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Frans A Helmond - One of the best experts on this subject based on the ideXlab platform.

  • Tibolone histology of the endometrium and breast endpoints study design of the trial and endometrial histology at baseline in postmenopausal women
    Fertility and Sterility, 2007
    Co-Authors: David F Archer, Janice Rymer, Victoria Stathopoulos, Susan L Hendrix, Alex Ferenczy, Juan C Felix, Chris J Gallagher, Sven O Skouby, Wil Den Hollander, Frans A Helmond
    Abstract:

    Objective To address the endometrial safety of Tibolone. Design The Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) is a randomized, double-blind, parallel-group trial of Tibolone compared with continuous combined conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA). Setting Multi-country, multi-center ambulatory care setting. Patient(s) A total of 5,185 subjects were screened, and biopsies were obtained from 4,446 women. Intervention(s) Participants were randomized in a 1:1:2 ratio, to Tibolone (1.25 or 2.5 mg/d) or CEE-MPA. Main Outcome Measure(s) The one-sided 95% confidence intervals for the incidence of hyperplasia or cancer were evaluated for Tibolone compared with CEE-MPA. Result(s) Endometrial biopsy results at baseline: atrophic (87.29%), inactive (0.25%), proliferative (6.12%), secretory (2.86%), menstrual type (0.40%), and hyperplasia (0.18%). Only subjects with atrophic or inactive endometrium were eligible for this study, and 3% of the women at screening either had no tissue (0.18%) or had an amount of tissue that was insufficient for diagnosis (2.72%). Three thousand two hundred forty postmenopausal women with a mean (±SD) age of 54.4 ± 4.4 years and a mean time since menopause of 4.5 ± 3.6 years were randomized. Conclusion(s) The Tibolone Histology of the Endometrium and Breast Endpoints Study is a prospective, randomized clinical trial, designed to provide evidence of the endometrial safety of Tibolone compared with estrogen and progestogen. Screening endometrial histology shows a low prevalence of endometrial hyperplasia (0.18%) and no carcinoma.

  • endometrial effects of Tibolone
    The Journal of Clinical Endocrinology and Metabolism, 2007
    Co-Authors: David F Archer, Janice Rymer, Victoria Stathopoulos, Susan L Hendrix, Alex Ferenczy, Chris J Gallagher, Sven O Skouby, Wil Den Hollander, Frans A Helmond
    Abstract:

    Background and Objectives: The Tibolone Histology of the Endometrium and Breast Endpoints Study is a multicenter, randomized, double-blind study designed to address the conflicting reports in the literature about the endometrial safety of Tibolone (1.25 or 2.5 mg/d). Tibolone was compared with continuous combined conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) (0.625 + 2.5 mg/d). Methods: Subjects were randomized in a 1:1:2 ratio to Tibolone 1.25 mg/d, 2.5 mg/d, and CEE/MPA, respectively. The one-sided 95% confidence interval (CI) has been evaluated for the incidence of abnormal endometrial histology (hyperplasia or carcinoma) and hyperplasia and carcinoma separately for each of the two treatment groups and the treatment groups combined after 1 and 2 yr of treatment with Tibolone, compared with CEE/MPA. Results: A total of 3240 women were randomized, with 3224 receiving at least one dose of study medication. The incidence and upper one-sided 95% CI for the incidence of abnormal end...

  • effects of Tibolone and continuous combined conjugated equine estrogen medroxyprogesterone acetate on the endometrium and vaginal bleeding results of the opal study
    American Journal of Obstetrics and Gynecology, 2006
    Co-Authors: Robert Langer, Britt Marie Landgren, Janice Rymer, Frans A Helmond
    Abstract:

    Objectives The primary objective of the O steoporosis P revention and A rterial effects of tibo L one study was to compare the effect of Tibolone and placebo on the progression of the common carotid artery intima-medial thickness; the common carotid artery intima-medial thickness and bone data will be presented elsewhere. A secondary objective was to assess the effects of Tibolone (2.5 mg), continuous combined conjugated equine estrogen/medroxyprogesterone acetate [0.625/2.5 mg], and placebo on the endometrium and vaginal bleeding; these results are the subject of this report. Study design This 3-year, three-arm, international, randomized, double-blind, parallel group, placebo-controlled clinical trial enrolled 866 postmenopausal women (aged 45-79 years). The endometrium was assessed by annual transvaginal ultrasound scans and end-of-study biopsies (United States/United Kingdom centers only). Vaginal bleeding was recorded in daily diaries. Results Endometrial thickness measured by transvaginal ultrasound scan increased slightly during the first year with Tibolone and conjugated equine estrogen/medroxyprogesterone acetate, without any further progression. After 3 years, there were no significant differences between the Tibolone, conjugated equine estrogen/medroxyprogesterone acetate, and placebo groups in the incidence of proliferation (1.4%, 4.8%, and 0%, respectively), endometrial hyperplasia (0% in all groups), or cancer (1, 0, and 1 case, respectively). During the first 3 months, bleeding/spotting rates were greater with conjugated equine estrogen/medroxyprogesterone acetate (48%) than with Tibolone (18%; P P P = .023 vs Tibolone; P P P P P = .001). Conclusion Compared with conjugated equine estrogen/medroxyprogesterone acetate, Tibolone has a better tolerability profile with respect to vaginal bleeding but with a similar endometrial safety. These results reinforce the endometrial safety profile of Tibolone.

  • Tibolone for the treatment of moderate to severe vasomotor symptoms and genital atrophy in postmenopausal women a multicenter randomized double blind placebo controlled study
    Menopause, 2006
    Co-Authors: Stephen Swanson, Frans A Helmond, Steven Drosman, Victoria Stathopoulos
    Abstract:

    Objective: To demonstrate the safety and efficacy of Tibolone (1.25 and 2.5 mg) in the treatment of moderate to severe vasomotor symptoms and symptoms associated with vaginal atrophy. Design: A placebo-controlled, double-blind, randomized, multicenter study was conducted on 396 healthy postmenopausal women experiencing a minimum of 7 moderate to severe hot flashes per day (60 per week). Participants were randomized to receive Tibolone 1.25 or 2.5 mg or placebo once daily for 12 weeks. Assessments were done at weeks 4, 8, and 12. The severity and frequency of hot flashes were recorded in patient diaries on a daily basis. Results: Tibolone 2.5 mg significantly (P < 0.001) reduced the average number of hot flashes compared with placebo at week 4 (-7.82 vs -5.27), week 8 (-9.71 vs -5.86), and week 12 (-10.14 vs -5.85). The difference between Tibolone 1.25 mg and placebo was significant (P < 0.001) at week 8 (-7.96) and week 12 (-8.32). Findings for the average daily severity of hot flashes were similar, with significantly greater reductions at week 4 (P < 0.05) and weeks 8 and 12 (P < 0.001) for Tibolone 2.5 mg versus placebo and at weeks 8 and 12 for Tibolone 1.25 mg versus placebo (P < 0.001). A menopausal atrophic symptom questionnaire revealed that Tibolone 2.5 mg significantly (P < 0.05) reduced nocturia compared with placebo at weeks 4, 8, and 12 and urinary urgency at week 4. Compared with placebo, both doses of Tibolone also significantly (P < 0.001) increased the vaginal maturation value from baseline. The overall incidence of adverse events was similar in all treatment groups. Conclusions: Tibolone is effective and well tolerated for the treatment of moderate to severe vasomotor symptoms and the effects of vaginal atrophy associated with menopause.

  • the effect of Tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima media thickness the osteoporosis prevention and arterial effects of Tibolone opal study
    European Heart Journal, 2006
    Co-Authors: Michiel L Bots, Frans A Helmond, Gregory W Evans, Ward A Riley, Karen H Mcbride, Electra D Paskett, Diederick E Grobbee
    Abstract:

    Aims At the time of the design of the Osteoporosis Prevention and Arterial effects of Tibolone (OPAL) study in 1996, oral hormone therapy (HT) was assumed to reduce cardiovascular risk. The evidence mainly came from the effects of combined conjugated equine oestrogens plus medroxyprogesterone acetate (CEE/MPA) therapy. Other HT regimes had not been studied widely. Tibolone, a selective tissue oestrogenic activity regulator, has several effects on cardiovascular risk factors, one of which is HDL lowering. Because the overall effect of Tibolone on cardiovascular risk was unknown, the OPAL study was designed. Methods and results The OPAL study was a three-arm, randomized, placebo-controlled, double-blind study to determine the effect of Tibolone (2.5 mg daily) and of CEE/MPA (0.625/2.5 mg daily) over 3 years on progression of carotid intima–media thickness (CIMT) in 866 healthy post-menopausal women. The women were recruited from six US and five European centres. The primary outcome was change in mean common CIMT. Annual common CIMT progression rates in the Tibolone and CEE/MPA groups were higher than in the placebo group: 0.0077 mm [95% confidence interval (CI) 0.0051–0.0103] in the Tibolone group, 0.0074 mm (0.0048–0.0099) in the CEE/MPA group, and 0.0035 mm (0.009–0.0061) in the placebo group. The differences with placebo (0.0042 mm/year for Tibolone and 0.0039 mm/year for CEE/MPA) were statistically significant. HDL cholesterol increased in CEE/MPA group and was lowered in the Tibolone group. Conclusion Both Tibolone and CEE/MPA showed increased progression of common CIMT. Translation of the increased common CIMT progression of the CEE/MPA group into cardiovascular disease risk could not fully explain the observed increased cardiovascular risk as observed in the Women's Health Initiative study. This suggests that the net effect of Tibolone and CEE/MPA on cardiovascular events may depend on the combined effects on the arterial wall, clotting factors, and possibly inflammation.

Bo Von Schoultz - One of the best experts on this subject based on the ideXlab platform.

  • Different effects of Tibolone and continuous combined estrogen plus progestogen hormone therapy on sex hormone binding globulin and free testosterone levels -an association with mammographic density
    2020
    Co-Authors: Marie Hofling, Kjell Carlströ M, Gunilla Svane, Edward Azavedo, Helenius Kloosterboer, Bo Von Schoultz
    Abstract:

    Abstract Objective To compare the effects of Tibolone and continuous combined hormone therapy on circulating sex steroids and their binding proteins and their relationship to mammographic density. Study design A prospective, double-blind placebo-controlled study. A total of 166 postmenopausal women were equally randomized to receive Tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA) or placebo. Serum analyses of sex steroids, insulin-like growth factor (IGF-I) and binding proteins and assessment of mammographic breast density were performed at baseline and after 6 months of treatment. Results Estrogens were markedly increased and androgens decreased by E2/NETA. In contrast, Tibolone had only a minor influence on circulating estrogens. Sex hormone binding globulin (SHBG) levels were reduced by 50%, while levels of androgens increased. Baseline values of estrone sulfate (E1S), around 1.0-1.1 nmol/l, were increased to 44.7 nmol/l by E2/ NETA and to only 1.7 nmol/l by Tibolone (p 5 0.001). Mammographic breast density displayed a negative correlation with age and body mass index and a positive association with SHBG. After 6 months there was also a negative correlation with levels of free testosterone. Conclusion We found that Tibolone and E2/NETA caused distinct differences in estrogen/androgen status and blood levels of possible breast mitogens. The negative association between free testosterone and mammographic density could be a possible explanation for Tibolone having less influence on the breast

  • Tibolone increases bone mineral density but also relapse in breast cancer survivors liberate trial bone substudy
    Breast Cancer Research, 2012
    Co-Authors: N J Bundred, Piero Sismondi, Peter Kenemans, Jeanmichel Foidart, Cheng Har Yip, Matthias W Beckmann, Bo Von Schoultz, Rena Vassilopoulousellin, Rachid El Galta, Eugenie Van Lieshout
    Abstract:

    The Livial Intervention Following Breast Cancer: Efficacy, Recurrence and Tolerability Endpoints (LIBERATE: Clinical http://Trials.gov number NCT00408863), a randomized, placebo-controlled, double-blind trial that demonstrated that Tibolone (Livial), a tissue-selective hormone-replacement therapy (HRT), increased breast cancer (BC) recurrence HR 1.40 (95% CI, 1.14 to 1.70; P = 0.001). A subgroup of women was entered into a study of bone mineral density (BMD). Women with surgically excised primary BC (T1-3, N0-2, M-0) within the last 5 years, complaining of vasomotor symptoms, were assigned to Tibolone, 2.5 mg daily, or placebo treatment for a maximum of 5 years. The BMD substudy enrolled 763 patients, using dual-energy X-ray absorptiometry (DXA) scanning at baseline and at 2 years. In the bone substudy, 699 of 763 women were eligible (345 allocated to Tibolone, and 354, to placebo). After undergoing DXA scans, 300 (43%) women had normal BMD; 317 (45%), osteopenia; and 82 (11.7%), osteoporosis. Low body-mass index (P < 0.001), Asian race (P < 0.001), and late age at menarche (P < 0.04) predicted low bone mass at baseline. Tibolone increased BMD by 3.2% at the lumbar spine and 2.9% at the hip compared with placebo (both P < 0.001). The majority of fractures (55%) occurred in osteopenic patients. Women with normal BMD had increased recurrence with Tibolone, 22 (15.6%) of 141 compared with placebo, 11 (6.9%) of 159 (P = 0.016), whereas no increased BC recurrence was seen in women with low BMD; 15 (7.4%) of 204 taking Tibolone versus 13 (6.7%) of 195 taking placebo. Tibolone is contraindicated after BC treatment, as it increases BMD and BC recurrence. Risk of BC recurrence was elevated in BC women with normal BMD (compared with low) who took Tibolone.

