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 (original) (raw)
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Mammographic breast density changes after 1 year of tibolone use
Maturitas, 2004
Hormone replacement therapy (HRT) is widely used with a large variety of regimens and medications. For each of these regimens the goal is the same but there is always a fear about side effects, especially on breast. Mammographic screening is a standard tool for all women receiving hormone replacement therapy. Breast density is very important, because it interferes with the sensitivity of the evaluation and it is also a predictor of malignity. Objective: We planned a study to investigate the effects of tibolone on mammographic breast density. Design and methods: We studied 70 postmenopausal women who started tibolone therapy (2.5 mg per day) after initial mammography and blood samples taken for biochemical examinations. None of the women used any hormone replacement therapy before. Eleven of them either discontinued the therapy or lost contact. After 1 year, we evaluated 59 women by mammographic status, using Wolfe classification. Mammographies were analyzed by two independent radiologists. Results: Mammographies of 59 women were compared with the initial ones. While in the low density patterns, there was a slight increase (15%; P < 0.05); in the higher density groups, there was a decrease of 25% as observed by one radiologist, and 16% according to the other (P < 0.05). None of the women had a diffuse, high density pattern. There was no statistically significant inter-observer variation between two radiologists (P > 0.05). Conclusions: Wolfe classification allows easy interpretation of mammographic evaluation and the results are reproducible. Tibolone, as a tissue-specific steroid, does not have an estrogenic effect on breast cells. We found that it might limit, even reverse breast density increase, especially in postmenopausal women with high breast density.
Effects of tibolone on the breast
European Journal of Obstetrics & Gynecology and Reproductive Biology, 1998
Objective: to evaluate the effect of hormone replacement therapy and tibolone on the breast. Study design: prospective, controlled, randomized study. Setting: Outpatient Menopause Clinic of the Second University of Naples. Participants: forty four women in spontaneous menopause without any risk factor for breast cancer were randomly allocated to three groups: 15 patients (group A) were treated with transdermal oestrogens 50 mg, 2 patches / week for 3 weeks per month, plus acetate nomegestrolo per os 5 mg / die for 12 days per cycle, 17 patients (group B) were treated with tibolone 2.5 mg / die. Twelve patients not given any medication represented the control group (group C). Methods: at the time of recruitment and after at least 12 months of therapy the patients were subjected to a questionnaire aimed at quantifying the slight, moderate or severe presence of the tension / mastodynia symptoms and to a mammographic test to assess the parenchymal pattern according to a quantitative method: type 1 (less than 25% of mammary gland covered by dense tissue), type 2 (from 25% to 75% of total glandular area covered by dense tissue), type 3 (more than 75% of mammary parenchyma covered by dense tissue). Statistical analysis was carried out by means of Fisher's exact test. Results: after at least 12 months of treatment in Group A 5 out of 15 patients (33%) showed a trend of increase in mammographic density not statistically significant (P50.22) when compared with group B in which one patient showed a swift from type 1 to type 2 and another from type 2 to type 3. The analysis of tension / mastodynia symptoms revealed a significantly difference between the two groups (P50.02): in group A mastodynia appeared in three previously asymptomatic women and increased in five women, with a total increase in the symptomatology in 8 out of 15 patients (53.3%), in group B only in one case (5%) mastodynia turned from slight to moderate. Conclusion: in postmenopausal women oestroprogestogenic replacement therapy may be associated with an increase in mammographic density and with the onset or increase in mastodynia. On the contrary tibolone does not seem to affect normostructured mammas and may be considered a first-rate replacement therapy in case of mammas showing particular density or benign mastopathies. menopause spontaneously were recruited into our study.
Fertility and Sterility, 1998
Objective: To investigate the effects of tibolone therapy for menopausal symptoms on mammographic findings and to identify any association between mammographic changes and the demographic and hormonal characteristics of women receiving tibolone.Design: A prospective study.Setting: A university hospital.Patient(s): Seventy-five women who were in the climacteric or postmenopausal period were recruited, and 25 of them were followed up for 24 months.Intervention(s): After high-resolution mammographies were performed and blood samples were collected, tibolone (2.5 mg/d) was administered orally to all patients. At the end of the 24-month follow-up period, blood samples were collected again and mammographies were repeated.Main Outcome Measure(s): Serum levels of LH, FSH, prolactin, estradiol, testosterone, and DHEAS were determined from the collected samples, and mammographies were interpreted.Result(s): At the end of the 24-month follow-up period, mammographic changes were observed in only two women (8%). Women who had no change in mammography constituted group I (n = 23). Women who had a change constituted group II (n = 2). Although the initial hormone levels were not different, the increase in serum DHEAS in group I was significantly higher than in group II (z = 2.30, P = 0.021).Conclusion(s): The frequency of mammographic changes in women receiving tibolone therapy was found to be 8% at the end of the 24-month follow-up. The serum DHEAS level may be an important hormonal marker complementary to mammographic screening for women receiving tibolone therapy. We strongly believe that tibolone is safe in terms of mammographic changes in postmenopausal women.
