at 1, 1.25, 2.25, 4, 6, and 24 h after the final dose. The plasma and tissue levels of active, nonsulfated (tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta(4)-tibolone), monosulfated (3alpha-sulfate,17beta-hydroxytibolone and 3beta-sulfate,17beta-hydroxytibolone), and disulfated (3alpha,17beta-disulfated-tibolone and 3beta,17betaS-disulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1 to 0.5 ng/ml (plasma) and 0.5 to 2 ng/g (tissues). In brain tissues, estrogenic 3alpha-hydroxytibolone was predominant with 3 to 8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major nonsulfated metabolites were 3alpha-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone; disulfated metabolites were predominant. Remarkably high levels of monosulfated metabolites were found in the proximal vagina. In endometrium, myometrium, and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites were high (about 98% disulfated). Delta(4)-Tibolone/3-hydroxytibolone ratios were 2 to 3 in endometrium, about equal in breast and proximal vagina, and 0.1 in plasma and brain. It is concluded that tibolone metabolites show a unique tissue-specific distribution pattern explaining the tissue effects in monkeys and the clinical effects in postmenopausal women.

Estrogen and Tibolone Metabolite Levels in Blood and Breast Tissue of Postmenopausal Women Recently Diagnosed With Early-Stage Breast Cancer and Treated With Tibolone or Placebo for 14 Days

Unlike estrogens plus progestagens, tibolone, a selective tissue estrogenic activity regulator, does not increase breast tenderness and mammographic density. To elucidate this, serum and breast levels of tibolone and estrogenic metabolites are measured. Postmenopausal women (n = 102) with early-stage, ER(+ve), primary breast cancer received tibolone or placebo for 14 days in an exploratory, double-blind, randomized trial (STEM carcinoma tissue). Baseline and presurgery sera were collected; tumor tissues were obtained at surgery. E(1) (estrone), E(2) (estradiol), E(1)S (estrone-sulfate), tibolone-its nonsulfated, monosulfated, and disulfated 3-hydroxymetabolites-and Delta(4)-tibolone were measured by validated gas chromatography and mass spectrometry and liquid chromatography with tandem mass spectrometry assays. More than 12 hours after the final dose, serum E(1), E(2), and E(1)S levels were unchanged with placebo, whereas tibolone significantly increased E(1)S and the E(1)S/(E(1) + E(2)) ratio. In tumors, E(1) and E(2) levels were higher than in serum, and E(1)S levels were lower, with placebo and tibolone administration. The percentage of E(1)S was about 90% in serum and 16% in tissue. Tibolone did not affect tissue levels of endogenous estrogens. Serum levels of estrogenic 3alpha- and 3beta-hydroxytibolone, progestagenic/androgenic Delta(4)-tibolone, and monosulfate metabolites were low. Serum 3alphaS,17betaS-tibolone and 3 betaS,17betaS-tibolone levels were 250 and 52 ng/mL, respectively. Tumor levels of 3alpha- and 3beta-hydroxytibolone and Delta(4)-tibolone were higher than in serum, but disulfate levels were lower. The percentage of sulfated tibolone metabolites was 99% in serum and 96% in tumor. Serum metabolite patterns of estradiol and tibolone are different from those in tissues and are compatible with neutral effects of tibolone on breast Ki67 expression.

New Selective Tissue Estrogenic Activity Regulator (STEAR) in Menopausal Therapy in Taiwan

Summary Objective The compliance of women living in Taiwan with the selective tissue estrogenic activity regulator (STEAR) tibolone has seldom been reported. The purpose of this study was to evaluate the short-term compliance of perimenopausal women living in Taiwan in taking tibolone, and the efficacy of the drug. Materials and Methods A total of 289 perimenopausal women who had experienced mild to severe climacteric symptoms were enrolled in this study. Every woman was evaluated before (baseline), during (end of the third month), and after therapy (end of the sixth month) with 2.5 mg tibolone daily. Efficacy was assessed from improvement in climacteric symptoms and compliance was also assessed. Results A total of 275 women were still on tibolone treatment by the end of the study, revealing a high rate (95.2%) of retention. Breast tenderness was significantly reduced, from 26.5% to 2.8%. The reported rate of insomnia was 50.5% at baseline, and had been reduced to 20.4% by the end of the study. Bleeding episodes dropped from 87.4% at baseline to 39.4% at the end of the study. The rate of mood instability was significantly reduced, from 84.1% at baseline to 44.3% at the end of the study. Libido improved from 15.9% at baseline to 61.6% at the end of the study, a unique benefit of tibolone due to the androgenic effect of its d-isomer. Most women (84.1%) had an increase in body weight ranging from 0.5 to 3 kg. Fourteen subjects dropped out for the following reasons: three women had acne and/or allergic reaction, four had a significant increase in body weight and/or water retention, one had headache, and the other six dropped out for personal reasons. Conclusion Tibolone can improve the climacteric symptoms of perimenopausal women living in Taiwan. With the exception of increased body weight, no major side-effect was noted during this short-term study.

