Tibolone Group Research Articles

Effects of menopausal hormone therapy on the risk of ovarian cancer: Health Insurance Database in South Korea-based cohort study.

This study aimed to evaluate the risk of ovarian cancer associated with hormone therapy regimens using a Korean population-based study. This retrospective cohort study used national health checkup and insurance data from January 1, 2002, to December 31, 2019, provided by Korea's National Health Insurance Service. Women older than 40 years who recorded "menopause" in the questionnaire from 2002 to 2011 were included in this study. Menopausal hormone therapy (MHT) preparations were classified into tibolone, combined estrogen plus progestin by the manufacturer, combined estrogen plus progestin by physician, estrogen, and topical estrogen groups. The number of participants recorded as menopausal during the national health examination between 2002 and 2011 was 2,506,271. The MHT and non-MHT groups consisted of 373,271 and 1,382,653 patients, respectively. The hazard ratios (HR) of ovarian cancer according to MHT type, age at inclusion, body mass index, region, socioeconomic status, Charlson comorbidity index, age at menarche, age at menopause, parity, smoking, alcohol consumption, physical exercise, and period from menopause to inclusion were evaluated. The risk of ovarian cancer was reduced in the tibolone group (HR, 0.84; 95% confidence interval, 0.75-0.93; P = 0.003) and in patients in rural areas (HR, 0.90; 95% confidence interval, 0.845-0.98; P = 0.013). The risk of ovarian cancer was not related to the other MHT treatments. Tibolone was associated with a lower risk of ovarian cancer. No other MHT was associated with ovarian cancer.

Menopausal hormone therapy and the risk of type 2 diabetes mellitus: Health Insurance Database in South Korea-based retrospective cohort study.

Menopausal hormone therapy (MHT) is known to reduce the incidence of type 2 diabetes mellitus (T2DM); however, since the Women's Health Initiative study, the types and doses of female hormones used for MHT have changed considerably. Therefore, this study was conducted to determine whether MHT, which is currently widely prescribed, increases the risk of T2DM. We performed a retrospective cohort study based on national health insurance data and cancer screening data from 2002 to 2019. We included the MHT group as postmenopausal women older than 40 years who used at least one MHT for at least 6 months between 2003 and 2011. We subclassified the MHT group into five categories; tibolone, combined estrogen plus progestin by the manufacturer (CEPM), oral estrogen, combined estrogen plus progestin by the physician (CEPP), and transdermal estrogen. We selected the non-MHT group as postmenopausal women who had never been prescribed MHT from 2002 to 2019. We compared the incidence of T2DM between the MHT group and the non-MHT group. We enrolled 330,771 women in the MHT group and 798,550 women in the control group. T2DM was diagnosed in 15.2% of the non-MHT group, 16.6% of the tibolone group, 12.1% of the CEPM group, 16.6% of the oral estrogen group, 15.4% of the CEPP group, and 17% of the transdermal estrogen group. In Cox proportional hazard analysis adjusted for variable factors, tibolone, oral estrogen, CEPP, and transdermal estrogen increased the incidence of T2DM. In contrast, there was no change in the risk of T2DM in the CEPM group. MHT, including tibolone, which is currently the most prescribed agent, increased the risk of T2DM; however, CEPM did not increase the risk of T2DM. Only tibolone increased the risk of T2DM in participants older than 70 years.

Tibolone Improves Memory and Decreases the Content of Amyloid-β Peptides and Tau Protein in the Hippocampus of a Murine Model of Alzheimer's Disease.

