ArticleLiterature Review

Short-term and long-term effects of tibolone in postmenopausal women

Authors:
  • Local Health Authority, Reggio Emilia (Italy)
  • Emilia-Romagna Health and Welfare Directorate
  • Health and Social Agency (ASSR), Emilia-Romagna, Italy
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Abstract

Background: Tibolone is a synthetic steroid used for the treatment of menopausal symptoms, on the basis of short-term data suggesting its efficacy. We considered the balance between the benefits and risks of tibolone. Objectives: To evaluate the effectiveness and safety of tibolone for treatment of postmenopausal and perimenopausal women. Search methods: In October 2015, we searched the Gynaecology and Fertility Group (CGF) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO (from inception), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinicaltrials.gov. We checked the reference lists in articles retrieved. Selection criteria: We included randomised controlled trials (RCTs) comparing tibolone versus placebo, oestrogens and/or combined hormone therapy (HT) in postmenopausal and perimenopausal women. Data collection and analysis: We used standard methodological procedures of The Cochrane Collaboration. Primary outcomes were vasomotor symptoms, unscheduled vaginal bleeding and long-term adverse events. We evaluated safety outcomes and bleeding in studies including women either with or without menopausal symptoms. Main results: We included 46 RCTs (19,976 women). Most RCTs evaluated tibolone for treating menopausal vasomotor symptoms. Some had other objectives, such as assessment of bleeding patterns, endometrial safety, bone health, sexuality and safety in women with a history of breast cancer. Two included women with uterine leiomyoma or lupus erythematosus. Tibolone versus placebo Vasomotor symptomsTibolone was more effective than placebo (standard mean difference (SMD) -0.99, 95% confidence interval (CI) -1.10 to -0.89; seven RCTs; 1657 women; moderate-quality evidence), but removing trials at high risk of attrition bias attenuated this effect (SMD -0.61, 95% CI -0.73 to -0.49; odds ratio (OR) 0.33, 85% CI 0.27 to 0.41). This suggests that if 67% of women taking placebo experience vasomotor symptoms, between 35% and 45% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with greater likelihood of bleeding (OR 2.79, 95% CI 2.10 to 3.70; nine RCTs; 7814 women; I(2) = 43%; moderate-quality evidence). This suggests that if 18% of women taking placebo experience unscheduled bleeding, between 31% and 44% of women taking tibolone will do so. Long-term adverse eventsMost of the studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Breast cancerWe found no evidence of differences between groups among women with no history of breast cancer (OR 0.52, 95% CI 0.21 to 1.25; four RCTs; 5500 women; I(2)= 17%; very low-quality evidence). Among women with a history of breast cancer, tibolone was associated with increased risk (OR 1.5, 95% CI 1.21 to 1.85; two RCTs; 3165 women; moderate-quality evidence). Cerebrovascular eventsWe found no conclusive evidence of differences between groups in cerebrovascular events (OR 1.74, 95% CI 0.99 to 3.04; four RCTs; 7930 women; I(2) = 0%; very low-quality evidence). We obtained most data from a single RCT (n = 4506) of osteoporotic women aged 60 to 85 years, which was stopped prematurely for increased risk of stroke. Other outcomesEvidence on other outcomes was of low or very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 2.04, 95% CI 0.79 to 5.24; nine RCTs; 8504 women; I(2) = 0%.• Cardiovascular events: OR 1.38, 95% CI 0.84 to 2.27; four RCTs; 8401 women; I(2) = 0%.• Venous thromboembolic events: OR 0.85, 95% CI 0.37 to 1.97; 9176 women; I(2) = 0%.• Mortality from any cause: OR 1.06, 95% CI 0.79 to 1.41; four RCTs; 8242 women; I(2) = 0%. Tibolone versus combined HT Vasomotor symptomsCombined HT was more effective than tibolone (SMD 0.17, 95% CI 0.06 to 0.28; OR 1.36, 95% CI 1.11 to 1.66; nine studies; 1336 women; moderate-quality evidence). This result was robust to a sensitivity analysis that excluded trials with high risk of attrition bias, suggesting a slightly greater disadvantage of tibolone (SMD 0.25, 95% CI 0.09 to 0.41; OR 1.57, 95% CI 1.18 to 2.10). This suggests that if 7% of women taking combined HT experience vasomotor symptoms, between 8% and 14% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with a lower rate of bleeding (OR 0.32, 95% CI 0.24 to 0.41; 16 RCTs; 6438 women; I(2) = 72%; moderate-quality evidence). This suggests that if 47% of women taking combined HT experience unscheduled bleeding, between 18% and 27% of women taking tibolone will do so. Long-term adverse eventsMost studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Evidence was of very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 1.47, 95% CI 0.23 to 9.33; five RCTs; 3689 women; I(2) = 0%.• Breast cancer: OR 1.69, 95% CI 0.78 to 3.67; five RCTs; 4835 women; I(2) = 0%.• Venous thromboembolic events: OR 0.44, 95% CI 0.09 to 2.14; four RCTs; 4529 women; I(2) = 0%.• Cardiovascular events: OR 0.63, 95% CI 0.24 to 1.66; two RCTs; 3794 women; I(2) = 0%.• Cerebrovascular events: OR 0.76, 95% CI 0.16 to 3.66; four RCTs; 4562 women; I(2) = 0%.• Mortality from any cause: only one event reported (two RCTs; 970 women). Authors' conclusions: Moderate-quality evidence suggests that tibolone is more effective than placebo but less effective than HT in reducing menopausal vasomotor symptoms, and that tibolone is associated with a higher rate of unscheduled bleeding than placebo but with a lower rate than HT.Compared with placebo, tibolone increases recurrent breast cancer rates in women with a history of breast cancer, and may increase stroke rates in women over 60 years of age. No evidence indicates that tibolone increases the risk of other long-term adverse events, or that it differs from HT with respect to long-term safety.Much of the evidence was of low or very low quality. Limitations included high risk of bias and imprecision. Most studies were financed by drug manufacturers or failed to disclose their funding source.

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... After absorption, tibolone is metabolized in different tissues, producing estrogenically active metabolites that stimulate estrogen, progesterone, and androgen receptors, with an effect on bone preserving or increasing BMD [5,6]. In addition, tibolone's clinical efficacy is similar to conventional HT, without stimulating breast and endometrium [7], and unscheduled bleeding is lower than that induced by HT [8]. ...
... The present systematic review and meta-analysis synthesizes the evidence of the effect of tibolone in BMD in the lumbar spine, femoral neck, and total hip in postmenopausal women. Concerning that a Cochrane systematic review evaluates the effectiveness and safety of tibolone treatment in postmenopausal and perimenopausal women, most of the included studies reported the effect on vasomotor symptoms (VMS), and five of them had different objectives such as bone loss or fracture prevention, without describing the effect on BMD [8]. Besides, there are two systematic reviews with meta-analysis in the literature regarding the effect of tibolone on bone at 24 months. ...
... In addition, our analysis supports that tibolone is associated with a lower rate of vaginal bleeding compared to estrogen therapy, and it is suggested that if 47% of women taking combined hormone therapy experience unscheduled bleeding, between 18% and 27% of women taking tibolone will do so [8]. A study has demonstrated that tibolone improved persistent bleeding and breast discomfort after switching from estrogen treatment [37]. ...
Article
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Low bone mineral density (BMD) on postmenopausal women causes bone fragility and fracture risk. Tibolone seems to prevent bone loss. Therefore, this systematic review with meta-analysis synthesizes the tibolone effect on BMD percent change in lumbar spine (LS), femoral neck (FN), and total hip (TH) in postmenopausal women. Controlled trials that provided tibolone evidence on the efficacy of tibolone in preventing loss of BMD were included. Regarding the included studies, a pooled mean difference (MD) with 95% confidence intervals (95%CI) was estimated to determine the BMD percentage change. Eleven studies were identified and eight were included in the quantitative analysis. Tibolone at a dose of 2.5 mg increased BMD compared with non-active controls at 24 months in LS (MD 4.87%, 95%CI: 4.16–5.57, and MD 7.35%, 95%CI: 2.68–12.01); and FN (MD 4.85%, 95%CI: 1.55–8.15, and 4.21%, 95%CI: 2.99–5.42), with Hologic and Lunar scanners, respectively. No difference was observed when tibolone 2.5 mg dose was compared with estrogen therapy (ET) at 24 months, LS (MD −0.58%, 95%CI: −3.77–2.60), FN (MD −0.29%, 95%CI: −1.37–0.79), and TH (MD −0.12%, 95%CI: −2.28–2.53). Therefore, tibolone increases BMD in LS and FN compared to non-active controls, and there was no showed difference with ET.
... Among these alternatives is TIB (Livial®; ORG OD 14), a synthetic steroid widely prescribed to postmenopausal women in more than 70 countries (except the USA) as HT [10]. TIB combines estrogenic, androgenic, and progestagenic actions in one compound, with differential metabolism in each tissue. ...
... These metabolites are estrogen receptor (ER) agonists and bind preferentially to ER alpha (ERα) [11]. Despite showing a considerably lower activation potency than estradiol over its receptors [20], the high circulating concentration of these metabolites [14] explains the comparable effects of TIB with the effects of E-HT [10]. The third metabolite, Δ4-isomer, has progestagenic and androgenic properties. ...
... The androgenic activity of Δ4-isomer, combined with the observed decrease in sex hormonebinding globulin (SHBG) [with the corresponding increase of the bioavailability of testosterone, estradiol, and dehydroepiandrosterone-sulfate (DHEA-S)] [23,[26][27][28] can explain the beneficial effects of TIB on libido and sexual health [10,29]. Secondarily, it has been observed that both TIB and Δ4-isomer have a certain antagonistic activity on mineralocorticoid receptors (MRs) 5 Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá, Colombia and glucocorticoid receptors (GRs) [16], with predominance for MRsactivity that could explain the observed decrease in blood pressure in TIB clinical trials [30,31]. ...
Article
Tibolone (TIB), a selective tissue estrogenic activity regulator (STEAR) in clinical use by postmenopausal women, activates hormonal receptors in a tissue-specific manner. Estrogenic activity is present mostly in the brain, vagina, and bone, while the inactive forms predominate in the endometrium and breast. Conflicting literature on TIB’s actions has been observed. While it has benefits for vasomotor symptoms, bone demineralization, and sexual health, a higher relative risk of hormone-sensitive cancer has been reported. In the brain, TIB can improve mood and cognition, neuroinflammation, and reactive gliosis. This review aims to discuss the systemic effects of TIB on peri- and post-menopausal women and its role in the brain. We suggest that TIB is a hormonal therapy with promising neuroprotective properties.
... [1] Most of the postmenopausal women face common issues such as hot flashes, sleep problems, mood changes, osteoporosis, and sexual problems. [2] Some studies suggest that women's quality of life (QOL), especially during the first 5 years of menopause, is reduced. [3][4][5] In addition, studies show that postmenopausal women usually lack enough knowledge to manage their complications. ...
... The scoring is based on the Likert method. [1][2][3][4][5] High scores indicate high self-care behaviors and low scores indicate to the low self-care behaviors. The validity of this scale through Cronbach's alpha was 0.93. ...
Article
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Background: Women during menopause stages experience many symptoms, for which they lack enough knowledge to manage them. This study aimed to compare the effect of self-directed and support group health education on the quality of life (QOL (and self-care of postmenopausal women. Materials and methods: This field trial study was carried out with three groups. One hundred and eight menopause women were selected through convenient sampling method based on the inclusion criteria from three comprehensive health centers. Health centers were randomly assigned to support (n = 36), self-directed (n = 36), and control groups (n = 36). In the self-directed group, education was provided through educational package, and the control group received routine care from the health center. The support group received education through four group sessions by trained healthy volunteers. Data were collected by menopause-specific QOL and self-care standard questionnaire. Results: Immediately after the intervention, the mean scores of QOL in the self-directed group, support group, and control group were 41.82 ± 7.61, 40.31 ± 4.80, and 48.17 ± 8.45, respectively (P < 0.05). In addition, the mean scores of self-care were significantly different between the self-directed (40.67 ± 7.36) and support (36.50 ± 3.36) groups compared to the control group (47.83 ± 8.47) (P < 0.05). After 1 month from intervention, QOL scores in the self-directed group (40.67 ± 7.36), support group (36.50 ± 3.36), and control group (47.83 ± 8.47) were significantly different (P < 0.05). In addition, the mean scores of self-care were 64 ± 6.79 and 65 ± 8.32 in the self-directed and support groups, respectively, compared to the control group (49.09 ± 9.43). Post hoc test (least significant difference) revealed higher effectiveness of the support group (P < 0.001). Conclusions: Results indicated QOL and self-care in menopause women in self-directed and support groups improved. However, the support group provided higher effectiveness. Therefore, we recommended paying more attention to the capabilities of healthy volunteers for the promotion of QOL in menopause women.