  • effects of Tibolone and continuous combined hormone replacement therapy on mammographic breast density
    American Journal of Obstetrics and Gynecology, 2002
    Co-Authors: Eva Lundstrom, Mirjam Molarts, Gunilla Svane, Edward Azavedo, Alexander Christow, W M Kersemaekers, Gunnar Soderqvist, Jan Barkfeldt, Bo Von Schoultz
    Abstract:

    Abstract Objective: Our purpose was to compare the effects of Tibolone, continuous combined hormone replacement therapy, and placebo on mammographic breast density. Study design: A prospective, randomized, double-blind placebo-controlled study was performed. A total of 166 postmenopausal women were equally randomized to receive Tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E 2 /NETA), or placebo. Mammograms were performed at baseline and after 6 months of treatment. Mammographic density was quantified according to the Wolfe classification and by the percentage area of the breast that had a dense pattern. Results: An increase in mammographic density was much more common among women receiving continuous combined hormone replacement therapy (46%-50%) than among those receiving Tibolone (2%-6%) and placebo (0%) treatment. The difference between E 2 /NETA and placebo was highly significant ( P 2 /NETA versus Tibolone was found to be 8.3 (95% CI 2.7-25.0). Conclusion: An increase in mammographic density should be regarded as an unwanted side effect of hormone replacement therapy. In contrast to estrogen/progestogen treatment, Tibolone seems to exert little stimulation of breast tissue. (Am J Obstet Gynecol 2002;186:717-22.)

Eva Lundstrom - One of the best experts on this subject based on the ideXlab platform.

  • digitized assessment of mammographic breast density effects of continuous combined hormone therapy Tibolone and black cohosh compared to placebo
    Maturitas, 2011
    Co-Authors: Eva Lundstrom, Angelica Linden Hirschberg, Gunnar Soderqvist
    Abstract:

    Abstract Objectives To determine the effects of continuous combined hormone therapy, Tibolone, black cohosh, and placebo on digitized mammographic breast density in postmenopausal women. Study design A prospective, double-blind, placebo-controlled study of 154 postmenopausal women randomized to estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA), Tibolone 2.5 mg or placebo and a prospective, open, uncontrolled drug safety study, of which 65 postmenopausal women were treated with black cohosh. Mammograms, at baseline and after six months of treatment, were previously classified according to visual quantification scales. Main outcome measures Reanalysis of assessable mammograms by digitized quantification of breast density. Results Treatment groups were comparable at baseline. During treatment, both E2/NETA and Tibolone significantly increased breast density (mean increase 14.3%, p p p Conclusions Digitized mammographic breast density is a highly sensitive method confirming significant increase in density by standard E2/NETA treatment and to a lesser extent by Tibolone, whereas black cohosh does not influence mammographic breast density during six months treatment. Digitized assessment also yields data on individual variation and small increases left undetectable by visual classification.

  • effects of Tibolone and continuous combined hormone replacement therapy on mammographic breast density
    American Journal of Obstetrics and Gynecology, 2002
    Co-Authors: Eva Lundstrom, Mirjam Molarts, Gunilla Svane, Edward Azavedo, Alexander Christow, W M Kersemaekers, Gunnar Soderqvist, Jan Barkfeldt, Bo Von Schoultz
    Abstract:

    Abstract Objective: Our purpose was to compare the effects of Tibolone, continuous combined hormone replacement therapy, and placebo on mammographic breast density. Study design: A prospective, randomized, double-blind placebo-controlled study was performed. A total of 166 postmenopausal women were equally randomized to receive Tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E 2 /NETA), or placebo. Mammograms were performed at baseline and after 6 months of treatment. Mammographic density was quantified according to the Wolfe classification and by the percentage area of the breast that had a dense pattern. Results: An increase in mammographic density was much more common among women receiving continuous combined hormone replacement therapy (46%-50%) than among those receiving Tibolone (2%-6%) and placebo (0%) treatment. The difference between E 2 /NETA and placebo was highly significant ( P 2 /NETA versus Tibolone was found to be 8.3 (95% CI 2.7-25.0). Conclusion: An increase in mammographic density should be regarded as an unwanted side effect of hormone replacement therapy. In contrast to estrogen/progestogen treatment, Tibolone seems to exert little stimulation of breast tissue. (Am J Obstet Gynecol 2002;186:717-22.)

H J Kloosterboer - One of the best experts on this subject based on the ideXlab platform.

  • Selective Tissue Distribution of Tibolone Metabolites in Mature Ovariectomized Female Cynomolgus Monkeys after Multiple Doses of Tibolone
    2020
    Co-Authors: H A M Verheul, L P C Delbressine, M L P S Van Iersel, H J Kloosterboer
    Abstract:

    ABSTRACT: 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, 3␣-hydroxyTibolone, 3␤-hydroxyTibolone, and ⌬ 4 -Tibolone), monosulfated (3␣-sulfate,17␤-hydroxyTibolone and 3␤-sulfate,17␤-hydroxyTibolone), and disulfated (3␣,17␤-disulfated-Tibolone and 3␤,17␤S-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 3␣-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 3␣-hydroxyTibolone and the androgenic/progestagenic ⌬ 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). ⌬ 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

  • molecular analysis of human endometrium short term Tibolone signaling differs significantly from estrogen and estrogen progestagen signaling
    Journal of Molecular Medicine, 2007
    Co-Authors: P Hanifimoghaddam, H J Kloosterboer, Curt W Burger, Herman A M Verheul, Bianca Boerssijmons, Anet H A Klaassens, F H Van Wijk, M Den A Bakker, G L Shipley, Leen J Blok
    Abstract:

    Tibolone, a tissue-selective compound with a combination of estrogenic, progestagenic, and androgenic properties, is used as an alternative for estrogen or estrogen plus progesterone hormone therapy for the treatment of symptoms associated with menopause and osteoporosis. The current study compares the endometrial gene expression profiles after short-term (21 days) treatment with Tibolone to the profiles after treatment with estradiol-only (E2) and E2 + medroxyprogesterone acetate (E2 + MPA) in healthy postmenopausal women undergoing hysterectomy for endometrial prolapse. The impact of E2 treatment on endometrial gene expression (799 genes) was much higher than the effect of Tibolone (173 genes) or E2 + MPA treatment (174 genes). Furthermore, endometrial gene expression profiles after Tibolone treatment show a weak similarity to the profiles after E2 treatment (overlap 72 genes) and even less profile similarity to E2 + MPA treatment (overlap 17 genes). Interestingly, 95 Tibolone-specific genes were identified. Translation of profile similarity into biological processes and pathways showed that ER-mediated downstream processes, such as cell cycle and cell proliferation, are not affected by E2 + MPA, slightly by Tibolone, but are significantly affected by E2. In conclusion, Tibolone treatment results in a Tibolone-specific gene expression profile in the human endometrium, which shares only limited resemblance to E2 and even less resemblance to E2 + MPA induced profiles.

  • histological and immunohistochemical evaluation of postmenopausal endometrium after 3 weeks of treatment with Tibolone estrogen only or estrogen plus progestagen
    Fertility and Sterility, 2006
    Co-Authors: Anet H A Klaassens, H J Kloosterboer, Leen J Blok, Heidy F Van Wijk, Payman Hanifimoghaddam, Bianca Sijmons, Patricia C Ewing, Marian Ten J Katebooij, Sjarlot G Kooi, Curt W Burger
    Abstract:

    Objective To evaluate histological and immunohistochemical parameters of short-term (21 days) Tibolone, estrogen-only, and estrogen+progestagen treatment in the human postmenopausal endometrium. Design An observational, open, nonrandomized, controlled study. Setting Three collaborating centers: Amphia Hospital in Breda, Albert Schweitzer Hospital in Dordrecht, Erasmus Medical Center in Rotterdam, the Netherlands. Patient(s) Thirty healthy, postmenopausal women. Intervention(s) Control group (n = 9), no hormonal treatment; Tibolone group (n = 8), patients were treated with 2.5 mg of Tibolone (administered orally) every day, starting 21 days before surgery; estrogen group (n = 7), patients were treated with 2 mg of E 2 (Zumenon, administered orally; Zambon, Amerfoort; The Netherlands) every day, starting 21 days before surgery; estrogen+progestagen group (n = 6), patients were treated with 2 mg of E 2 (Zumenon, administered orally) and 5 mg of medroxyprogesterone acetate (administered orally) every day, starting 21 days before surgery. Main Outcome Measure(s) Uterine tissues were collected, and two pathologists independently assessed histology. Immunohistochemical parameters measured were estrogen receptor α, progesterone receptor A/B, Hoxa10, Ki67, and Bcl-2. Result(s) On the basis of a number of histological and immunohistochemical parameters measured after 21 days of treatment, it was observed that Tibolone displays clearly less stimulation (proliferation) of the human postmenopausal endometrium than estrogen at the beginning of a treatment, but the stimulation is higher than with estrogen+progestagen. Conclusion(s) Short-term (21 days) Tibolone treatment results in a small stimulation of proliferation of the endometrium, and because long-term treatment with Tibolone has been demonstrated to lead to an atrophic endometrium, it may be concluded that the stimulatory effect, as observed in this study, is transient in nature. It is hypothesized that Tibolone first displays a more estrogenic mode of action, which over time, is counterbalanced by the induction of its progestagenic properties.

  • Tibolone and its metabolites enhance tissue factor and pai 1 expression in human endometrial stromal cells evidence of progestogenic effects
    Steroids, 2005
    Co-Authors: Frederick Schatz, Edward Kuczynski, H J Kloosterboer, Lynn Buchwalder, Caroline Tang, Graciela Krikun, Charles J Lockwood
    Abstract:

    Tibolone is a highly effective postmenopausal hormone treatment that has its biological activity dependent on metabolism to 3alpha- and 3beta-OH Tibolone, which bind solely to the estrogen receptor. Despite the high levels of estrogen receptor-binding metabolites in the circulation, the endometrium becomes atrophic, suggesting inactivation of the estrogen response in this tissue which may be due to the progestogenic activity of Tibolone and the Delta-4 Tibolone metabolite. We evaluated the effects of Tibolone and its metabolites on tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI-1) expression in human endometrial stromal cells (HESCs). Since TF and PAI-1 exhibit long-term in vivo and in vitro up-regulation by progestin they serve as endpoints for assessing chronic effects of progestin exposure. Confluent HESCs were primed in serum-containing medium with vehicle control, 10(-8)mol/L estradiol, 10(-7)mol/L medroxyprogesterone acetate, or 10(-8) to 10(-6)mol/L Tibolone or its metabolites, then switched to a defined medium with corresponding vehicle or steroids. After 24h, ELISAs indicated that the progestin elevated TF (6.2-fold +/-3.0; p<0.05) and PAI-1 (eight-fold +/-2.1; p<0.05) levels, whereas the cells were refractory to estradiol exposure. Tibolone and Delta-4 Tibolone (10(-8) to 10(-6)mol/L) were as effective as 10(-7)mol/L medroxyprogesterone acetate in enhancing TF and PAI-1 output (p<0.05). Unexpectedly, at the higher concentrations 3alpha- and 3beta-OH Tibolone also elevated TF and PAI-1 expression (p<0.05). Western blotting confirmed the ELISA results. Our findings suggest that HESCs metabolize 3alpha- and 3beta-OH Tibolone to Tibolone and subsequently to Delta-4 Tibolone, which can both stimulate the progesterone receptor. Since TF and PAI-1 promote hemostasis by complementary mechanisms, our findings account for the reduced occurrence of abnormal uterine bleeding associated with Tibolone therapy.