Alzheimer's disease (AD) affects women more than men and consequently has been associated with menopause. Tibolone (TIB) has been used as a hormone replacement therapy to alleviate climacteric symptoms. Neuroprotective effects of TIB have also been reported in some animal models. This study aimed to assess the effect of TIB on memory and Aβ peptides and tau protein content in the hippocampus and cerebellum of transgenic 3xTgAD ovariectomized mice. Three-month-old female mice were ovariectomized. Ten days after surgery, animals were divided into four groups: wild-type (WT)+vehicle; WT+TIB (1 mg/kg); 3xTgAD+vehicle; and 3xTgAD+TIB (1 mg/kg). TIB was administered for three months, and memory was evaluated using the object-in-context recognition task. Subsequently, animals were decapitated, and the hippocampus and cerebellum were dissected. Using commercial ELISA kits, these brain structures were homogenized in a PBS buffer for quantifying Aβ40 and Aβ42 and phosphorylated and total tau.ResultsA long-term memory deficit was observed in the 3xTgAD+vehicle group. In contrast, TIB treatment improved long-term memory in the 3xTgAD+TIB group than those treated with vehicle (p < 0.05). Furthermore, TIB treatment decreased Aβ and tau content in the hippocampus of 3xTgAD mice compared to vehicle-treated groups (p < 0.05). No significant changes were observed in the cerebellum. Chronic treatment with TIB showed neuroprotective effects and delayed AD neuropathology in the 3xTgAD mice. Our results support hormone replacement therapy with TIB in menopausal women for neuroprotection.

Relationship between Menopausal Hormone Therapy and Oral Cancer: A Cohort Study Based on the Health Insurance Database in South Korea.

The association between the development of oral cavity cancer and sex hormones is unclear and inconsistent. This study aimed to evaluate the relationship between menopausal hormone therapy (MHT) and oral cavity cancer in menopausal women in Korea. In this retrospective cohort study, data were provided by the Korean National Health Insurance Service regarding a screening examination conducted from 1 January 2002 to 31 December 2019. Postmenopausal patients aged ≥40 years were considered, including 333,072 women in the MHT group and 847,558 women in the non-MHT group. Participants were divided into MHT types (tibolone, combined estrogen plus progestin by manufacturer, estrogen, combined estrogen plus progestin by physician, and topical estrogen), and the risk factors for oral cavity cancer development were analyzed. There was no significant association between smoking, alcohol consumption, age at menarche, and age at menopause with oral cavity cancer in postmenopausal women. However, the oral estrogen (hazard ratio [HR]: 1.633; 95% confidence interval [CI]: 1.35–1.976) and tibolone groups (HR: 1.633; 95% CI: 1.35–1.976) were associated with an elevated risk of oral cavity cancer. The results of this study suggest that MHT increases the risk of oral cavity cancer in postmenopausal women.

Short-term administration of tibolone reduces inflammation and oxidative stress in the hippocampus of ovariectomized rats fed high-fat and high-fructose

ABSTRACT Inflammation and oxidative stress are critical events involved in neurodegeneration. In animal models, it has been shown that chronic consumption of a hypercaloric diet, which leads to inflammatory processes, affects the hippocampus, a brain region fundamental for learning and memory processes. In addition, advanced age and menopause are risk factors for neurodegeneration. Hormone replacement therapy (HRT) ameliorates menopause symptoms. Tibolone (TB), a synthetic hormone, exerts estrogenic, progestogenic and androgenic effects on different tissues. We aimed to determine the effect of short-term TB administration on oxidative stress and inflammation markers in the hippocampus of ovariectomized rats fed a high-fat-and-fructose diet (HFFD). Adult female rats were ovariectomized (OVX) and fed standard diet or HFFD—consisting of 10% lard supplemented chow and 20% high-fructose syrup in the drinking water—and administered vehicle or TB (1 mg/kg for seven days). Finally, we administered hormone receptor antagonists (MPP, RU486 or FLU) to each of the OVX + HFFD + TB groups. Bodyweight, triglycerides and cholesterol, oxidative stress and inflammation markers, and the activity and expression of antioxidant enzymes were quantified in the hippocampus of each experimental group. We observed that short-term TB administration significantly reduced body weight, AGEs, MDA levels, increased SOD and GPx activity, improved GSH/GSSG ratio, and reduced IL-6 and TNF-α. Our findings suggest that short-term administration of TB decreases oxidative stress and reduces inflammation caused by HFFD and early estrogenic decline. These effects occurred via estrogen receptor alpha.