... Tibolone is a synthetic steroid compound that has metabolites with estrogenic, progestogenic and androgenic activity [109][110][111]. It is indicated for mitigating vasomotor symptoms and osteoporosis in postmenopausal women, independently of hysterectomy status [17]. ...
... Available data suggest that even a low dose of tibolone (1.25 mg daily; the standard dose is 2.5 mg) has been shown to be effective in decreasing the rates of vertebral and non-vertebral fracture in postmenopausal women aged 60-85 years [112]. On the other hand, treatment with tibolone increases the risk of stroke in women over the age of 60 years and is also associated with a higher risk of breast cancer recurrence [111,113]. ...
Article
This care pathway from the European Menopause and Andropause Society (EMAS) provides an updated pathway for monitoring and guidance of women at midlife, focusing on those approaching the end of the reproductive life-cycle, going through the menopausal transition and beyond. The care pathway is written by professionals involved in women's health and provides a stepwise individualized approach, stratified according to needs, symptoms and reproductive stage. Furthermore, the pathway provides details on screening for chronic diseases related to menopause and ageing. Treatment options for climacteric symptoms range from menopausal hormone therapy to non-hormonal alternatives and lifestyle modifications. Therapy should be tailored to personal needs and wishes. The pathway aims to offer a holistic, balanced approach for monitoring middle-aged women, aiming to control health problems effectively and ensure healthy ageing.
... (6) For Singapore women, absolute fracture numbers have increased by 3.3% (95% confidence interval [CI] 3.0-3.6) annually, leading to an absolute average increase of 46.3 (95% CI [41][42][43][44][45][46][47][48][49][50][51][52] fractures/ year (Fig. 1a). (6) However, a decreasing trend was observed when fractures rates were age-adjusted and expressed per 100,000 population (Fig. 1b), indicating the influence of ageing on the increase in absolute numbers. ...
... The effect on bone is similar to that of MHT and bisphosphonates with 30% lower risk of hip fractures (RR 0.69 [0.32-1.51]). (51) For menopausal symptoms, tibolone is more effective than a placebo but less effective than MHT. The side effects and contraindications are the same as those of oral MHT. ...
Article
Screening for osteoporosis in women can be based on age and weight, using the Osteoporosis Screening Tool for Asians and assessment for other risk factors such as early menopause, Chinese ethnicity and other secondary factors. Based on the resulting risk profile, women can be triaged to dual-energy X-ray absorptiometry (DEXA) scanning for definite diagnosis of osteoporosis. Treatment should be considered in women with previous fragility fractures, DEXA-diagnosed osteoporosis and high risk of fracture. Exercise improves muscle function, can help prevent falls and has moderate effects on improvements in bone mass. Women should ensure adequate calcium intake and vitamin D. Menopausal hormone therapy (MHT) effectively prevents osteoporosis and fractures, and should be encouraged in those aged < 50 years. For women aged < 60 years, MHT or tibolone can be considered, especially if they have vasomotor or genitourinary symptoms. Risedronate or bisphosphonates may then be reserved for those aged over 60 years.
... Continuous combined HT should be used only in women who are at least 2 years past their last menstrual period as it can cause irregular bleeding in perimenopausal women due to the unpredictable residual production of oestradiol by remaining primordial ovarian follicles. Based on a woman's individual clinical profile, progestogen-free therapeutic alternatives such as tibolone (synthetic steroid), 32 raloxifene for postmenopausal osteoporosis 33 and TSEC (conjugated oestrogens + bazedoxifene) to prevent bone loss 34 may be appropriate for use. ...
Article
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Hormone therapy use has undergone dramatic changes over the past 20 years. Widespread use of hormone therapy in the 1980s and 1990s came to an abrupt halt in the early 2000s after initial findings of the Women’s Health Initiative trial were published and the study was terminated. Since then, much has been learned about the characteristics of women most likely to benefit from hormone therapy. There is general agreement that women younger than 60 years or who initiate hormone therapy within 10 years of menopause onset gain short-term benefit in terms of symptomatic relief and long-term benefit in terms of protection from chronic diseases that affect postmenopausal women. Despite accumulating evidence in support of hormone therapy for symptomatic menopausal women, the slow response by the medical community has led to a ‘large and unnecessary burden of suffering’ by women worldwide. Greater efforts are clearly needed to educate physicians and medical students about the pathophysiology of menopause and the role of hormone therapy in supporting women through the transition. This article provides a brief historical perspective of events that led to the backlash against hormone therapy, explores the current position of guideline groups, and provides practical recommendations to guide first-line management of symptomatic menopausal women.
... The synthetic steroid tibolone, indicated for postmenopausal symptoms, seems to have a positive effect on sexual symptoms. Classified as a selective tissue estrogenic activity regulator, it exhibits different properties in different tissues and has been shown to improve mood and enhance sexual desire through improvement of genital circulation and vaginal pulse amplitude [183,184]. Vulvovaginal atrophy (VVA) may be treated with local estrogen therapy in the form of low-dose intravaginal preparations, and this may be particularly pertinent in women receiving HD [185]. Transdermal testosterone creams/gels and systemic and intravaginal DHEA may improve dyspareunia [186]. ...
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Patient survival continues to increase with the growing quality of dialysis and management of chronic kidney disease (CKD). As such, chronic therapy must include considerations of quality of life (QOL), and this includes the disproportionate prevalence of sexual dysfunction (SD) in this patient population. This review aims to describe the pathophysiological and the psychosocial causes of SD with regard to renal replacement therapy, particularly hemo- and peritoneal dialysis. The differences in its manifestation in men and women are compared, including hormonal imbalances—and therefore fertility, libido, and sexual satisfaction—the experience of depression and anxiety, and QOL. The impact of comorbidities and the iatrogenic causes of SD are described. This review also presents validated scales for screening and diagnosis of SD in CKD patients and outlines novel therapies and strategies for the effective management of SD. Increased prevalence of CKD invariably increases the number of patients with SD, and it is crucial for health care professional teams to become familiar with the clinical tools used to manage this sensitive and under-quantified field. As a known predictor of QOL, sexual function should become a point of focus in the pursuit of patient-centered care, particularly as we seek to achieve as “normal” a life as possible for individuals who receive dialysis.
... Regarding the different administration routes of systemic MHT, there was no evidence that they were associated with CRC risks in this study.Additionally, this study assessed tibolone use separately, although the ATC coding of the World Health Organisation lists it as an E-MHT. Tibolone is a frequently prescribed synthetic progestogen in Sweden, whose metabolites have oestrogenic, progestogenic and androgenic properties.28,29 Tibolone use was associated with an increased risk of left-sided colon adenocarcinoma, in particularly, rectal adenocarcinoma. ...
Article
Full-text available
Background: Menopausal hormone therapy (MHT) has been associated with various malignancies. Aims: To investigate the association of various MHT regimens with the risk of colorectal cancer (CRC). Methods: All MHT ever-users (n = 290 186) were included through the Swedish Prescribed Drug Registry, with a 1:3 group-level matching to non-users. Ever-users were defined as women who received ≥1 dispensed prescription of systemic MHT during 2005-2012 in Sweden. All CRC cases after drug initiation were extracted from the Swedish Cancer Registry. The association was assessed by multivariable conditional logistic and Cox regression models, presented as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) considering different regimens, duration and age at treatment initiation. Results: Compared with non-users, MHT users had an overall reduced odds for colon (OR = 0.67, 95% CI 0.63-0.72) and rectal adenocarcinoma (OR = 0.66, 95% CI 0.60-0.73), especially among women aged 40-60 years. Current users of oestrogen-only preparations (E-MHT) showed a reduced odds (colon OR = 0.73, 95% CI 0.65-0.82; rectal OR = 0.76, 95% CI 0.64-0.90) compared to non-users, particularly with oestradiol and oestriol. Past E-MHT use showed stronger odds reductions (colon OR = 0.49, 95% CI 0.43-0.56; rectal OR = 0.36, 95% CI 0.28-0.45). Current use of oestrogen combined progestin therapy (EP-MHT) indicated a less prominent odds reduction (colon adenocarcinoma OR 0.62, 95% CI 0.54-0.72; rectal adenocarcinoma OR = 0.60, 95% CI 0.49-0.74) than past users. Tibolone showed an increased risk of left-sided colorectal adenocarcinoma. Oral and cutaneous MHT usage showed similar patterns. Conclusions: MHT use may decrease colorectal adenocarcinoma risk, for both E-MHT and EP-MHT, and especially in past users.
... Thus, this patient subgroup should not be prescribed tibolone [100]. These hypotheses were also confirmed by in systematic review of the Cochrane Database Gynaecology and Fertility Group, however the authors pointed out that the evidence from the analyzed RCTs was marked by (very) low quality [101]. ...
Article
Inconsistencies exist with regard to influence of tibolone treatment on the lipid profile. The reasons for these inconsistencies might derive from several factors, i.e., differences in baseline variables, intervention duration, participants’ health status or baseline body mass index (BMI). To address these inconsistencies, based on a systematic search in Scopus, PubMed/Medline, Web of Science, and Embase for papers published until 21 December 2020, we conducted the current dose-response meta-analysis of randomized controlled trials (RCTs) to determine the impact of tibolone treatment on the lipid profile. The overall findings were derived from 26 RCTs. Tibolone administration decreased total cholesterol (TC) (weighted mean difference, WMD: -18.55 mg/dL, CI: -25.95 to -11.16, P<0.001), high-density lipoprotein-cholesterol (HDL-C) (WMD: -9.42 mg/dL, CI: -11.83 to -7.01, P<0.001) and triglyceride (TG) (WMD: -21.43 mg/dL, CI: -27.15 to -15.70, P<0.001) levels. A significant reduction in LDL-C occurred when tibolone was prescribed for ≤26 weeks (WMD: -7.64 mg/dL, 95% CI: -14.58 to -0.70, P=0.031) versus ˃26 weeks (WMD: -8.84 mg/dL, 95% CI: -29.98, 12.29, P=0.412). The decrease in TG (WMD: -22.64 mg/dL) and TC (-18.55 mg/dL) concentrations was more pronounced in patients with BMI ≥25 kg/m² versus BMI ˂25 kg/m². This systematic review and meta-analysis discovered that tibolone decreases TC, HDL-C and TG levels. LDL-C concentrations are significantly reduced when tibolone administration lasts for ≤26 weeks.
... What needs to be explained was that in our study cohort, patients received tibolone treatment due to multiple systematic symptoms rather than genitourinary symptoms alone, in strict accordance with the medicine guidelines (Pinkerton, 2020). Tibolone, a synthetic steroid with estrogenic, progestogenic, and androgenic properties, has long been used worldwide for menopausal symptoms (Formoso et al., 2016). Obviously, we proved that women receiving tibolone had significantly milder GSM symptoms than non-treated women, especially for vulvovaginal dryness and burning, as well as decreased libido, which was similar to previously reported studies (Kenemans and Speroff, 2005). ...
Article
Full-text available
Genitourinary syndrome of menopause (GSM) is a chronic and progressive condition with a series of vulvovaginal, sexual, and lower urinary tract discomforts, mainly due to hypoestrogenism. Menopausal hormone therapy (MHT) has generally been considered as the most effective treatment for GSM. In addition, vaginal microbiota is of particular significance to gynecological and reproductive illnesses and potentially has some intimate connections with GSM. Consequently, we sought to evaluate how MHT impacts the composition and structure of vaginal microbiota while alleviating GSM in Chinese menopausal women aged 45–65 years, which has not been investigated previously. 16S rRNA gene sequencing was performed to analyze microbial diversity and composition using vaginal swabs obtained from 100 menopausal women, classified as MHT women who have been taking tibolone regularly ( n = 50) and non-treated women who never received any treatment ( n = 50). Vaginal Health Index Score (VHIS) and GSM symptoms inquiry were also performed. We found that the vaginal microbial diversity decreased and that the abundance of Lactobacillus increased to be the dominant proportion significantly in the MHT group, in considerable contrast to vaginal microbiota of the non-treated group, which significantly comprised several anaerobic bacteria, namely, Gardnerella , Prevotella , Escherichia-Shigella , Streptococcus , Atopobium , Aerococcus , Anaerotruncus , and Anaerococcus . In this study, women without any MHT had significantly more severe GSM symptoms than those receiving tibolone, especially with regard to vulvovaginal dryness and burning, as well as decreased libido ( P < 0.01). However, there was no significant difference in the severity of urological symptoms between the groups ( P > 0.05). Furthermore, Lactobacillus was demonstrated to be associated with VHIS positively ( r = 0.626, P < 0.001) and with GSM negatively ( r = −0.347, P < 0.001). We also identified Chlamydia ( r = 0.277, P < 0.01) and Streptococcus ( r = 0.270, P < 0.01) as having a prominent association with more serious GSM symptoms. Our study provided an elucidation that MHT could notably alleviate GSM and conspicuously reshape the composition of the vaginal microbiota, which is of extreme importance to clinical practice for the management of GSM.