The need for tissue selective menopausal agents

For decades, hormone therapy (HT) has been the mainstay for managing menopausal symptoms. However, fear of breast cancer, as well as side-effects such as breast pain and return of vaginal bleeding, have made many women stop HT or refuse to take it. There is therefore a clear need for alternative treatments. Recent years have seen the development of hormonal agents with selective effects, such as tibolone. Tibolone has a unique mode of action and is described as a STEAR (Selective Tissue Estrogenic Activity Regulator). The main action of tibolone is mediated through two 3-hydroxy metabolites; small amounts of a third metabolite are also found in the circulation. In the brain, the effect is estrogenic and perhaps androgenic and, as such, tibolone relieves hot flushes and improves energy and sexual well-being. The uterus converts tibolone and its hydroxy metabolites into a Δ4 metabolite that has a progestogenic effect. In the breast, the metabolites of tibolone inhibit key enzymes that result in estrogen depletion within the breast itself. Clinically, tibolone does not stimulate the breast and it does not increase mammographic density. There are several key large, placebo-controlled international trials of tibolone currently underway, one of which (LIBERATE) aims to test the safety of tibolone (vs placebo) in women with a history of breast cancer who are suffering from climacteric symptoms.

Mood Scores in Relation to Hormone Replacement Therapies during Menopause: A Prospective Randomized Trial

There is lack of studies in literature about the long-term effects of hormone replacement therapies and cholesterol levels on mood scores in menopause. In the present study we have investigated whether serum lipid levels affect mood scores in menopause and evaluated the long-term effects of the combined hormone replacement regimens (HRT) on depressive symptoms in postmenopausal women. In this prospective-randomized, placebo-controlled, double-blind study, 286 women in menopause were divided into four groups according to therapeutic regimens they received; 1) Conjugated equine estrogen (CEE) of 0.625 mg plus medroxyprogesterone acetate (MPA) of 2.5 mg (n = 79), 2) CEE (0.625 mg) plus MPA of 5 mg (n = 77), 3) tibolone of 2.5 mg (a selective tissue estrogenic activity regulator) (n = 76), and 4) Calcium (Ca) of 1,000 mg (n = 54). Beck Depression Inventory (BDI), and serum levels of lipoprotein lipids were assessed before and after 12-months of treatment with oral continuous HRT and Ca supplementation. BDI scores in the study groups were not correlated with lipid profiles. We compared two subgroups of patients with initial BDI scores 0-14 (normal mood scores) in order to asses for the possible relation between the lipid profile and mood. Following treatment, first subgroup had increased scores to 15-30 (mildly depressed women, n = 27) and the second subgroup preserved BDI scores of 0-14 (normal mood scores, n = 23). Serum levels of total cholesterol, high-density lipoprotein, low-density lipoprotein and body mass index were found to be similar between these two groups. BDI scores decreased significantly in all HRT groups after 12 months of treatment, compared to Ca group (p < 0.05). We did not observe any correlation between BDI scores and lipid profiles before and following continuous HRT or Ca supplementation. Continuous combined hormone replacement regimens, CEE + MPA and tibolone, have superior long-term effects on mood scores in menopause and should be considered during the decision process for use of HRT due to menopausal symptoms.

Tibolone: a selective tissue estrogenic activity regulator (STEAR)

Tibolone: a selective tissue estrogenic activity regulator (STEAR)

Tibolone: how does its mechanism of action translate into clinical effects

The various biological mechanisms that could explain the wide variety of clinical effects seen with postmenopausal hormonal therapy (HT) are presented in this Maturitas supplement, and in particular the mechanism of action of tibolone is unravelled in more detail. The claim is documented that tibolone is a selective tissue estrogenic activity regulator (STEAR), with estrogenic effects on brain, bone and vagina, while avoiding the undesired estrogenic effects on endometrium and breast. These up-to-date papers reflect to a large extent the subjects discussed in a multi-disciplinary workshop in Rome, for which I had been asked to act as an independent chairman.

Tibolone: a selective tissue estrogenic activity regulator (STEAR)

Tibolone was first synthesized and its properties tested in the late 1960s and early 1970s. Various biological tests revealed that it possesses estrogenic, progestogenic and androgenic properties. Based on its structure, however, this estrogenic activity was not expected because of the lack of essential structural characteristics such as an aromatic A-ring with a C3 phenolic group. Nevertheless, a clear estrogenic effect was observed on the vagina.