The effect of tibolone treatment on fasting blood sugar, insulin, insulin resistance and endothelial function in postmenopausal women: A meta-analysis of randomized controlled trials.

The menopause is associated in females with the presence of dysglycemia, insulin resistance and with the development of endothelial dysfunction. Tibolone (TIB) is a synthetic steroid compound with selective oestrogenic and, to a lesser extent, progestogenic and androgenic properties prescribed to postmenopausal women to alleviate the symptoms of the climaterium and to prevent the development of osteoporosis. However, the impact of TIB on fasting blood sugar (FBS), insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) index and flow-mediated dilation (FMD) in women has not been evaluated so far. Thus, to investigate this research question, we conducted the present systematic review and meta-analysis. Two independent reviewers searched the Scopus, Web of Science, PubMed/Medline and Embase databases up to 20 December 2020. The weighted mean differences (WMDs) and the 95% confidence intervals (CI) were calculated using the DerSimonian and Laird random effects models between the TIB and control groups and included in the forest plot. The overall findings were generated from 12 eligible randomized controlled trials. As compared to controls, TIB administration resulted in a significant reduction of FBS (WMD: -3.06mg/dL, 95% CI: -5.30 to -0.82, P=0.007), and of the HOMA-IR index (WMD: -0.61, 95% CI: -1.11 to -0.11, P=0.01). However, treatment with TIB did not lead to significant changes of the FMD (WMD: 0.78%, 95% CI: -0.20 to 1.77, P=0.12) or of insulin levels (WMD: -0.10 mIU/L, 95% CI: -2.04 to 1.83, P=0.91). TIB administration can decrease FBS and the HOMA-IR index in postmenopausal women. However, the use of TIB does not influence insulin levels or FMD.

CCDC114, DNAI2 and TOP2A involves in the effects of tibolone treatment on postmenopausal endometrium

BackgroundThis study aimed to explore the molecular mechanisms of tibolone treatment in postmenopausal women.MethodsThe gene set enrichment profile, GSE12446, which includes 9 human endometrial samples from postmenopausal women treated with tibolone (tibolone group) and 9 control samples (control group), was downloaded from GEO database for analysis. Differentially expressed genes (DEGs) in tibolone vs. control groups were identified and then used for function and pathway enrichment analysis. Protein–protein interaction (PPI) network and module analyses were also performed. Finally, drug–target interaction was predicted for genes in modules, and then were validated in Pubmed.ResultsA total of 238 up-regulated DEGs and 72 down-regulated DEGs were identified. These DEGs were mainly enriched in various biological processed and pathways, such as cilium movement (e.g., CCDC114 and DNAI2), calcium ion homeostasis, regulation of hormone levels and complement/coagulation cascades. PPI network contained 368 interactions and 166 genes, of which IGF1, DNALI1, CCDC114, TOP2A, DNAH5 and DNAI2 were the hue genes. A total of 96 drug–gene interactions were obtained, including 94 drugs and eight genes. TOP2A and HTR2B were found to be targets of 28 drugs and 38 drugs, respectively. Among the 94 obtained drugs, only 12 drugs were reported in studies, of which 7 drugs (e.g., epirubicin) were found to target TOP2A.ConclusionsCCDC114 and DNAI2 might play important roles in tibolone-treated postmenopausal women via cilium movement function. TOP2A might be a crucial target of tibolone in endometrium of postmenopausal women.

Tibolone, alendronate, and simvastatin enhance implant osseointegration in a preclinical in vivo model.