  • tissue selectivity the mechanism of action of Tibolone
    Maturitas, 2004
    Co-Authors: H J Kloosterboer
    Abstract:

    Abstract Tibolone is effective in preventing bone loss and treating climacteric symptoms, without stimulating the endometrium. The effects on bone, brain and vagina can be accurately explained by the oestrogenic activity of Tibolone, but oestrogenic activity is not expressed in the endometrium. Tibolone behaves differently from oestrogen plus progestogen combinations on the breast. Therefore, Tibolone can be characterised as a selective oestrogen activity regulator. The objective of this review is to characterise the typical properties of Tibolone in order to explain its tissue-selective action. Tibolone is rapidly converted into three major metabolites: 3α- and 3β-hydroxy-Tibolone, which have oestrogenic effects, and the Δ4-isomer, which has progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulphated form. The tissue-selective effects of Tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone preserving effects are the result of oestradiol receptor activation, whilst other steroid receptors, notably the progesterone and androgen receptor, are not involved. Breast tissue of monkeys is not stimulated, as occurs with oestrogen plus progestogen, because Tibolone and its metabolites inhibit sulphatase and 17β-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17β-HSD type II, the combined effects of which prevent conversion to active oestrogens. In addition, Tibolone affects cellular homeostasis in the breast by inhibiting proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium because of the action of the highly stable progestogenic metabolite (Δ4-isomer) in combination with an effect on the sulphatase (inhibition)–sulphotransferase (stimulation) system. The oestrogenic metabolites of Tibolone have direct favourable effects on the cardiovascular system and, in in vivo models, Tibolone has shown no adverse consequences. In conclusion, Tibolone shows oestrogenic effects in brain, vagina and bone and has direct oestrogenic effects on the cardiovascular system. In the endometrium, the progestogenic activity of the Δ4-metabolite and the effect on oestrogen-inactivating enzymes prevent oestrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone appears to regulate estrogenic activity in the various tissues by influencing the availability of estrogenic compounds for the estradiol receptor in a tissue-selective manner.

Gunnar Soderqvist - One of the best experts on this subject based on the ideXlab platform.

  • digitized assessment of mammographic breast density effects of continuous combined hormone therapy Tibolone and black cohosh compared to placebo
    Maturitas, 2011
    Co-Authors: Eva Lundstrom, Angelica Linden Hirschberg, Gunnar Soderqvist
    Abstract:

    Abstract Objectives To determine the effects of continuous combined hormone therapy, Tibolone, black cohosh, and placebo on digitized mammographic breast density in postmenopausal women. Study design A prospective, double-blind, placebo-controlled study of 154 postmenopausal women randomized to estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA), Tibolone 2.5 mg or placebo and a prospective, open, uncontrolled drug safety study, of which 65 postmenopausal women were treated with black cohosh. Mammograms, at baseline and after six months of treatment, were previously classified according to visual quantification scales. Main outcome measures Reanalysis of assessable mammograms by digitized quantification of breast density. Results Treatment groups were comparable at baseline. During treatment, both E2/NETA and Tibolone significantly increased breast density (mean increase 14.3%, p p p Conclusions Digitized mammographic breast density is a highly sensitive method confirming significant increase in density by standard E2/NETA treatment and to a lesser extent by Tibolone, whereas black cohosh does not influence mammographic breast density during six months treatment. Digitized assessment also yields data on individual variation and small increases left undetectable by visual classification.

  • effects of Tibolone and continuous combined hormone replacement therapy on mammographic breast density
    American Journal of Obstetrics and Gynecology, 2002
    Co-Authors: Eva Lundstrom, Mirjam Molarts, Gunilla Svane, Edward Azavedo, Alexander Christow, W M Kersemaekers, Gunnar Soderqvist, Jan Barkfeldt, Bo Von Schoultz
    Abstract:

    Abstract Objective: Our purpose was to compare the effects of Tibolone, continuous combined hormone replacement therapy, and placebo on mammographic breast density. Study design: A prospective, randomized, double-blind placebo-controlled study was performed. A total of 166 postmenopausal women were equally randomized to receive Tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E 2 /NETA), or placebo. Mammograms were performed at baseline and after 6 months of treatment. Mammographic density was quantified according to the Wolfe classification and by the percentage area of the breast that had a dense pattern. Results: An increase in mammographic density was much more common among women receiving continuous combined hormone replacement therapy (46%-50%) than among those receiving Tibolone (2%-6%) and placebo (0%) treatment. The difference between E 2 /NETA and placebo was highly significant ( P 2 /NETA versus Tibolone was found to be 8.3 (95% CI 2.7-25.0). Conclusion: An increase in mammographic density should be regarded as an unwanted side effect of hormone replacement therapy. In contrast to estrogen/progestogen treatment, Tibolone seems to exert little stimulation of breast tissue. (Am J Obstet Gynecol 2002;186:717-22.)