Fertility and Sterility, 2004
To determine the effects of tibolone and continuous combined HRT (ccHRT) on parameters in the clotting cascade. Design: Randomized, double-blind study. Setting: Hemostasis unit of a university hospital clinic in Germany. Patient(s): Sixty healthy postmenopausal women. Intervention(s): Twenty-nine subjects were treated with tibolone (2.5 mg/d) and 31 with oral ccHRT containing estradiol (2 mg/d) ϩ estriol (1 mg/d) ϩ norethindrone acetate (1 mg/d). Main Outcome Measure(s): Effects on parameters in the clotting cascade at baseline and after 12 and 24 weeks of treatment. Result(s): Tibolone increased fibrinolysis parameters without significantly altering coagulation parameters. Treatment with ccHRT resulted in a stimulating effect on parameters of both fibrinolysis and coagulation. Tibolone showed a stronger reduction of factor VII activity; less reduction of AT-III, protein C activity, and protein S activity; stronger increase of the activated partial thromboplastin time, plasminogen and plasminogen-antiplasminogen complexes; and less increase of D-Dimer than ccHRT. Both preparations similarly reduced climacteric complaints, whereas tibolone showed less breast complaints than ccHRT.
Tissue-selective effects of tibolone on the breast
Maturitas, 2004
Hormone treatment with an estrogen plus a progestagen (EPT) increases the risk of breast cancer. Both hormone activities are also induced by tibolone. In order to assess the breast safety of tibolone, it was evaluated in several pre-clinical models. The effects were inconclusive in breast cancer cell lines but, in various in vivo models, it did not stimulate the breast. In the 17,12-dimethylbenz(a)anthracene (DMBA) model, tibolone clearly inhibited the growth of breast tumors and, when given prophylactally, far less tumors developed. Ovariectomized monkeys showed no increase in the expression of the proliferation marker Ki67. The effects of tibolone and its metabolites on the steroid metabolizing enzymes in breast tissues were investigated in order to unravel its mode of action in the breast. Tibolone and its metabolites did not inhibit aromatase, but sulfatase was profoundly inhibited. The sulfated 3␣-OH tibolone metabolite even showed irreversible inhibition of sulfatase. In addition, 17ß-hydroxysteroid dehydrogenase activities were slightly inhibited and sulfotransferase activity was stimulated at low concentrations. The consequence of these effects is that, for both endogenous estrogens and estrogenic-metabolites of tibolone, the equilibrium is preferential for the sulfated forms. The intracellular hormonal milieu tibolone and its metabolites also influence cellular homeostasis. It inhibits cell proliferation of normal breast epithelial cells and stimulates apoptosis. In this respect, tibolone behaves differently from estrogens. Clinical studies have shown that tibolone users experience less breast tenderness and do not show an increase in mammographic density as found with continuous combined EPT. The data concerning tibolone and breast cancer risk are inconclusive and require further investigation.
Clinical Drug Investigation, 2000
Objective: To compare the effects of tibolone, estriol and conventional hormone replacement therapy (HRT) on mammographic parenchymal density in postmenopausal women. Design and Setting: This was a non-randomised, prospective, longitudinal, comparative study conducted at two specialist outpatient clinics in Chile. Patients and Participants: 210 non-obese, postmenopausal women aged <65 years with a normal mammogram at baseline. Methods: Participants received one of seven oral HRT regimens for 1 year. Treatments (daily doses) were: (i) estradiol 2mg; (ii) estradiol 2mg plus sequential medroxyprogesterone acetate (MPA) 5mg for 10 to 16 days/cycle; (iii) estradiol 2mg plus continuous MPA 2.5mg; (iv) combined equine estrogens (CEE) 0.625mg; (v) CEE 0.625mg plus sequential MPA 5mg; (vi) estriol 2mg; or (vii) tibolone 2.5mg. In addition, an age-matched group of 30 untreated control individuals was studied. Results: Increased mammographic density occurred in 67, 57, 30, 43 and 27% of patients receiving regimens (i) to (v), respectively. No patients receiving tibolone or estriol experienced increases (both p < 0.05 vs conventional HRT). Overall, 67 of 210 treated patients [31.9%; 95% confidence interval (CI) 25.7%, 38.6%] experienced increases, compared with one of 30 controls (3.3%; 95% CI 0%, 17.2%). Conclusions: Neither the tissue-specific agent tibolone nor the short-acting estrogen estriol induced any breast density increase. Increased breast density was more frequent with regimens containing estradiol than CEE, and with unopposed rather than opposed regimens. Tibolone (or estriol, if suitable) may be a preferable HRT for women in whom this is a concern.