The objective of the study was to evaluate and compare the effect of different drugs such as simvastatin, alendronate, and tibolone for titanium implant osseointegration enhancement. Eighty female albino Wistar rats were equally divided into five groups: Group I (ovariectomy), Group II (sham ovariectomy), Group III (alendronate+ovariectomy), Group IV (simvastatin+ovariectomy), and Group V (tibolone+ovariectomy). Three months after ovariectomy, we performed bilateral titanium intramedullary nailing in all groups, followed by oral administration of alendronate, simvastatin, or tibolone for 12weeks. Examinations included micro-CT, mechanical pull-out test, histology, and bone serum markers. Peri-implant micro-CT analysis showed a significantly higher overall bone tissue in tibolone compared to the ovariectomy group, while no significant difference was found between the treatment groups. Sham ovariectomy, alendronate, and tibolone groups had a higher body mass density compared to ovariectomy and simvastatin groups. All treatment groups had a greater thickness of the peri-implant compact bone layer compared to ovariectomy group, but the results were not statistically significant. Tibolone presented the highest values in pull-out test, but alendronate showed more consistently positive results compared to other groups. Osteocalcin had in the tibolone group almost three times the value in the ovariectomy group, but the results were not statistically significant. The hypothesis that alendronate, simvastatin, and tibolone enhance the osseointegration process of intramedullary titanium implants in ovariectomized rats has been accepted, while tibolone could offer the best results.

Is the Expression of the Components of the Carotid Matrix of Rats Influenced by Estrogen, Progestin and Tibolone?

To analyze the effects of estrogen alone or in combination with progestogens and tibolone (TIB) on the expression of the extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), of perlecan, and of heparanase (HPSE) of the vascular walls of the carotid arteries. A total of 30 250-day-old ovariectomized Wistar rats were orally treated for 5 weeks with: a) 1 mg/kg of estradiol benzoate (EB); b) EB + 0.2 mg/kg of medroxyprogesterone acetate (MPA); c) EB + 0.2mg/kg of norethisterone acetate (NETA); d) EB + 2 mg/kg of dydrogesterone (DI); e) 1 mg/kg of TIB; f) placebo (CTR). Following treatment, the expression of mRNA for MMP-2, MMP-9, and HPSE was analyzed by real-time polymerase chain-reaction (PCR), and the expression of MMP-2, of MMP-9, of tissue inhibitor of metalloproteinase 2 (TIMP-2), and of perlecan was quantified by immunohistochemistry in the carotid arteries. The groups showed significant differences on mRNA HPSE expression (p = 0.048), which was higher in the EB, EB + MPA, and TIB groups. There was no statistically significant difference in mRNA MMP-2 or MMP-9 expression. The immunohistochemical expression of MMP-2, of TIMP-2, of MMP-9, of HPSE, and of perlecan showed no differences between groups. Estradiol alone or associated with MPA and TIB treatment can increase mRNA HSPE expression of the walls of the carotid arteries in ovariectomized rats.

Comparison of the Efficacy of Tibolone and Transdermal Estrogen in Treating Menopausal Symptoms in Postmenopausal Women.

ObjectivesThis study aimed to compare the efficacy of tibolone and transdermal estrogen in treating menopausal symptoms in postmenopausal women with an intact uterus.MethodsOverall, 26 women consumed tibolone orally and 31 women received transdermal estrogen gel mixed with progestogen. The menopause rating scale (MRS) was used to assess their menopausal symptoms at their first outpatient visit and 6 months later.ResultsThe transdermal estrogen group showed significant improvements in more items of the MRS questionnaire. There was a favorable change in body weight in the transdermal estrogen group compared with that in the tibolone group. Depressive mood, irritability, physical and mental exhaustion, sexual and bladder problems, and joint and muscular discomfort improved only in the transdermal estrogen group, whereas heart discomfort and vaginal dryness improved only in the tibolone group. Nevertheless, the intergroup differences in each item were insignificant after adjusting for body mass index and hypertension, which differed before treatment.ConclusionsBoth the therapeutic options improved menopausal symptoms within 6 months of use. However, transdermal estrogen appeared to be more effective in preventing weight gain in menopausal women than tibolone.

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.

Effect of tibolone pretreatment on kinases and phosphatases that regulate the expression and phosphorylation of Tau in the hippocampus of rats exposed to ozone.