... With regard to safety, some of the treatment options studied have been associated with adverse effects. For example, in a Cochrane review, tibolone was associated with vaginal bleeding and recurrent breast cancer in those with a history of breast cancer and may be associated with stroke in women over 60 years old [74]. SSRI/SNRI were associated with risks of bleeding, hyponatremia [75], nausea, headache, insomnia and sexual dysfunction [76]. ...
Article
This systematic review provides an overview of the effects of menopausal symptom treatment options on palpitations, defined as feelings of missed or exaggerated heart beats, reported by perimenopausal and postmenopausal women. Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searches were conducted in PubMed, CINAHL and PsycINFO to identify articles meeting pre-specified inclusion criteria. Of 670 unique articles identified, 37 were included in the review. Treatments included drug therapies and non-drug therapies. Palpitations were studied as an outcome in 89% of articles and as an adverse effect in 11%. Articles provided mostly level II/III evidence due to their design and/or small sample sizes. Based on available evidence, no therapies can be fully recommended for clinical practice. Only some hormonal agents (e.g. estradiol) can be recommended with caution based on some positive evidence for reducing palpitation prevalence or severity. However, other drug therapies (e.g. moxonidine, atenolol), dietary supplementary treatments (e.g. isoflavones, Rheum rhaponticum, sage), cognitive-behavioral intervention and auricular acupressure cannot be recommended given the existing evidence. Additional well-designed randomized controlled treatment trials focusing on palpitations during the menopause transition as an inclusion criteria and outcome are needed to advance the field.
... Breast cancer recurrence risk, however, was shown to be increased by tibolone in two moderate quality trials (odds ratio 1.5, 95% CI: 1.21-1.85). 21 Of note, is that most of these results pertain to women quite a bit older than our study population. The mean age was around 52 to 55 in the Cochrane review and 50 in the meta-analysis (although not reported for the tibolone-subgroup specifically), and the results may therefore not fully apply for women in our study, who are undergoing RRSO at a young age (ie, around the age of 40). ...
Article
Full-text available
Objective: To compare the effect of tibolone to conjugated estrogens with medroxyprogesterone-acetate (CEE + MPA) on breast density, as a predictor for breast cancer risk, in women with a high risk of breast and ovarian cancer. Methods: Women aged 30-50 (N = 114) who had undergone risk-reducing salpingo-oophorectomy (RRSO) were randomized to tibolone or CEE + MPA. Results: Breast density decreased 46% after RRSO in untreated women, 39% after treatment with tibolone, and 17% after treatment with CEE + MPA; the decrease in breast density after CEE + MPA was significantly different compared with that of untreated women (P = 0.017). Conclusions: A decline in breast density is seen after premenopausal RRSO despite the use of both CEE + MPA or tibolone, although lower breast density is seen after tibolone use.
... In perimenopausal women the 52 mg levonorgestrel intrauterine system is an appropriate option since it provides contraception, endometrial protection, and in women who become amenorrhoeic can also benefit migraine [48]. In postmenopausal women who favor oral MHT, tibolone may be a better option than other oral preparations, although data regarding migraine are limited to comparison with estradiol plus norethisterone and it is less effective for menopause symptoms than estrogen/progestogen MHT [49,50]. For medically induced menopause, the addition of estradiol significantly benefits migraine [51]. ...
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Migraine is affected by the changing hormone environment, with perimenopause associated with increased migraine, particularly menstrual migraine. Menstrual attacks are recognised to be more disabling and less responsive to treatment compared with non-menstrual attacks. Perimenstrual estrogen ‘withdrawal’ is implicated in the pathophysiology of menstrual migraine, with increased prevalence of migraine in perimenopause associated with unpredictable estrogen fluctuations. Perimenopausal women often have contraceptive needs as well as menopause symptoms and it is important to understand the potential effects of exogenous hormones on migraine. Maintaining stable estrogen levels with exogenous hormones can benefit migraine but clinical trial data are limited. This short narrative review addresses the diagnosis and management of menstrual migraine in perimenopausal women, and discusses the management of menopause symptoms in peri- and postmenopausal women with migraine.
... Tibolone is a synthetic steroid with metabolites that have estrogenic, androgenic and progestogenic properties. Approved for use in Europe, but not in the US, it is associated with weight gain, impaired glucose tolerance, decreased HDL-C, but also a decrease in LDL-C, lipoprotein (a) and triglycerides [57,98]. Tibolone increases the stroke risk in women over the age of 60 years, but based on low or very low quality evidence, there does not appear to be an increased risk of other cardiovascular events including VTE. ...
Article
(137 words) Hormone therapy is the most effective treatment for menopausal symptoms. Current evidence supports its use in young healthy menopausal women, under the age of 60 years and within 10 years of menopause, with benefits typically outweighing risks. However, decision making is more complex in the more common clinical scenario of a symptomatic woman with one or more chronic medical conditions that potentially alter the risk-benefit balance of hormone therapy use. In this review, we present the evidence relating to the use of hormone therapy in women with chronic medical conditions such as obesity, hypertension, dyslipidemia, diabetes, venous thromboembolism, and autoimmune diseases. We discuss the differences between oral and transdermal routes of administration of estrogen and the situations when one route might be preferred over another. We also review evidence regarding the effect of different progestogens, when available.
... Nevertheless, the high bone mineral density could potentially lead to the same pathological fractures described in bisphosphonate use (Mathonet, Willems, & Ciornohac, 2018;Saita et al., 2015 showed that tibolone did not increase the risk of long-term adverse events, this drug represents a right candidate for postoperative enhancement of orthopedic titanium implants osseointegration (Formoso et al., 2016). ...
Article
Objectives 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. Materials and methods 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 12 weeks. Examinations included micro‐CT, mechanical pull‐out test, histology, and bone serum markers. Results Periimplant 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 periimplant 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. Conclusion 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.
... Tibolone is a synthetic steroid compound that is, in itself, inert, but whose metabolites have estrogenic, progestogenic and androgenic actions. It is classified as menopausal hormone therapy [16]. Availability of different menopausal hormone therapy preparations varies worldwide. ...
... It is classified as menopausal hormone therapy. 16 Availability of different menopausal hormone therapy preparations varies worldwide. ...
Article
Worldwide, it is estimated that about 1.3 million new gynecological cancer cases are diagnosed each year. For 2018, the predicted annual totals were cervix uteri 569 847, corpus uteri 382 069, ovary 295 414, vulva 44 235, and va gina 17 600. Treatments include hysterectomy with or without bilateral salpingo-oophorectomy, radiotherapy, and chemotherapy. These can result in loss of ovarian function and, in women under the age of 45 years, early menopause. The aim of this position statement is to set out an individualized approach to the management, with or without menopausal hormone therapy, of menopausal symptoms and the prevention and treatment of osteoporosis in women with gynecological cancer. Our methods comprised a literature review and consensus of expert opinion. The limited data suggest that women with low-grade, early-stage endometrial cancer may consider systemic or topical estrogens. However, menopausal hormone therapy may stimulate tumor growth in patients with more advanced disease, and non-hormonal approaches are recommended. Uterine sarcomas may be hormone dependent, and therefore estrogen and progesterone receptor testing should be undertaken to guide decisions as to whether menopausal hormone therapy or non-hormonal strategies should be used. The limited evidence available suggests that menopausal hormone therapy, either systemic or topical, does not appear to be associated with harm and does not decrease overall or disease-free survival in women with non-serous epithelial ovarian cancer and germ cell tumors. Caution is required with both systemic and topical menopausal hormone therapy in women with serous and granulosa cell tumors because of their hormone dependence, and non-hormonal options are recommended as initial therapy. There is no evidence to contraindicate the use of systemic or topical menopausal hormone therapy by women with cervical, vaginal, or vulvar cancer, as these tumors are not considered to be hormone dependent.
... More importantly, in a Danish cohort consisting of almost 700,000 healthy women with 51-69 years, no increased risk of myocardial infarction was found for tibolone therapy for 6 years [72]. Additionally, a Cochrane systematic review ratifies that there are no long-term adverse events and increased risk upon tibolone administration [73], thus far. ...
Article
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The clinical effects of tibolone on cardiometabolic markers are an underlying question in postmenopausal women. We aimed to meta-analyze the effects of tibolone on anthropometric indicators of obesity, blood pressure (BP), and on C-reactive protein (CRP) levels in postmenopausal women. Two independent reviewers searched Scopus, Web of Science, PubMed/Medline, and Embase up to until 20 April 2021. Weighted mean differences (WMDs) and 95% confidence interval (CI) were calculated through the DerSimonian and Laird random-effect models between the tibolone and the control groups. Data from 20 eligible included showed that tibolone treatment increased the body mass index (BMI) by 0.23 kg/m² (95% CI: 0.017 to 0.45, p=0.03) but did not significantly increase body weight (WMD: 1.128 kg, 95% CI: -1.76 to 4.02, p=0.44) or waist circumference (WC) (WMD: 0.64 cm, 95% CI: -3.18 to 4.48, p = 0.74). Also, tibolone treatment neither changed the systolic BP (WMD: 2.60 mmHg, 95% CI: -2.52 to 7.72, p = 0.31) nor the diastolic BP (WMD: 0.711 mmHg, 95% CI: -2.52 to 3.94, p = 0.66), but increased CRP levels by 0.44 mg/L (95% CI: 0.10 to 0.78, p = 0.01). Tibolone treatment administered in postmenopausal women increased BMI and CRP but did not change body weight, WC, and SBP. Diastolic BP decreased after the tibolone intervention only in the studies lasting 26 weeks versus ˃26 weeks. .
... Tibolone is a synthetic steroid with estrogenic, progestogenic and weak androgenic activity indicated for the management of menopausal symptoms and urogenital atrophy in postmenopausal women. It does not require the addition of a progestogen in women with an intact uterus [32]. ...
Article
Introduction The menopause, or the cessation of menstruation, is a stage of the life cycle which will occur in all women. Managing perimenopausal and postmenopausal health is a key issue for all areas of healthcare, not just gynecology. Aim To provide recommendations for the curriculum of education programs for healthcare professionals worldwide, so that all can receive high quality training on menopause. Materials and methods Literature review and consensus of expert opinion. Summary recommendations Training programs for healthcare professionals worldwide should include menopause and postmenopausal health in their curriculum. It should include assessment, diagnosis and evidence-based management strategies.
... VTE risk does not increase with tibolone [83][84][85]. Nevertheless, tibolone may increase the risk of stroke in older women [84,86]. ...
Article
Full-text available
Background and Objectives: Data emerging from the Women’s Health Initiative (WHI) study point toward an association between menopausal hormone therapy (MHT) and cardiovascular (CV) risk. However, post hoc subgroup analyses stratifying participants according to their age and time since menopause, have opened the way to a better understanding of the relationship between estrogen and CV risk. The aim of this review was to revise the current literature and evaluate the CV risk or benefit following administration of MHT considering several factors such as MHT timing, dose, route of administration, and formulation. Materials and Methods: An electronic databases search of MEDLINE (PubMed), Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, congress abstracts, and Grey literature (Google Scholar; British Library) was performed, with the date range from each database’s inception until June 2019. All the studies evaluating MHT and cardiovascular risk, including thromboembolism or stroke, were selected. Results: Timing of MHT initiation was shown to be a critical factor in CV risk assessment. In concordance with the “timing hypothesis”, healthy symptomatic women who initiated MHT when aged younger than 60 years, or who were within 10 years of menopause onset, have demonstrated a reduction in both coronary heart disease (CHD) risk and all-cause mortality. In particular, MHT therapy was associated with improvement of subclinical signs of atherosclerosis. Venous thromboembolism (VTE) risk is reduced when low doses of oral estrogen are used. Moreover, transdermal hormonal application significantly reduces CV risk compared with oral administration. MHT impact on the CV system is influenced by either factors inherent to the specific regimen, or factors inherent to the specific patient. Hence, individualization of care is necessary. Conclusion: CV risk calculation should be considered by clinicians in order to exclude patients with high CV risk, in whom MHT is contraindicated. Assessing risks and benefits in a patient-centered approach according to individual’s features, health status, and personal preferences is important in order to realize a safe and effective treatment.