Mammographic Changes in Women Receiving Tibolone Therapy
Fertility and Sterility, 1998
Objective: To investigate the effects of tibolone therapy for menopausal symptoms on mammographic findings and to identify any association between mammographic changes and the demographic and hormonal characteristics of women receiving tibolone. Design: A prospective study. Setting: A university hospital. Patient(s): Seventy-five women who were in the climacteric or postmenopausal period were recruited, and 25 of them were followed up for 24 months. Intervention(s): After high-resolution mammographies were performed and blood samples were collected, tibolone (2.5 mg/d) was administered orally to all patients. At the end of the 24-month follow-up period, blood samples were collected again and mammographies were repeated. Main Outcome Measure(s): Serum levels of LH, FSH, prolactin, estradiol, testosterone, and DHEAS were determined from the collected samples, and mammographies were interpreted. Result(s): At the end of the 24-month follow-up period, mammographic changes were observed in only two women (8%). Women who had no change in mammography constituted group I (n ϭ 23). Women who had a change constituted group II (n ϭ 2). Although the initial hormone levels were not different, the increase in serum DHEAS in group I was significantly higher than in group II (z ϭ 2.30, P ϭ 0.021). Conclusion(s): The frequency of mammographic changes in women receiving tibolone therapy was found to be 8% at the end of the 24-month follow-up. The serum DHEAS level may be an important hormonal marker complementary to mammographic screening for women receiving tibolone therapy. We strongly believe that tibolone is safe in terms of mammographic changes in postmenopausal women.
Long-term effects of tibolone on mammographic density
Fertility and Sterility, 2004
Objective: To investigate the long-term effect of tibolone on mammographic density. Design: Open-label, nonrandomized study. Setting: Academic research environment. Patient(s): Postmenopausal women. Intervention(s): Tibolone was administered orally, mammograms were performed annually. Main Outcome Measure(s): Mammographic density according to the Wolfe classification, performed by two independent radiologists, both of whom were blinded to treatment group. Result(s): No statistically significant differences were found between the two groups in baseline demographic data. There were no statistically significant differences in mammographic density between the control and active groups at baseline or at 10 years. Conclusion(s): This pilot study shows that tibolone does not adversely alter the mammographic density of the breasts over 10 years of treatment.
American Journal of Epidemiology, 2005
Mammographic density is an independent risk factor for breast cancer. In postmenopausal women, higher levels of endogenous sex steroids are associated with an increased risk of breast cancer. Limited prior data suggest that endogenous sex steroids either are not associated (total estradiol and progesterone) or are negatively associated (free estradiol) with higher mammographic density. To analyze the associations between endogenous sex steroids and mammographic density, the authors conducted a 1998-2005 cross-sectional analysis of baseline clinical trial data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial for US women who had not used hormone therapy for at least 3.1 months prior to baseline. In models adjusted for age, body mass index, parity, prior use of hormone therapy, time since last use of hormone therapy, and the interaction between prior hormone therapy use and time since last hormone therapy use, higher levels of estrone (b ¼ 0.0013, p ¼ 0.014), estradiol (b ¼ 0.0009, p ¼ 0.009), and bioavailable estradiol (b ¼ 0.0021, p ¼ 0.018) were statistically significantly related to greater mammographic density. (Beta coefficients express the increment in mammographic density per-unit increment (pg/ml) of each hormone.) These results suggest that some sex steroids may increase the risk of breast cancer by stimulating breast epithelial or stromal proliferation, which appears on a mammogram as higher density. breast neoplasms; mammography; menopause; receptors, steroid; risk factors Abbreviations: BDL, below detectable limits; BMI, body mass index; PEPI, Postmenopausal Estrogen/Progestin Interventions; SHBG, sex hormone-binding globulin.
Breast Cancer Research, 2007
Background: High breast density is associated with increased breast cancer risk. Epidemiologic studies have shown an increase in breast cancer risk in postmenopausal women with high levels of sex steroids. Hence, sex steroids may increase postmenopausal breast cancer risk via an increase of breast density. The objective of the present study was to study the relation between circulating oestrogens and androgens as well as sex hormone binding globulin (SHBG) in relation to breast density. Methods: We conducted a cross-sectional study among 775 postmenopausal women, using baseline data of a random sample of the Prospect-EPIC study. Prospect-EPIC is one of two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition, and women were recruited via a breast cancer screening programme. At enrolment a nonfasting blood sample was taken and a mammogram was made. Oestrone, oestradiol, dehydroepiandrosterone sulfate, androstenedione, testosterone and SHBG levels were measured, using double-antibody radioimmunoassays. Concentrations of free oestradiol and free testosterone were calculated from the measured oestradiol, testosterone and SHBG levels Mammographic dense and nondense areas were measured using a semiquantitative computerized method and the percentage breast density was calculated. Mean breast measures for quintiles of hormone or SHBG levels were estimated using linear regression analyses. Results: Both oestrogens and testosterone were inversely related with percent breast density, but these relationships disappeared after adjustment for BMI. None of the sex steroids or SHBG was associated with the absolute measure of breast density, the dense area. Conclusion: The results of our study do not support the hypothesis that sex steroids increase postmenopausal breast cancer risk via an increase in breast density.