Oxidative stress (OS) is a key process in the development of many neurodegenerative diseases, memory disorders, and other pathological processes related to aging. Tibolone (TIB), a synthetic hormone used as a treatment for menopausal symptoms, decreases lipoperoxidation levels, prevents memory impairment and learning disability caused by ozone (O3) exposure. However, it is not clear if TIB could prevent the increase in phosphorylation induced by oxidative stress of the microtubule-associated protein Tau. In this study, the effects of TIB at different times of administration on the phosphorylation of Tau, the activation of glycogen synthase kinase-3β (GSK3β), and the inactivation of Akt and phosphatases PP2A and PTEN induced by O3 exposure were assessed in adult male Wistar rats. Rats were divided into 10 groups: control group (ozone-free air plus vehicle [C]), control + TIB group (ozone-free air plus TIB 1 mg/kg [C + TIB]); 7, 15, 30, and 60 days of ozone exposure groups [O3] and 7, 15, 30, and 60 days of TIB 1 mg/kg before ozone exposure groups [O3 + TIB]. The effects of O3 exposure and TIB administration were assessed by western blot analysis of total and phosphorylated Tau, GSK3β, Akt, PP2A, and PTEN proteins and oxidative stress marker nitrotyrosine, and superoxide dismutase activity and lipid peroxidation of malondialdehyde by two different spectrophotometric methods (Marklund and TBARS, respectively). We observed that O3 exposure increases Tau phosphorylation, which is correlated with decreased PP2A and PTEN protein levels, diminished Akt protein levels, and increased GSK3β protein levels in the hippocampus of adult male rats. The effects of O3 exposure were prevented by the long-term treatment (over 15 days) with TIB. Malondialdehyde and nitrotyrosine levels increased from 15 to 60 days of exposure to O3 in comparison to C group, and superoxide dismutase activity decreased. Furthermore, TIB administration limited the changes induced by O3 exposure. Our results suggest a beneficial use of hormone replacement therapy with TIB to prevent neurodegeneration caused by O3 exposure in rats.

Hormone Replacement Therapy for Surgical Menopause: Is there an Ideal Drug? A Comparative Study of Conjugated Equine Estrogens and Tibolone

ABSTRACT Objective To compare the effects of continuous combined conjugated equine estrogens (CEE) with those of tibolone on symptom control, lipid profile, and tolerability in women with surgical menopause. Materials and methods This was a randomized controlled trial study conducted in the Department of Obstetrics and Gynaecology of Global Rainbow Hospital Pvt. Ltd., Agra (2014–2016) comprising 150 women. Generally, healthy postmenopausal women having undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy irrespective of age and indication of surgery and no absolute contraindications to hormone replacement therapy (HRT) or tibolone were enrolled. Fifty subjects did not receive any HRT, 50 were treated with CEE 0.625 mg, and 50 were given tibolone 2.5 mg for 13 treatment cycles, each of 28 days. Results were statistically analyzed regarding drug efficacy in amelioration of menopausal symptoms and side effects at follow-up periods of 1, 6, and 12 months. Results A total of 150 subjects were enrolled and received at least one dose of the study medication, of which 134 (89.4%) subjects completed the study (n = 40 in CEE and n = 44 in tibolone). The incidence of postmenopausal symptoms decreased significantly over time in the treatment groups, compared with baseline, including significant decreases in the incidence of urogenital and sexual health symptoms, with p-values 0.001 and 0.004 in cases that received CEE and tibolone respectively. Significant differences in symptom control (other than hot flashes) were observed between treatment groups in a few different cycles for different symptoms, but no consistent or clinically significant trends were observed. Significant decreases in total cholesterol (5.6%) and low-density lipoprotein cholesterol (7.5%) were observed at cycle 13, compared with baseline, in the CEE group, and significant decreases in high-density lipoprotein cholesterol (8.5%) and triglycerides (13.7%) were observed at cycle 13, compared with baseline, in the tibolone group. Significant weight gain was observed at cycle 13 in the tibolone group (3.05 kg), compared with the CEE group (0.96 kg). The incidences of adverse events were similar in both treatment groups. Conclusion Women treated with CEE and tibolone showed significant improvement of climacteric symptoms, including urogenital and sexual health symptoms. Treatment with either preparation significantly improved subjective wellbeing, vasomotor symptoms, and vaginal dryness. The CEE and tibolone each induced a different mix of beneficial changes in the lipid profile. It is seen that tibolone seems to be effective on estrogen withdrawal symptoms and with its acceptable androgenic side effects can be an appropriate selection for HRT in postmenopausal women with decreased sexual desire. How to cite this article Gupta N. Hormone Replacement Therapy for Surgical Menopause: Is there an Ideal Drug? A Comparative Study of Conjugated Equine Estrogens and Tibolone. J South Asian Feder Menopause Soc 2017;5(1):11-15.