... Tibolone is a selective estrogen receptor modulator with anti-estrogenic activity in the endometrium. Tibolone may be used to treat vasomotor symptoms, but appears to be less effective than estrogen-based MHT 17 and has been shown to increase the risk of breast cancer recurrence 18 . Safety after other cancers is unknown. ...
Article
The joint burden of cancer and menopause impacts millions of women globally. This review provides an approach to management of menopausal symptoms after cancer in all settings. This includes an overview of current evidence for both hormonal and non-hormonal treatments for vasomotor symptoms and vaginal dryness after cancer. Systemic menopausal hormone therapy provides symptom control and may be used after most cancers but should be avoided after estrogen receptor-positive breast cancer and after some other estrogen-dependent cancers. Non-hormonal therapies have been minimally studied in women after a cancer diagnosis and, where they have been studied, it is usually in women with breast cancer. Non-hormonal methods to manage vasomotor symptoms include cognitive behavioral therapy, hypnosis, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, clonidine, and gabapentin. Vaginal estrogen may be useful to address vaginal dryness. However, safety data in breast cancer patients are still lacking and there is currently no consensus. Lubricants may also help with pain with sexual activity. Management of menopausal symptoms after cancer may be challenging and should include information about induced menopause and possible symptoms as well as available treatments. Management then requires a holistic and multidisciplinary approach with individualized care.
... What needs to be explained was that in our study cohort, patients received tibolone treatment due to multiple systematic symptoms rather than genitourinary symptoms alone, in strict accordance with the medicine guidelines (Pinkerton, 2020). Tibolone, a synthetic steroid with estrogenic, progestogenic, and androgenic properties, has long been used worldwide for menopausal symptoms (Formoso et al., 2016). Obviously, we proved that women receiving tibolone had significantly milder GSM symptoms than non-treated women, especially for vulvovaginal dryness and burning, as well as decreased libido, which was similar to previously reported studies (Kenemans and Speroff, 2005). ...
... Two studies suggest that tibolone may worsen vaginal infection, although neither of them has provided an etiology. One study reports urinary tract infections [47]. There was a case of a patient with polycythemia secondary to the use of tibolone [48]. ...
Article
Introduction Dyslipidemias are common and increase the risk of cardiovascular disease. The menopause transition is associated with an atherogenic lipid profile, with an increase in the concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein B (apoB) and potentially lipoprotein (a) [Lp(a)], and a decrease in the concentration of high-density lipoprotein cholesterol (HDL-C). Aim The aim of this clinical guide is to provide an evidence-based approach to management of menopausal symptoms and dyslipidemia in postmenopausal women. The guide evaluates the effects on the lipid profile both of menopausal hormone therapy and of non-estrogen-based treatments for menopausal symptoms. Materials and methods Literature review and consensus of expert opinion. Summary recommendations Initial management depends on whether the dyslipidemia is primary or secondary. An assessment of the 10-year risk of fatal cardiovascular disease, based on the Systematic Coronary Risk Estimation (SCORE) system, should be used to set the optimal LDL-C target. Dietary changes and pharmacological management of dyslipidemias should be tailored to the type of dyslipidemia, with statins constituting the mainstay of treatment. With regard to menopausal hormone therapy, systemic estrogens induce a dose-dependent reduction in TC, LDL-C and Lp(a), as well as an increase in HDL-C concentrations; these effects are more prominent with oral administration. Transdermal rather than oral estrogens should be used in women with hypertriglyceridemia. Micronized progesterone or dydrogesterone are the preferred progestogens due to their neutral effect on the lipid profile. Tibolone may decrease TC, LDL-C, TG and Lp(a), but also HDL-C concentrations. Low-dose vaginal estrogen and ospemifene exert a favorable effect on the lipid profile, but data are scant regarding dehydroepiandrosterone (DHEA). Non-estrogen-based therapies, such as fluoxetine and citalopram, exert a more favorable effect on the lipid profile than do sertraline, paroxetine and venlafaxine. Non-oral testosterone, used for the treatment of hypoactive sexual desire disorder/dysfunction, has little or no effect on the lipid profile.
Article
Objective: To compare the effects of 1) tibolone, 2) continuous combined oestrogen plus progestogen and 3) placebo on plasma lipid and lipoprotein markers of cardiovascular risk in healthy post-menopausal women. Study design: randomised, single-centre, placebo-controlled, double-blind study PATIENTS: 101 post-menopausal women were randomised (1:1:1) into one of three groups taking daily 2.5mg tibolone, continuous oral oestradiol-17β 2mg plus norethisterone acetate 1mg daily (E2 /NETA) or placebo. Main outcome measures: Fasting serum lipid, lipoprotein and apolipoprotein concentrations measured at baseline and after 6, 12 and 24 months of treatment. Results: Both tibolone and E2 /NETA lowered plasma total cholesterol concentrations relative to placebo. With tibolone, high-density lipoprotein cholesterol (HDL-C) was reduced (-27% at 24 months, p<0.001), the greatest effect being in the cholesterol-enriched HDL2 subfraction (-40%, p<0.001). Tibolone's effect on HDL concentrations was also apparent in the principal HDL protein component, apolipoprotein AI (-29% at 24 months, p<0.001). However, there was no significant effect of tibolone on low-density or very-low-density lipoprotein cholesterol (LDL-C and VLDL-C, respectively). By contrast, the greatest reduction in cholesterol with E2 /NETA was in LDL-C (-22% at 24 months, p=0.008). E2 /NETA reduced HDL-C to a lesser extent than tibolone (-12% at 24 months, p<0.001). Effects on HDL apolipoproteins were similarly diminished relative to tibolone. E2 /NETA had no effect on VLDL-C or on the protein component of LDL, apolipoprotein B. Conclusion: Tibolone reduces serum HDL. E2 /NETA reduces LDL cholesterol but not apolipoprotein B, suggesting decreased cholesterol loading of LDL. Any impact these changes may have on CVD risk needs further investigation.
Article
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The purpose of this experimental study was to investigate the influence of airflow via high-flow nasal cannula (HFNC) on the duration of laryngeal vestibule closure (dLVC) and Penetration-Aspiration Scale (PAS) scores. Twenty-nine healthy adults participated in a repeated-measures design. Each participant completed a videofluoroscopic swallow study while receiving airflow via HFNC across a control condition of zero flow and conditions of 10, 20, 30, 40, 50, and 60 L/min. Five raters rated dLVC and PAS scores. Laryngeal vestibule closure was complete on all swallows. Linear regression revealed that the amount of airflow via HFNC significantly influenced dLVC, F(1, 810) = 19.056, p < .001. The mode of airway invasion for each airflow condition was PAS 2, with > 80% frequency compared to other PAS scores. Aspiration (PAS 7 or 8) did not occur. A Fisher's Exact test determined there was no association between normal/abnormal PAS score and no airflow/HFNC (p = .610). Findings indicate that for healthy adults, airflow via HFNC influenced dLVC in a dose-dependent manner with no change in airway invasion. The influence of HFNC on dLVC was a positive relationship, meaning when airflow increased, dLVC increased, and when airflow decreased, dLVC decreased. Modulation of dLVC in response to the amount of airflow highlights the ability of healthy adults to adapt to swallow conditions as needed to protect the airway.
Article
Objective: The aim of the study was to review the role of hormone therapy in menopausal patients with breast cancer and gynecologic malignancies. Methods: We searched MEDLINE (via PubMed) using a combination of keywords and database-specific subject headings for the following concepts: menopause, hormone therapy, and cancer. Editorials, letters, case reports, and comments were excluded, as were non-English articles. Additional references were identified by hand-searching bibliographies of included articles. The searches yielded a total of 1,484 citations. All citations were imported into EndNote X9, where they were screened by the authors. Results: In breast cancer survivors, systemic hormone therapy is not recommended, whereas local low-dose estrogen therapy may be considered after discussion with the patient's oncologist. Among endometrial cancer survivors, hormone therapy is considered safe in low-risk cancers but should be avoided in high-risk subtypes. For survivors of epithelial ovarian cancer and cervical cancer, hormone therapy can be considered, but should be avoided in women with estrogen-sensitive histologic subtypes. Conclusions: The risks of hormone therapy should be assessed on an individual basis, with consideration of age, type of hormone therapy, dose, duration of use, regimen, route, and prior exposure. Systemic hormone therapy is not recommended in breast cancer survivors, whereas vaginal low-dose estrogen appears safe. Hormone therapy may be used by endometrial, cervical, and ovarian cancer survivors with low-risk, non-estrogen-receptor-positive subtypes.Video Summary:http://links.lww.com/MENO/A516.
Article
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Resumen: Se revisa la evidencia científica en las actividades preventivas de la atención de la mujer en relación con el seguimiento del embarazo, las actividades preventivas en la planificación y seguimiento de los métodos anticonceptivos, actividades preventivas en la menopausia, y la prevención de las fracturas osteoporóticas. Abstract: A review is presented of the scientific evidence on preventive activities in women's care in relation to pregnancy follow-up, preventive activities in the planning and follow-up of contraceptive methods, preventive activities in menopause, and the prevention of osteoporotic fractures.
Article
Premenopausal breast cancer is usually estrogen receptor positive, and hence, prolonged ovarian suppression by medical or surgical means to prevent recurrence has become standard of management to improve disease-free survival. Ten-year adjuvant tamoxifen therapy is associated with 3.5% fewer recurrences compared to five years. The SOFT trial demonstrated small but statistically significant incremental improvements in long-term disease-free survival by the addition of gonadotropin-releasing hormone analog treatment (triptorelin) to an aromatase inhibitor (exemestane). Profound hypoestrogenism in the premenopausal age group may not be well tolerated due to a host of bothersome side effects (primarily vasomotor symptoms, musculoskeletal complaints, genitourinary syndrome of menopause, and mood disorders). Prolonged hypoestrogenism in younger women is associated with premature development of cardiovascular disease, bone loss, cognitive decline, and all-cause mortality. This paper explores multi-system consequences of prolonged hypoestrogenism in premenopausal women derived from studies of women with and without breast cancer. Pretreatment counseling in estrogen receptor positive breast cancer should emphasize the benefit of prolonged estrogen suppression on breast cancer recurrence and established risks of lifelong hypoestrogenism on quality of life and all-cause mortality. Future genomic research may help identify the best candidates for extended ovarian suppression to avoid treating many women when only a minority benefit.
Article
Aim The aim of these recommendations is to set forth an individualized approach to the management of early postmenopausal women (i.e., within the first 10 years after natural menopause) covering all aspects of lifestyle and therapeutic management, with or without menopause hormone therapy (MHT). Materials and methods Literature review and consensus of French expert opinion. Recommendations were graded according to the HAS methodology and levels of evidence derived from the international literature, except when there was no good-quality evidence. Summary recommendations The beginning of menopause is an ideal time for each woman to evaluate her health status by assessing her bone, cardiovascular, and cancer-related risk factors that may be amplified by postmenopausal estrogen deficiency and by reviewing her lifestyle habits. Improving lifestyle, including nutrition and physical activity, and avoiding risk factors (notably smoking), should be recommended to all women. MHT remains the most effective treatment for vasomotor symptoms but it could be also recommended as first-line treatment for the prevention of osteoporosis in early postmenopausal women at low to moderate risk for fracture. The risks of MHT differ depending on its type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. There is reasonable evidence that using transdermal estradiol in association with micronized progesterone or dydrogesterone may limit both the venous thromboembolic risk associated with oral estrogens and the risk of breast cancer associated with synthetic progestins. Treatment should be individualized to each woman, by using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of its benefit–risk balance. For bothersome genitourinary syndrome of menopause (GSM) symptoms, vaginal treatment with lubricants and moisturizers is recommended as first-line treatment together with low-dose vaginal estrogen therapy, depending on the clinical course. No recommendation of an optimal duration of MHT can be made, but it must take into consideration the initial indication for MHT as well as each woman's benefit–risk balance. Management of gynecological side-effects of MHT is also examined. These recommendations are endorsed by the Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVI) and the Collège National des Gynécologues-Obstétriciens Français (CNGOF).