Short-term tibolone does not interfere with endothelial function: a double-blinded, randomized, controlled trial

ABSTRACTObjective To evaluate the effect of short-term hormone replacement therapy with tibolone 2.5 mg daily on endothelial function of healthy postmenopausal women, using flow-mediated dilation (FMD) of the brachial artery.Methods We performed a randomized, double-blinded, placebo-controlled study. A total of 100 healthy postmenopausal women were randomly allocated to receive tibolone (n = 50) or placebo (n = 50) for 28 days. Measurement of the FMD of the brachial artery was performed before and after the use of tibolone and placebo.Results A total of 31 women completed the study in the tibolone group, and 32 women completed the study in the control group. The results of the FMD measurements obtained from the women in the two groups before treatment were similar (0.018 and 0.091, for tibolone and placebo, p = 0.57). The values of the FMD in women who used tibolone and placebo, before and after the treatment, were similar in both groups. The numbers of women who presented an increase in the values of the FMD in both groups were also similar.Conclusion Our results demonstrate that the administration of 2.5 mg tibolone to healthy postmenopausal women for 28 days does not promote endothelial-dependent vasodilation, measured by FMD of the brachial artery.

Efeitos da tibolona sobre o parênquima mamário: estudo experimental

To assess the effect of tibolone on mammary tissue of castrated rats over 3 different periods of time. Sixty virgin female Wistar rats were submitted to oophorectomy. Twenty-one days after surgery, with hypoestrogenism confirmed, the experimental rats were randomly assigned to six groups: Tibolone 1 (n=10) received tibolone 1 mg/day for 23 days, tibolone 2 (n=10) for 59 days and tibolone 3 (n=10) for 118 days. The groups control 1 (n=8), control 2 (n=7) and control 2 (n=10) received distilled water for 23, 59 and 118 days, respectively. After treatment, all six pairs of mammary glands were removed and stained with hematoxylin and eosin (HE) for histological analysis after euthanasia. The histological parameters evaluated were: epithelial cell proliferation and secretory activity. The variables were analyzed statistically, with the level of significance set at 0.05. Histological changes were observed in 20/55 rats, mild epithelial hyperplasia in 7/55, moderate epithelial hyperplasia in 5/55, alveolar-nodular hyperplasia in 7/55, atypia without epithelial proliferation in 1/55, and no cases of severe epithelial hyperplasia were found. Secretory activity was observed in 31/55 rats. The secretory activity was significantly higher in the tibolone groups compared to control at all the time points assessed (p=0,001). The histological changes were did not show significance when the control and tibolone groups were compared. The time of exposure to tibolone did not show significance when the three different periods of evaluation were compared. No relation between histological modification and tibolone treatment was verified after short-, medium- and long-term treatment.

Is expression of rat breast matrix components influenced by estrogen, progestins and tibolone?

Aim To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of heparanase (HSPE), extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), perlecan and proliferating cell nuclear antigen (PCNA) in normal breast tissue.Methods Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expressions of mRNA for HSPE, MMP-2 and MMP-9 were analyzed by real-time PCR and the protein expressions of HSPE, MMP-2, MMP-9, perlecan and PCNA were quantified by immunohistochemistry.Results There was a statistically significant difference among the groups for the expression of HSPE mRNA due to high levels in the tibolone group. The groups differed in terms of PCNA, with lower levels found in the tibolone group followed by the estradiol benzoate + dydrogesterone group. A statistically significant positive correlation was observed for PCNA versus perlecan and MMP-9.Conclusions There was no difference in the effects of combinations of estradiol and different progestogens on extracellular matrix components, and breast cell proliferation was associated with increases in perlecan and MMP-9.

Efficacy and Safety Investigation of Kuntai Capsule for the Add-back Therapy of Gonadotropin Releasing Hormone Agonist Administration to Endometriosis Patients

Background:As a Chinese Traditional Medicine product, Kuntai capsule could improve the peri-menopausal symptoms in postmenopausal women. But it is still not clear whether Kuntai capsule has a good effect on alleviating peri-menopausal symptoms induced by gonadotropin releasing hormone agonist (GnRH-a) treatment. The purpose of this study was to investigate the clinical effectiveness and safety of Kuntai capsule, on peri-menopausal symptoms in endometriosis (EMS) patients, with postoperative GnRH-a treatment.Methods:Ninety EMS ovarian cyst women with postoperative GnRH-a administration were enrolled in the study, and were randomly divided into Kuntai group, Tibolone group, or blank Control group. The therapeutic strategy in Kuntai group was 4 Kuntai capsules tid,po for 12 weeks after the first GnRH-a injection, while Tibolone 2.5 mg qd, po for 12 weeks in Tibolone group. There was no drug addition in Control group. Climacteric complaints were evaluated by Kupperman menopausal index (KMI) and hot flash/sweating score. Liver and renal functions, lipid profile, serum sex hormone levels and endometrial thickness were measured, and the frequency of adverse events in Kuntai and Tibolone groups was recorded.Results:(1) Before GnRH-a therapy, the baseline parameter results were comparable in the three groups (P > 0.05). (2) After GnRH-a therapy, KMI and hot flash/sweating scores in all the three groups increased significantly (P < 0.05). At the 4th week after GnRH-a therapy, KMI and hot flash/sweating score results were as follows: Control group > Kuntai group > Tibolone group (P < 0.05); at the 8th and 12th week after GnRH-a therapy, KMI and hot flash/sweating score in Control group were significantly higher than the other two groups (P < 0.05), and no significant difference was identified between Kuntai and Tibolone group (P > 0.05). (3) No statistical change took place in the liver and renal functions and lipid profile in all the three groups after the treatment (P > 0.05). (4) The posttherapeutic serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) level and endometrial thickness decreased significantly in all the three groups (P < 0.05). After therapy, serum E2 level in Tibolone group was obviously higher than the other two groups (P < 0.05), while FSH and LH levels were obviously lower (P < 0.05). (5) The incidence of vaginal bleeding, breast distending pain in Tibolne group was obviously higher than Kuntai group (P < 0. 05).Conclusions:Kuntai capsule is effective on the peri-menopausal symptoms induced by postoperative GnRH-a administration to EMS patients, although its clinical effect might be a few weeks later than Tibolone. Kuntai capsule might be a little safer than Tibolone tablet.

The Comparison of Tibolone and Hormone Replacement Therapy on Bone Densitometry and Bone Turnover in Postmenopausal Women

nine months of entering into the study. Results: After the treatments, ALP reduced significantly in the CEE/MPA and tibolone groups (P = 0.02, P = 0.002), but increased in the control group (P = 0.03) in comparison with the baseline. After the treatments with respect to femoral BMD, significantly increase occurred only in the tibolone group in comparison with the baseline (0.95 ± 0.13, 0.97 ± 0.12, P = 0.004). Conclusions: Tibolone may be considered as an alternative for preventing of osteoporosis in postmenopausal women.

Efficacy and safety of remifemin on peri-menopausal symptoms induced by post-operative GnRH-a therapy for endometriosis: a randomized study versus tibolone.