Article
Résumé Introduction: Le syndrome génito-urinaire de la ménopause (SGUM) est défini comme un ensemble de symptômes associés à une diminution des œstrogènes et autres stéroïdes sexuels lors de la ménopause. Les principaux symptômes sont vulvovaginaux (sécheresse, brûlure, irritation), sexuels (dyspareunie), et urinaires (infections urinaires, pollakiurie, nycturie, douleur à la miction, incontinence urinaire par urgenturie). Le SGUM entraîne une altération de la qualité de vie, en particulier de la sexualité des femmes. Objectif: L’objectif de ce travail est d’élaborer des recommandations pour la pratique clinique concernant la prise en charge du SGUM chez les femmes ménopausées, et en particulier, chez les femmes ayant un antécédent de cancer du sein, traitées ou non par hormonothérapie. Matériels et méthodes: Une revue systématique de la littérature à propos de la prise en charge du SGUM a été réalisée sur Pubmed, Medline et Cochrane Library. Les recommandations des sociétés savantes internationales ont également été prises en compte: International Menopause society (IMS) https://www.imsociety.org, The North American Menopause society (NAMS) https://www.menopause.org, Canadian Menopause society https://www.sigmamenopause.com, European Menopause and Andropause Society (EMAS) https://www.emas-online.org, International Society for the Study of Women’s Sexual Health (ISSWSH) https://www.isswsh.org. Résultats: L’utilisation de lubrifiants, hydratants et acide hyaluronique par voie vaginale entraîne une amélioration des symptômes du SGUM et pourra être proposée pour toutes les patientes. Pour les femmes ménopausées, les œstrogènes par voie locale seront préférés à la voie orale en raison de leur innocuité et efficacité sur l’ensemble des symptômes du SGUM lors d’une utilisation à faible dose. La Prastérone est un traitement local qui pourra être proposé comme alternative efficace pour la prise en charge de la dyspareunie et trouble de la fonction sexuelle. Les données actuelles concernant la testostérone par voie orale, la tibolone, la DHEA par voie orale ou transdermique et la phytothérapie sont actuellement limitées. L’Ospémifène qui a démontré une amélioration significative des symptômes, notamment sexuels, n’est actuellement pas commercialisé en France. Dans le cas particulier des femmes avec antécédent de cancer du sein, les schémas non hormonaux sont une thérapie de première ligne. Les données actuelles concernant le risque de récidive de cancer du sein lors de l’administration d’œstrogènes locaux faible dose sont rassurantes mais ne permettent pas de conclure à l’innocuité de ce traitement. Conclusion: Le SGUM est un symptôme fréquent pouvant altérer la qualité de vie des femmes ménopausées. Une prise en charge devra être systématiquement proposée. Le traitement local non hormonal pourra être proposé chez toutes les femmes. L’oestrogénothérapie locale à faible dose et la Prastérone ont démontré un intérêt pour la prise en charge des symptômes du SGUM. Chez les femmes avant antécédent de cancer du sein, le traitement local non hormonal devra être proposé en première intention. L’innocuité de l’oestrogénothérapie locale à faible dose et de la Prastérone ne peut pas être établie actuellement. D’autres alternatives existent mais ne sont actuellement pas recommandées en France du fait du manque de données.
Article
Objective: Although menopausal hormone therapy (MHT) is the most effective treatment for menopausal symptoms, menopausal women hesitate to start MHT due to concerns about adverse events. Recently, however, it has been recommended to use it for appropriate patients who have been evaluated for baseline diseases, age, and timing of initiation. We aimed to investigate the association of MHT with cardiovascular diseases (CVDs) and type 2 diabetes among middle-aged postmenopausal women in Korea. Methods: Data were collected from the National Health Insurance Service database in Korea from 2002 to 2016. A total of 58,060 postmenopausal women (including 8,013 [13.8%] MHT users and 50,047 [86.2%] nonusers) were included. The time-dependent Cox regression model with a 1-year latency period was used to evaluate the hazard ratio (HR) and 95% confidence interval (CI) of the associations of MHT with CVDs and type 2 diabetes outcomes. Subgroup analyses by regimen type and cumulative duration were conducted. Results: In the multivariate-adjusted model, MHT was not significantly associated with CVDs (HR = 1.085, 95% CI: 0.899-1.310) or type 2 diabetes (HR = 1.104, 95% CI: 0.998-1.221). Differential effects were not observed by regimen type, cumulative duration, and years since menopause subgroups. Sensitivity analyses also did not show adverse events by MHT on CVDs and type 2 diabetes. Conclusions: Although protective effects of MHT against CVDs or type 2 diabetes were not observed among postmenopausal women who had screened underlying diseases, our results may contribute to reducing the current concerns about the use of MHT for middle-aged postmenopausal women in Korea. Video Summary:http://links.lww.com/MENO/A807.
Article
The skin is an endocrine organ and a major target of hormones such as estrogens, androgens and cortisol. Besides vasomotor symptoms (VMS), skin and hair symptoms often receive less attention than other menopausal symptoms despite having a significant negative effect on quality of life. Skin and mucosal menopausal symptoms include dryness and pruritus, thinning and atrophy, wrinkles and sagging, poor wound healing and reduced vascularity, whereas skin premalignant and malignant lesions and skin aging signs are almost exclusively caused by environmental factors, especially solar radiation. Hair menopausal symptoms include reduced hair growth and density on the scalp (diffuse effluvium due to follicular rarefication and/or androgenetic alopecia of female pattern), altered hair quality and structure, and increased unwanted hair growth on facial areas. Hormone replacement therapy (HRT) is not indicated for skin and hair symptoms alone due to the risk-benefit balance, but wider potential benefits of HRT (beyond estrogen's effect on VMS, bone, breast, heart and blood vessels) to include skin, hair and mucosal benefits should be discussed with women so that they will be able to make the best possible informed decisions on how to prevent or manage their menopausal symptoms.
Chapter
Menopause is the permanent cessation of menstrual cycles secondary to follicle depletion in the ovary. Some women may have their menopause at an early age, before age 40. This occurs in around 1% of the population who receive a diagnosis of primary ovarian insufficiency, also known as premature ovarian failure or premature menopause. The staging of reproductive aging workshop criteria only applies to women who present with spontaneous menopause. Vasomotor symptoms are considered one of the primary determinants of impaired quality of life across perimenopause and post‐menopause in some women. Menopause is a period of vulnerability and may predispose women to an increased risk of mood disturbances, particularly if they are susceptible to dysphoric changes associated with hormonal fluctuations. Osteoporosis is a disease in which the reduction of bone mass and the deterioration of bone tissue microarchitecture increase the risk of fragility fracture.
Article
Objective: To establish the effectiveness of tibolone in menopausal symptoms and sexual function, as well as the incidence of adverse effects, in postmenopausal women. Material and methods: Quasi-experimental study, before-after; in 127 postmenopausal women older than 40 years, with climacteric symptoms and last menstrual period at least 2 years before entering the study, with a stable partner. In a private university clinic in Armenia (Quindío), Colombia, between 2012 and 2015. The Quality of Life Scale Menopause Rating Scale (MRS) and the Female Sexual Function Index (IFSF) were used as instruments. Simple random sampling was done. The Stata® 16.1 program was used. Results: The average age was 56.91 ± 7.34 years. At the end of the study, an improvement in menopausal symptoms of 94.48% (. < 0.05) was achieved, with a decrease in the MRS score from 15.91 ± 3.21 to 6.18 ± 3, 75 points (. < 0.05). Sexual dysfunctions reported an improvement of 86.56%; the IFSF went from 23.19 ± 6.41 points to 28.02 ± 6.63 (. < 0.05). Adverse effects were present from the first 3 months of initiation of therapy, the most frequent being: amenorrhea (85.82%), mastalgia (18.89%), and edema (17.32%). Conclusions: Tibolone has a positive effectiveness in the treatment of the symptoms of menopause, reducing both the amount and the severity of the same; associated with a clear improvement in sexual function, with mild, tolerable and transitory adverse effects.
Chapter
Estrogen, or estrogen with a progestogen or bazedoxifene in women with a uterus, are indicated for relief of vasomotor symptoms and vaginal dryness, and for prevention of osteoporosis in women in the menopause transition. Estrogen is available in a number of formulations for oral, transdermal, or transvaginal routes. Progestogens, including micronized progesterone and synthesized progestins, vary in potency and half-life, leading to differences in doses required for endometrial protection. Associated risks of menopause hormone therapy include the uncommon risks of venous thrombotic events and gallbladder disease. Additional cases of breast cancer are classified as rare events and are seen with long duration of use primarily of estrogen and progestogen. Observational and physiological data indicate a superiority of micronized progesterone, sometimes called bioidentical progesterone, over synthetics in reduced breast cancer risk increase and in cardiovascular protection. There are limited studies comparing estrogen formulations. Strong evidence indicates amelioration or elimination of increased risk of thrombosis and gallbladder disease with transdermal delivery route. Compounding of hormones has different market penetrations and is associated with misunderstanding among women using the products. Bioidentical formulations of both estradiol and progesterone are available via approved regulatory pathways.
Article
Objective: Provide strategies for improving the care of perimenopausal and postmenopausal women based on the most recent published evidence. Target population: Perimenopausal and postmenopausal women. Benefits, harms, and costs: Target population will benefit from the most recent published scientific evidence provided via the information from their health care provider. No harms or costs are involved with this information since women will have the opportunity to choose among the different therapeutic options for the management of the symptoms and morbidities associated with menopause, including the option to choose no treatment. Evidence: Databases consulted were PubMed, MEDLINE, and the Cochrane Library for the years 2002-2020, and MeSH search terms were specific for each topic developed through the 7 chapters. Validation methods: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: physicians, including gynaecologists, obstetricians, family physicians, internists, emergency medicine specialists; nurses, including registered nurses and nurse practitioners; pharmacists; medical trainees, including medical students, residents, fellows; and other providers of health care for the target population. Summary statements: RECOMMENDATIONS.
Article
Objectif: Proposer des stratégies pour améliorer les soins aux femmes en périménopause ou ménopausées d'après les plus récentes données probantes publiées. Population cible: Femmes en périménopause ou ménopausées. BéNéFICES, RISQUES ET COûTS: La population cible bénéficiera des plus récentes données scientifiques publiées que leur communiqueront les fournisseurs de soins de santé. Aucun coût ni préjudice ne sont associés à cette information, car les femmes seront libres de choisir parmi les différentes options thérapeutiques, y compris le statu quo, pour la prise en charge des symptômes et morbidités associés à la ménopause. DONNéES PROBANTES: Les auteurs ont interrogé les bases de données PubMed, Medline et Cochrane Library pour extraire des articles publiés entre 2002 et 2020 en utilisant des termes MeSH spécifiques à chacun des sujets abordés dans les 7 chapitres. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique d'évaluation, de développement et d'évaluation (GRADE). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles). PROFESSIONNELS CONCERNéS: médecins, y compris gynécologues, obstétriciens, médecins de famille, internistes, urgentologues; infirmières, y compris infirmières autorisées et infirmières praticiennes; pharmaciens; stagiaires, y compris étudiants en médecine, résidents, moniteurs cliniques; et autres fournisseurs de soins auprès de la population cible. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.
Article
Objectif: Proposer des stratégies pour améliorer les soins aux femmes ménopausées ou en périménopause d'après les plus récentes données probantes publiées. Population cible: Femmes ménopausées ou en périménopause. BéNéFICES, RISQUES ET COûTS: La population cible bénéficiera des plus récentes données scientifiques publiées que leur communiqueront les fournisseurs de soins de santé. Aucun coût ni préjudice ne sont associés à cette information, car les femmes seront libres de choisir parmi les différentes options thérapeutiques offertes pour la prise en charge des symptômes et morbidités associés à la ménopause, y compris l'abstention thérapeutique. DONNéES PROBANTES: Les auteurs ont interrogé les bases de données PubMed, Medline et Cochrane Library pour extraire des articles publiés entre 2002 et 2020 en utilisant des termes MeSH spécifiques à chacun des sujets abordés dans les 7 chapitres. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique d'évaluation, de développement et d'évaluation (GRADE). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles). PROFESSIONNELS CONCERNéS: médecins, y compris gynécologues, obstétriciens, médecins de famille, internistes, urgentologues; infirmières, y compris infirmières autorisées et infirmières praticiennes; pharmaciens; stagiaires, y compris étudiants en médecine, résidents, moniteurs cliniques; et autres fournisseurs de soins auprès de la population cible. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.
Article
This narrative review analyses the customization of Menopausal Hormone Therapy in the context of breast cancer risk in women with premature ovarian insufficiency (POI) and with menopause at a normal age. Women with Idiopathic POI, FMR-1 premutation or Turner syndrome, if left untreated, may have lower breast cancer risk compared to the healthy age-matched female population. These women should be treated with MHT until the age of 50, as the risk of breast cancer is equal to that of normally menstruating women. Carriers of BRCA 1 & 2 mutation after risk-reducing bilateral salpingo-oophorectomy (RRSO), without a personal history of cancer, have an increased breast cancer risk, but may probably be treated with MHT till the age of 50. POI resulting from endometriosis or cancer related treatment is discussed in a separate paper in this issue. In peri- and postmenopausal women with menopausal symptoms and/or risk factors for osteoporosis in need of MHT, the individual breast cancer risk can be evaluated using internet-based calculators. In most women the 5-year-breast cancer risk is low (<3%) and MHT is a safe option. MHT should be prescribed with caution in women who have an intermediate risk (3-6%) and should not be prescribed in those who have a high risk of breast cancer (>6%). Oestrogen-only MHT and oestrogen-progestogen MHT containing micronized progesterone or dydrogesterone are associated with lower breast cancer risk compared to other combined MHT regimens.
Article
Résumé Le traitement hormonal de la ménopause (THM) a été initialement développé pour corriger les manifestations climatériques associées à la carence estrogénique de la ménopause. Chez les femmes non hystérectomisées, il associe un estrogène et un progestatif, ce dernier s’opposant à la prolifération endométriale induite par les estrogènes. En France et contrairement aux États-Unis et aux pays d’Europe du Nord, le THM associe principalement le 17β-estradiol qui est l’estrogène physiologique de l’ovaire et la progestérone ou son dérivé, la dihydrogestérone. Également, la France a été pionnière dans le développement des voies d’administration cutanée (gel ou patch transdermique) de l’estradiol permettant une meilleure tolérance métabolique et une réduction significative du risque thromboembolique veineux par rapport à la voie orale. Le choix des doses tout comme du schéma thérapeutique doit répondre à l’objectif de la tolérance tout comme de l’acceptation et de l’observance du traitement. Le risque carcinologique mammaire qui est un des principaux risques du THM est plus élevé avec les associations estro-progestatives qu’avec les estrogènes seuls ; l’utilisation préférentielle de la progestérone ou de la dihydrogestérone apparaît limiter le sur-risque de cancer du sein associé au THM tout au moins pour des durées de l’ordre de 5 à 7 ans. La question de la durée optimale du THM reste ouverte et doit prendre en compte l’indication initiale du THM et la balance bénéfices/risques propre à chaque femme. La poursuite du THM est donc conditionnée par le maintien de la balance bénéfices/risques qui doit être évaluée régulièrement, tout comme par l’évolution des symptômes et des risques de santé liés à la ménopause ou induits par le THM. Après l’arrêt du THM, il est nécessaire de maintenir un suivi médical à adapter à la situation clinique de chaque femme et notamment ses facteurs de risque cardiovasculaires et gynécologiques.
Article
Menopause is the cessation of menstruation; it typically occurs at around 51 years of age. The postmenopausal phase of life is linked to a variety of health conditions, including osteoporosis, cardiovascular disease and cognitive decline. Beyond symptom control, hormonal replacement therapy (HRT) reduces the incidence of chronic health conditions. Some unfounded concerns and misunderstanding about the risks of HRT contribute to a low uptake of HRT, currently around 10% of menopausal women. This article highlights the symptoms of menopause and treatment options available. As the majority of menopause management occurs in primary care, a good understanding of the risks and benefits is paramount when guiding patients to make informed decisions about the treatment options.
Article
BACKGROUND Menopausal symptoms can be very distressing and considerably affect a woman’s personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to altered quality of life, reduced work productivity and, possibly, overall impaired health. Hormone therapy (HT) for the relief of menopausal symptoms has been the object of much controversy over the past two decades. At the beginning of the century, a shadow was cast on the use of HT owing to the concern for cardiovascular and cerebrovascular risks, and breast cancer, arising following publication of a large randomized placebo-controlled trial. Findings of a subanalysis of the trial data and extended follow-up studies, along with other more modern clinical trials and observational studies, have provided new evidence on the effects of HT. OBJECTIVE AND RATIONALE The goal of the following paper is to appraise the most significant clinical literature on the effects of hormones in postmenopausal women, and to report the benefits and risks of HT for the relief of menopausal symptoms. SEARCH METHODS A Pubmed search of clinical trials was performed using the following terms: estrogens, progestogens, bazedoxifene, tibolone, selective estrogen receptor modulators, tissue-selective estrogen complex, androgens, and menopause. OUTCOMES HT is an effective treatment for bothersome menopausal vasomotor symptoms, genitourinary syndrome, and prevention of osteoporotic fractures. Women should be made aware that there is a small increased risk of stroke that tends to persist over the years as well as breast cancer risk with long-term estrogen–progestin use. However, healthy women who begin HT soon after menopause will probably earn more benefit than harm from the treatment. HT can improve bothersome symptoms, all the while conferring offset benefits such as cardiovascular risk reduction, an increase in bone mineral density and a reduction in bone fracture risk. Moreover, a decrease in colorectal cancer risk is obtainable in women treated with estrogen–progestin therapy, and an overall but nonsignificant reduction in mortality has been observed in women treated with conjugated equine estrogens alone or combined with estrogen–progestin therapy. Where possible, transdermal routes of HT administration should be preferred as they have the least impact on coagulation. With combined treatment, natural progesterone should be favored as it is devoid of the antiapoptotic properties of other progestogens on breast cells. When beginning HT, low doses should be used and increased gradually until effective control of symptoms is achieved. Unless contraindications develop, patients may choose to continue HT as long as the benefits outweigh the risks. Regular reassessment of the woman’s health status is mandatory. Women with premature menopause who begin HT before 50 years of age seem to have the most significant advantage in terms of longevity. WIDER IMPLICATIONS In women with bothersome menopausal symptoms, HT should be considered one of the mainstays of treatment. Clinical practitioners should tailor HT based on patient history, physical characteristics, and current health status so that benefits outweigh the risks.
Article
Objective Provide strategies for improving the care of perimenopausal and postmenopausal women based on the most recent published evidence. Target Population Perimenopausal and postmenopausal women. Benefits, Harms, and Costs Target population will benefit from the most recent published scientific evidence provided via the information from their health care provider. No harms or costs are involved with this information since women will have the opportunity to choose among the different therapeutic options for the management of the symptoms and morbidities associated with menopause, including the option to choose no treatment. Evidence Databases consulted were PubMed, MEDLINE, and the Cochrane Library for the years 2002–2020, and MeSH search terms were specific for each topic developed through the 7 chapters. Validation Methods The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). Intended Audience physicians, including gynaecologists, obstetricians, family physicians, internists, emergency medicine specialists; nurses, including registered nurses and nurse practitioners; pharmacists; medical trainees, including medical students, residents, fellows; and other providers of health care for the target population.
Chapter
Menopause is diagnosed clinically after 12 months of amenorrhea that results from the loss of ovarian follicular activity that cannot be attributed to another physiologic or pathologic causes. It marks the end of reproductive life in women and is associated with clinical, physiological and psychological manifestations. This chapter discusses the process of reproductive ageing through the perimenopause and examines the symptomatology of the menopause with the associated hormonal changes and the causal associations between menopause and several symptoms and diseases. It also discusses the principles of managing the menopause with various hormonal and non-hormonal approaches. The use of hormone replacement therapy is discussed in detail including its benefits, risks and casual linkages to neoplasms. It is important to recognise that individuals place different values on various health outcomes associated with hormone therapy, so the decision to use it should be made jointly by each woman and her health-care provider after weighing the risks and benefits.
Article
The transition to menopause is associated with a changing hormonal milieu, leading to bothersome menopausal symptoms in the short-term and chronic health problems in the long-term. Premature ovarian insufficiency (POI) is characterized by the cessation of menses before the age of 40 years. Hormone replacement therapy (HRT) is indicated to restore sex hormones to normal premenopausal levels and prevent chronic diseases, such as osteoporosis and cardiovascular disease. Menopausal hormone therapy (MHT) is indicated in perimenopausal and postmenopausal women over 45 years of age for managing menopausal symptoms, symptoms of vulvovaginal atrophy, and reducing the risk of postmenopausal osteoporosis. Individualization is the key to management, aiming at maximizing efficacy and minimizing clinically relevant risks. This review aimed to present the hormone therapy regimens for women during the transition or after menopause and women with POI and early menopause, as well as advise on: i) the initiation of MHT, ii) steps for monitoring during follow up, iii) weaning and discontinuation of treatment.
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Background This study aimed to explore the molecular mechanisms of tibolone treatment in postmenopausal women. Methods The 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. Results A 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. Conclusions CCDC114 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.
Article
Every woman who lives past midlife will experience menopause, which, by definition, is complete cessation of ovarian function. This process might occur spontaneously (natural menopause) or be iatrogenic (secondary menopause), and can be further classified as ‘early’ if it occurs before the age of 45 years and ‘premature’ if it occurs before the age of 40 years. Globally, the mean age of natural menopause is 48.8 years, with remarkably little geographic variation. A woman’s age at menopause influences health outcomes in later life. Early menopause is associated with a reduced risk of breast cancer, but increased risks of premature osteoporosis, cardiovascular disease and premature death. The cardinal symptoms of menopause, and adverse health sequelae, are due to loss of ovarian oestrogen production. Consequently, menopausal hormone therapy (MHT) that includes oestrogen or an oestrogenic compound ameliorates menopausal symptoms, while preventing menopause-associated bone loss and cardiometabolic changes. Importantly, comprehensive care of postmenopausal women involves lifestyle optimization (attention to nutrition and physical activity, reducing alcohol consumption and not smoking) and treating other established chronic disease risk factors. This Review offers a commentary specifically on the contemporary use of MHT and novel pharmaceutical alternatives to manage menopausal symptoms. Menopause affects roughly half of the global population, yet many affected people do not receive the treatment they need. This Review discusses currently available menopausal hormonal therapies and novel pharmaceutical alternatives to manage menopausal symptoms. Most women experience menopause between the ages of 45 and 55 years, and 75% will experience oestrogen deficiency symptoms.Menopausal hormone therapy (MHT), including tibolone, remains the most effective treatment for menopausal symptoms.MHT considerably lowers the risk of hip, vertebral and other osteoporosis-related fracture in women with normal bone density, osteopenia and osteoporosis; fracture prevention is a primary indication for its use.Urogenital atrophy symptoms are common and should be treated, with several effective hormonal and non-hormonal treatments available.Several novel therapies for the treatment of menopausal symptoms are in development; however, the new non-hormonal therapies are specific for vasomotor symptoms and, unlike oestrogen therapy, will not prevent bone loss or cardiometabolic disease risk. Most women experience menopause between the ages of 45 and 55 years, and 75% will experience oestrogen deficiency symptoms. Menopausal hormone therapy (MHT), including tibolone, remains the most effective treatment for menopausal symptoms. MHT considerably lowers the risk of hip, vertebral and other osteoporosis-related fracture in women with normal bone density, osteopenia and osteoporosis; fracture prevention is a primary indication for its use. Urogenital atrophy symptoms are common and should be treated, with several effective hormonal and non-hormonal treatments available. Several novel therapies for the treatment of menopausal symptoms are in development; however, the new non-hormonal therapies are specific for vasomotor symptoms and, unlike oestrogen therapy, will not prevent bone loss or cardiometabolic disease risk.
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Zusammenfassung Frauen mit intaktem Uterus müssen bei der Anwendung eines systemisch wirksamen Östrogens zur Endometriumprotektion ein Gestagen erhalten. Gestagene lassen sich in verschiedene Wirkstoffgruppen einteilen, welche unterschiedliche Partialwirkungen haben. Dies bedeutet, dass es keinen Klasseneffekt der Gestagene gibt, sondern die Effekte auf Metabolismus sowie auf hormonsensible Gewebe wie Brust, Endometrium und Knochen variieren können. Mikronisiertes Progesteron und Dydrogesteron scheinen in Hinblick auf Herz-Kreislauf-System und Brust die sicherste Option zu sein. Ihre Effekte auf die Glukosehomöostase und den Lipidstoffwechsel sind neutral. Eine menopausale Hormontherapie, einschliesslich der Wahl des Gestagens, sollte immer entsprechend dem Risikoprofil und den Behandlungszielen der Patientin individualisiert werden.