BackgroundThe aim of this study was to investigate clinical efficacy and safety of Remifemin on peri-menopausal symptoms in endometriosis patients with a post-operative GnRH-a therapy.Material/MethodsWe treated 116 women who had endometriosis with either Remifemin (n=56) 20 mg bid po or Tibolone (n=60) 2.5 mg qd po for 12 weeks after GnRH-a injection. The efficacy was evaluated by Kupperman menopausal index (KMI), and hot flash/sweating scores. The safety parameters such as liver and renal functions, lipid profile, endometrial thickness, and serum sex hormone level, as well as the incidence of adverse events were recorded.Results(1) After GnRH-a therapy, KMI and hot flash/sweating scores in both groups increased significantly (P<0.05) but we found no significant difference for KMI (2.87±1.40 for Remifemin and 2.70±1.26 for Tibolone) and hot flash/sweating scores (0.94±1.72 for Remifemin and 1.06±1.78 for Tibolone) between the 2 groups (P>0.05). (2) No statistical change was observed in liver or renal functions and lipid profile in both groups before and after the treatment (P>0.05). The post-therapeutic serum FSH, LH, and E2 level and endometrial thickness decreased remarkably in both groups (P<0.05). E2 level in the Remifemin group was obviously lower than that in the Tibolone group (P<0.05), and FSH and LH levels were strongly higher (P<0.05). No significant difference in thickness were found in either group (P>0.05). The Remifemin group had far fewer adverse events than the Tibolone group (P<0. 05).ConclusionsCompared with Tibolone, Remifemin had a similar clinical efficacy and was safer for the peri-menopausal symptoms induced by GnRH-a in endometriosis patients.

Effects of zoledronic acid and tibolone on bone mineral density, indexes of bone metabolism, and the risk of fracture in patients with postmenopausal osteoporosis

Objective An open study was carried out to evaluate the effect of 2 year of zoledronic acid and tibolone treatment on bone mineral density(BMD),bone remodeling markers,and the risk of fracture in women with postmenopausal osteoporosis(PMOP).Methods In total,567 PMOP women,whose ages ranged 55-64 years,were randomized to 3 groups.185 patients received infusion zoledronic acid 5 mg/year,190 patients received oral tibolone 2.5 mg/d and the rest received oral caltrate and calcitriol (control group,n =192).All of them received oral caltrate 600 mg/d and calcitriol 0.25 μg/day.BMD measurements at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry (DEXA) and the biochemical markers of bone metabolism in serum were performed at the baseline and 6,12,and 24 months.Results Comparing baseline with 24 month's values,BMD increased in zoledronic acid and tibolone group,especially lumbar vertebra (L2-4,P＜ 0.01).But there was no significant deference between zoledronic acid and tibolone group (P ＞ 0.05).Zoledronic acid and tibolone resulted in a significantly greater reduction in bone-specific alkaline phosphatase (BALP),osteocalcin,tartrate-resistant acid phosphatase (TRACP5b),and collagen type Ⅰ C-end peptides (CTX) from baseline all post-baseline time (P＜0.01).There was a significant deference between zoledronic acid and tibolone group in TRACP-5b and CTX(P＜0.05).Treatment with zoledronic acid reduced the risk of new vertebral fracture by 61.9％ during a 2-year period,as compared with placebo (4.3％ in the zoledronic-acid group vs 12.6％ in the control group,P=0.033) and reduced the risk of total fracture by 65.9％ (4.3％ in the zoledronic-acid group,12.6％ in the control group,P =0.004).And in Tibolone group,incidence of total fracture were,significantly lower than in the control group (6.5％ vs 12.6％,P =0.047).There was no serious adverse event occurrence in all patientsm.Conclusions Zoledronic acid could significantly improve BMD and reduce the risk of bone fracture as tibolone.Thus it played an important role in the treatment of postmenopausal osteoporosis.There was no significant difference between these two drugs.Zoledronate can improve the compliance and safety of the patients.However,calcium tablet and vitamin D alone could not prevent the loss of bone. Key words: Zoledronic acid ; Tibolone ; Bone mineral density ; Fractures