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Objective: The aim of this study was to assess the impact of tibolone compared to dydrogesterone on endometrial thickness, breast density, quality of life and lipid profile status. Method: The double blind prospective-randomized study included forty-six perimenopausal women which were randomly assigned for treatment with either tibolone 2.5 mg/day (22 patients) or dydrogesterone 20 mg/day (24 patients) from day 14 to day 25 of the cycle, for 6 months. All women complained for climacteric symptoms and irregular menstrual cycle at least for the last six months. Results:During the 6 cycles of treatment, there was no significant difference between groups regarding the regularity of the cycles. Similarly, no significant difference was observed between groups regarding endometrial thickness, breast density, levels of estradiol, FSH, progesterone and lipid profiles. Regarding vertigo, mood disorder, depression, loss of libido, dryness of skin and vagina, tibolone therapy was found to be much more effective than progestin.
Article
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Many postmenopausal women who are on hormone replacement therapy discontinue medications due to vaginal bleeding. Tibolone, a synthetic steroid, has minimal stimulatory effect on the endometrium. The aim of this study was to assess the effects of continuous HRT regimen and tibolone on the onset of vaginal bleeding and vaginal maturation value. A total of 150 healthy women in postmenopausal period were randomly enrolled in this controlled clinical trial. Patients were randomly allocated into three groups, and were followed for six months. The first 50 women received 2.5 mg tibolone plus a Cal+D tablet (500 mg Calcium and 200 IU vitamin D) daily, the second 50 women received 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (CEE/MPA) plus one Cal+D tablet daily, and the remaining 50 received only one Cal+D tablet per day and served as the control group. Symptoms were recorded using a questionnaire that assessed vaginal bleeding or spotting, vaginal dryness and intention to continue the medications. Vaginal maturation value was assessed by examining vaginal smears before and after the treatment. The results for the three groups were analyzed using statistical methods. In comparison with the control group, CEE/MPA and tibolone increased vaginal maturation value and decreased the frequency of vaginal dryness (p < 0.01). Women in tibolone group were more likely to continue the treatment regimen than those in the CEE/MPA or the control groups (p < 0.01). Tibolone can serve as an appropriate choice for HRT as it has low rates of vaginal bleeding/ spotting episodes and high acceptance rate in postmenopausal women.
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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.
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To evaluate the efficacy, safety and tolerability of Tibolone use during the menopausal transition (MT). Sixty-five healthy women aged 40-55 years (48.5 ± 3.5 years) were recruited for a randomized, double-blind controlled trial. Thirty participants were recruited to receive oral Tibolone 2.5 mg/day - Tibolone Group (TG), and 35 participants were assigned to the Placebo Group (PG), which received one capsule of lactose/day. Both groups were treated for 12 consecutive weeks. The Blatt-Kupperman Menopausal Index (KMI) and the Greene Climacteric Scale (GCS) were used. The glycaemic and lipid profiles, biochemical measures of hepatic function and endometrial thickness were measured for safety. A daily registry of complaints related to the treatment was maintained, and anthropometric measures were obtained to assess tolerability. A total of 57 women completed the study. After 12 weeks of Tibolone use, the total score and percentage of the KMI and GCS were significantly decreased compared to baseline, which reflected the efficacy of the treatment of climacteric symptoms. The improvement in blood biochemistry, endometrial atrophy and maintenance of the anthropometrical measures reflected the safety of Tibolone use. The absence of serious side effects demonstrated good tolerability for Tibolone use. The results showed good efficacy, tolerability and safety of Tibolone use during the MT.
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Sexual desire is affected by endocrine and psychosocial factors. Menopausal hormonal changes are relevant to the causes of sexual dysfunction during reproductive aging. To evaluate the effects of different types of hormonal replacement therapy (HRT) on sexual function, frequency of sexual intercourse, and quality of relationship in early postmenopausal women. We recruited 48 healthy postmenopausal women aged 50-60 years (mean age 54.5 ± 3.3 years). Women with climacteric symptoms were uniformly randomized into three groups receiving either dehydroepiandrosterone (DHEA 10 mg) daily, or daily oral estradiol (1 mg) plus dihydrogesterone (5 mg), or daily oral tibolone (2.5 mg) for 12 months. Women who refused hormonal therapy were treated with oral vitamin D (400 IU). Efficacy was evaluated using the McCoy Female Sexuality Questionnaire before treatment and after 12 months. We evaluated the hormonal profile before treatment and after 3, 6 and 12 months. The groups receiving DHEA or HRT reported a significant improvement in sexual function compared to baseline (p < 0.001 and p < 0.01, respectively) using the McCoy total score. The quality of relationship was similar at baseline and after 3, 6 and 12 months of treatment. There were significant increases in the numbers of episodes of sexual intercourse in the previous 4 weeks in women treated with DHEA, HRT and tibolone in comparison with the baseline value (p < 0.01, p < 0.05, p < 0.01, respectively). No changes in the McCoy score occurred in women receiving vitamin D. Daily oral DHEA therapy at the dose of 10 mg, HRT and tibolone all provided a significant improvement in comparison with vitamin D in sexual function and in frequency of sexual intercourse in early postmenopausal women.
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Treatment decisions about menopause are predicated on a transient duration of vasomotor symptoms. However, evidence supporting a specific duration is weak. To estimate the natural progression of vasomotor symptoms during the menopause transition by systematically compiling available evidence using meta-analytic techniques. We searched MEDLINE, hand searched secondary references in relevant studies, book chapters, and review papers, and contacted investigators about relevant published research. English language, population-based studies reporting vasomotor symptom prevalence among women in menopausal transition in time intervals based on years to or from final menstrual period were included. Two reviewers independently assessed eligibility and quality of studies and extracted data for vasomotor symptom prevalence. The analyses included 10 studies (2 longitudinal, 8 cross sectional) with 35,445 participants. The percentage of women experiencing symptoms increased sharply in the 2 years before final menstrual period, peaked 1 year after final menstrual period, and did not return to premenopausal levels until about 8 years after final menstrual period. Nearly 50% of all women reported vasomotor symptoms 4 years after final menstrual period, and 10% of all women reported symptoms as far as 12 years after final menstrual period. When data were examined according to symptom severity ('any' vs. 'bothersome'), bothersome symptoms peaked about 1 year earlier and declined more rapidly than symptoms of any severity level. Our findings suggest a median symptom duration of about 4 years among symptomatic women. A longer symptom duration may affect treatment decisions and clinical guidelines. Further prospective, longitudinal studies of menopausal symptoms should be conducted to confirm these results.
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Most postmenopausal women have some of menopausal symptoms due to oestrogen deprivation. Many therapeutic options are available for managing menopausal problems. However, hormone therapy is associated with a heightened risk for thromboembolic events. To investigate the effects of different types of hormone therapy on some haemostatic parameters. This randomized, controlled study included 56 healthy, early postmenopausal women aged 46-58 years on different types of hormone therapy (tibolone 2.5 mg/day, 25 women, or CCHT 2 mg estradiol plus 1 mg norethisteron acetate, 31 women) and 20 healthy postmenopausal women of the same age receiving placebo. Effects of these 2 medicaments on some haemostasis parameters were measured 3 and 6 months after the onset of treatment. Short-term use (3 months) of both tibolone and CCHT had a detrimental effect on antithrombin, protein C and protein S levels (decreased), and even more so in the group treated with CCHT. Plasminogen-activator inhibitor type 1 levels were decreased by both tibolone and CCHT, but more so by CCHT; thrombin-antithrombin complex were increased in both groups. There were no changes in haemostatic parameters between 3-month and 6-month treatment in any group. Both therapeutic options are associated with an activation of thrombogenic and fibrinolytic markers within 3 months of use. Tibolone appears to produce a better balance between thrombogenesis and fibrinolysis. Since our results show a lower incidence of thrombotic events, further studies are required.
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Although breast cancer risk is greater in users of estrogen-progestin than estrogen-only formulations of menopausal hormonal therapy, reports on their effects have been somewhat inconsistent. We investigated whether the timing of these therapies affected breast cancer incidence. A total of 1,129,025 postmenopausal UK women provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk. We used Cox regression to estimate adjusted relative risks (RRs) of breast cancer in hormonal therapy users vs never users and calculated standardized incidence rates. All statistical tests were two-sided. During 4.05 million woman-years of follow-up, 15,759 incident breast cancers occurred, with 7107 in current users of hormonal therapy. Breast cancer incidence was increased in current users of hormonal therapy, returning to that of never users a few years after use had ceased. The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap (P(heterogeneity) < .001, for both estrogen-only and estrogen-progestin formulations). Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% confidence interval [CI] = 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51). A similar pattern was observed among current users of estrogen-progestin formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 to 2.14, respectively). At 50-59 years of age, annual standardized incidence rates for breast cancer were 0.30% (95% CI = 0.29% to 0.31%) among never users of hormone therapy and 0.43% (95% CI = 0.42% to 0.45%) and 0.61% (95% CI = 0.59% to 0.64%), respectively, among current users of estrogen-only and estrogen-progestin formulations who began use less than 5 years after menopause. There was substantial heterogeneity in breast cancer risk among current users of hormonal therapy. Risks were greater among users of estrogen-progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later.
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The metafor package provides functions for conducting meta-analyses in R. The package includes functions for fitting the meta-analytic fixed- and random-effects models and allows for the inclusion of moderators variables (study-level covariates) in these models. Meta-regression analyses with continuous and categorical moderators can be conducted in this way. Functions for the Mantel-Haenszel and Peto&apos;s one-step method for meta-analyses of 2 x 2 table data are also available. Finally, the package provides various plot functions (for example, for forest, funnel, and radial plots) and functions for assessing the model fit, for obtaining case diagnostics, and for tests of publication bias.
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To compare the effects of tibolone with those of conventional hormone replacement therapy on climacteric symptoms and sexual function in postmenopausal women. In a randomized, controlled trial, 140 postmenopausal women were allocated into three groups. Of the subjects included, 47 women received 2.5 mg tibolone + one Cal+D tablet (500 mg calcium and 200 IU vitamin D) daily; 46 women received 0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone (CEE/MPA) + one Cal+D tablet daily; and 47 women received only one Cal+D tablet as the control group. The Greene Climacteric Scale (GCS) questionnaire was used to detect the efficacy of treatment on climacteric symptoms. Rosen's Female Sexual Function Index (FSFI) was used for sexual function evaluation. Sex hormone binding globulin (SHBG), free estradiol index (FEI) and free testosterone index (FTI) were measured before and after treatment. The women were followed up for 6 months After treatment, all subscores in the GCS improved in the tibolone and CEE/MPA groups (p < 0.01), except the sexual subscore in the CEE/MPA group, compared with baseline. There were significant differences in the FSFI in the tibolone and CEE/MPA groups in comparison to the control group after treatment. Tibolone, in comparison to CEE/MPA, significantly lowered SHBG levels and increased the FTI and FEI and improved the desire, arousal and orgasm sexual domains of the FSFI (p < 0.001). Tibolone may be an alternative to conventional hormone replacement therapy in the treatment of climacteric symptoms and sexual dysfunction in postmenopausal women.
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Vasomotor symptoms and bone loss are complications frequently induced by adjuvant treatment for breast cancer. Tibolone prevents both side-effects, but its effect on cancer recurrence is unknown. The aim of this study was to show non-inferiority of tibolone to placebo regarding risk of recurrence in breast-cancer patients with climacteric complaints. Between July 11, 2002, and Dec 20, 2004, women surgically treated for a histologically confirmed breast cancer (T(1-3)N(0-2)M(0)) with vasomotor symptoms were randomly assigned to either tibolone 2.5 mg daily or placebo at 245 centres in 31 countries. Randomisation was done by use of a centralised interactive voice response system, stratified by centre, with a block size of four. The primary endpoint was breast-cancer recurrence, including contralateral breast cancer, and was analysed in the intention-to-treat (ITT) and per-protocol populations; the margin for non-inferiority was set as a hazard ratio of 1.278. This study is registered with ClinicalTrials.gov, number NCT00408863. Of the 3148 women randomised, 3098 were included in the ITT analysis (1556 in the tibolone group and 1542 in the placebo group). Mean age at randomisation was 52.7 years (SD 7.3) and mean time since surgery was 2.1 years (SD 1.3). 1792 of 3098 (58%) women were node positive and 2185 of 3098 (71%) were oestrogen-receptor positive. At study entry, 2068 of 3098 (67%) women used tamoxifen and 202 of 3098 (6.5%) women used aromatase inhibitors. The mean daily number of hot flushes was 6.4 (SD 5.1). After a median follow-up of 3.1 years (range 0.01-4.99), 237 of 1556 (15.2%) women on tibolone had a cancer recurrence, compared with 165 of 1542 (10.7%) on placebo (HR 1.40 [95% CI 1.14-1.70]; p=0.001). Results in the per-protocol population were similar (209 of 1254 [16.7%] women in the tibolone group had a recurrence vs 138 of 1213 [11.4%] women in the placebo group; HR 1.44 [95% CI 1.16-1.79]; p=0.0009). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (72 patients vs 63 patients, respectively), cardiovascular events (14 vs 10, respectively), or gynaecological cancers (10 vs 10, respectively). Vasomotor symptoms and bone-mineral density improved significantly with tibolone, compared with placebo. Tibolone increases the risk of recurrence in breast cancer patients, while relieving vasomotor symptoms and preventing bone loss. Schering-Plough (formerly NV Organon, Oss, Netherlands).
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Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)
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In medical research data are often collected serially on subjects. The statistical analysis of such data is often inadequate in two ways: it may fail to settle clinically relevant questions and it may be statistically invalid. A commonly used method which compares groups at a series of time points, possibly with t tests, is flawed on both counts. There may, however, be a remedy, which takes the form of a two stage method that uses summary measures. In the first stage a suitable summary of the response in an individual, such as a rate of change or an area under a curve, is identified and calculated for each subject. In the second stage these summary measures are analysed by simple statistical techniques as though they were raw data. The method is statistically valid and likely to be more relevant to the study questions. If this method is borne in mind when the experiment is being planned it should promote studies with enough subjects and sufficient observations at critical times to enable useful conclusions to be drawn. Use of summary measures to analyse serial measurements, though not new, is potentially a useful and simple tool in medical research.
Article
Objective: To study the effects of tibolone versus conjugated oestrogen as short-term treatment in improving HRQOL in surgical menopausal women utilizing Menopause Rating Scale II (MRS II). Materials and Methods: Sixty four women were randomized to two groups. Women in Group A (32 women) received tibolone 2.5 mg daily and women in Group B (32 women) received conjugated oestrogen 0.625 mg daily. For baseline assessment of the severity of menopausal symptoms, each woman scored herself on the MRS II, and then again after three months and twelve months of follow up. All women returned for follow up after three months but only ten women in Group A and nine women in Group B returned for follow up after twelve months. As a very short-term therapy (first three months), women receiving tibolone were found to have slightly better overall quality of life compared to those having conjugated oestrogen (psychological symptoms were predominantly improved with tibolone). Results: "Intent to treat" method of analysis showed that "probability" of relief and improvement of HRQOL after twelve months, were higher with tibolone than with conjugated oestrogen. Discussion: In a very short-term treatment, tibolone improves psychological symptoms of menopause better than conjugated oestrogen and on further continuation of the therapy, overall chances of relief are more with tibolone.
Article
Background: Evidence from systematic reviews of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women, however the results of randomised controlled trials (RCTs) have had mixed results. This is an updated version of a Cochrane review published in 2013. Objectives: To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women, and whether there are differential effects between use in primary or secondary prevention. Secondary aims were to undertake exploratory analyses to (i) assess the impact of time since menopause that treatment was commenced (≥ 10 years versus < 10 years), and where these data were not available, use age of trial participants at baseline as a proxy (≥ 60 years of age versus < 60 years of age); and (ii) assess the effects of length of time on treatment. Search methods: We searched the following databases on 25 February 2014: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE and LILACS. We also searched research and trials registers, and conducted reference checking of relevant studies and related systematic reviews to identify additional studies. Selection criteria: RCTs of women comparing orally administered hormone therapy with placebo or a no treatment control, with a minimum of six months follow-up. Data collection and analysis: Two authors independently assessed study quality and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for each outcome. We combined results using random effects meta-analyses, and undertook further analyses to assess the effects of treatment as primary or secondary prevention, and whether treatment was commenced more than or less than 10 years after menopause. Main results: We identified six new trials through this update. Therefore the review includes 19 trials with a total of 40,410 post-menopausal women. On the whole, study quality was good and generally at low risk of bias; the findings are dominated by the three largest trials. We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality, cardiovascular death, non-fatal myocardial infarction, angina, or revascularisation. However, there was an increased risk of stroke in those in the hormone therapy arm for combined primary and secondary prevention (RR 1.24, 95% CI 1.10 to 1.41). Venous thromboembolic events were increased (RR 1.92, 95% CI 1.36 to 2.69), as were pulmonary emboli (RR 1.81, 95% CI 1.32 to 2.48) on hormone therapy relative to placebo.The absolute risk increase for stroke was 6 per 1000 women (number needed to treat for an additional harmful outcome (NNTH) = 165; mean length of follow-up: 4.21 years (range: 2.0 to 7.1)); for venous thromboembolism 8 per 1000 women (NNTH = 118; mean length of follow-up: 5.95 years (range: 1.0 to 7.1)); and for pulmonary embolism 4 per 1000 (NNTH = 242; mean length of follow-up: 3.13 years (range: 1.0 to 7.1)).We performed subgroup analyses according to when treatment was started in relation to the menopause. Those who started hormone therapy less than 10 years after the menopause had lower mortality (RR 0.70, 95% CI 0.52 to 0.95, moderate quality evidence) and coronary heart disease (composite of death from cardiovascular causes and non-fatal myocardial infarction) (RR 0.52, 95% CI 0.29 to 0.96; moderate quality evidence), though they were still at increased risk of venous thromboembolism (RR 1.74, 95% CI 1.11 to 2.73, high quality evidence) compared to placebo or no treatment. There was no strong evidence of effect on risk of stroke in this group. In those who started treatment more than 10 years after the menopause there was high quality evidence that it had little effect on death or coronary heart disease between groups but there was an increased risk of stroke (RR 1.21, 95% CI 1.06 to 1.38, high quality evidence) and venous thromboembolism (RR 1.96, 95% CI 1.37 to 2.80, high quality evidence). Authors' conclusions: Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall, for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events.
Article
Objectives: We compared the change of body composition and body size in according to tibolone and drospirenone (DRSP) containing low dose hormone therapy in menopausal women. Methods: Fifteen postmenopausal women were enrolled in this prospective study. After 24 weeks, twelve women completed the study protocol and three women withdrew their participation. The participants were randomly assigned to either tibolone (2.5 mg; n=6, Tibolone group) or DRSP containing low dose hormone therapy (estradiol hemihydrates (EE) 1mg+DRSP 2mg, EE+DRSP group) (n=6) daily for 24 weeks. The body size and composition were measured with body mass index (BMI), weight, waist circumference (WC) and hip circumference (HC) before and after intervention. The fat mass (FM), fat-free mass (FFM), lean mass (LM) and total body water (TBW) were also measured by the Inbody 720 (Biospace, Korea) before and after intervention. Results: After 24 weeks, the WC was significantly decreased in DRSP group (P=0.04). However, it was not changed in the tibolone group (P=0.08). The fat-free mass, lean mass, body weight were increased in the tibolone group, but not significantly (Respectively P=0.12, P=0.17, P=0.08). The fat-free mass, lean mass were decreased but not significantly, and body weight was not changed in DRSP group (Respectively P=0.17, P=0.27, P=0.92). Conclusion: EE+DRSP reduce WC without change in body weight in postmenopausal women. However, tibolone made no significant change.
Article
IntroductionIndividual studiesThe summary effectHeterogeneity of effect sizesSummary points
Article
Postmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies. We conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence. After 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44-1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12-0.86), in HRT users <5 years (RR, 0.35; 95% CI 0.15-0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23-1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen. The addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study.
Article
Objective(s) The objective of this study was to compare the efficacy and safety of CEE, tibolone, and DHEA for prevention of menopausal symptoms. Method(s) One hundred patients with surgical menopause were included in this study: 25 of whom were not treated with any HRT, 25 were treated with 0.625 mg of CEE, 25 were treated with 2.5 mg of tibolone, and 25 were treated with 25 mg of DHEA for 1 year, and the results were statistically analyzed regarding drug efficacy and side effects at follow-up periods of 1, 6 and 12 months. Result(s) Frequency of menopausal symptoms was significantly less in cases received with CEE, tibolone, DHEA with p values 0.001, 0.004 and 0.004, respectively. Percentage gain in BMD was 2.8 % with CEE at lumbar spine, which was greater than that caused by DHEA and tibolone, but this difference was not statistically significant. CEE caused side effects like headache (40 %) and nausea (28 %). Conclusion(s) CEE, Tibolone, and DHEA are very effective in alleviating climacteric symptoms. CEE has beneficial effects on lipid and bone and is a low-cost drug but frequently causes side effects. Tibolone offers beneficial androgenic effects on mood and libido with fewer side effects but is a costly drug. DHEA shows positive effects on psychological symptoms. However, its cost and androgenic side effects limit its use as long-term HRT.
Article
Objective: To investigate a potential correlation between vaginal bleeding and oestradiol (E2) levels/endometrial morphology in early postmenopausal women using tibolone (Livial(R)). Methods: A 2-year randomised placebo-controlled study of 94 healthy women, 1-3 years after spontaneous menopause, receiving either placebo (n=23), 1.25 mg/day (n=36) or 2.5 mg/day (n=35) tibolone. Episodes of vaginal bleeding throughout the 2-year study period were recorded. Age, age of menopause, months since menopause and body mass index were recorded. Serum E2 levels were assessed at baseline and at 3-month intervals throughout the study period. In case of vaginal bleeding, endometrium morphology was assessed by Vabra Curettage. Results: Fifty-one percent (n=18, P<0.05) of women in the 2.5 mg/day tibolone group and 44% (n=16, P=0.07) in the 1.25 mg/day tibolone group presented with at least one period of vaginal bleeding, compared with 22% (n=5) in the placebo group. The women who bled in the placebo group were younger (P<0.01), had menopause at an earlier age (P<0.05), had a shorter duration since menopause (P<0.05) and had a higher median E2 serum level prior to bleeding (P<0.05). In contrast, in both tibolone groups, no determinants could be found for the vaginal bleeding. Ninety percent of the first bleedings occurred within 9 months after starting the treatment. At Vabra endometrium sampling, there was no evidence of endometrial stimulation. Conclusions: In the present study, early postmenopausal women using 1.25 or 2.5 mg/day tibolone are 2-2.5 times more likely to present with vaginal bleeding compared with placebo (P<0.05) without evidence of higher serum E2 levels or endometrial stimulation.
Article
Background: Ovarian cancer is the fourth most common cancer in women in the UK, with about 6700 developing the malignancy and 4600 dying from it every year. However, there is limited information about the risk of ovarian cancer associated with the use of hormone replacement therapy (HRT). Methods: 948,576 postmenopausal women from the UK Million Women Study who did not have previous cancer or bilateral oophorectomy were followed-up for an average of 5.3 years for incident ovarian cancer and 6.9 years for death. Information on HRT use was obtained at recruitment and updated where possible. Relative risks for ovarian cancer were calculated, stratified by age and hysterectomy status, and adjusted by area of residence, socioeconomic group, time since menopause, parity, body-mass index, alcohol consumption, and use of oral contraceptives. Findings: When they last reported HRT use, 287,143 women (30%) were current users and 186 751 (20%) were past users. During follow-up, 2273 incident ovarian cancers and 1591 deaths from the malignancy were recorded. Current users were significantly more likely to develop and die from ovarian cancer than never users (relative risk 1.20 [95% CI 1.09-1.32; p=0.0002] for incident disease and 1.23 [1.09-1.38; p=0.0006] for death). For current users of HRT, incidence of ovarian cancer increased with increasing duration of use, but did not differ significantly by type of preparation used, its constituents, or mode of administration. Risks associated with HRT varied significantly according to tumour histology (p<0.0001), and in women with epithelial tumours the relative risk for current versus never use of HRT was greater for serous than for mucinous, endometroid, or clear cell tumours (1.53 [1.31-1.79], 0.72 [0.52-1.00], 1.05 [0.77-1.43], or 0.77 [0.48-1.23], respectively). Past users of HRT were not at an increased risk of ovarian cancer (0.98 [0.88-1.11] and 0.97 [0.84-1.11], respectively, for incident and fatal disease). Over 5 years, the standardised incidence rates for ovarian cancer in current and never users of HRT were 2.6 (2.4-2.9) and 2.2 (2.1-2.3) per 1000, respectively-ie, one extra ovarian cancer in roughly 2500 users; death rates were 1.6 (1.4-1.8) and 1.3 (1.2-1.4) per 1000, respectively-ie, one extra ovarian cancer death in roughly 3300 users. Interpretation: Women who use HRT are at an increased risk of both incident and fatal ovarian cancer. Since 1991, use of HRT has resulted in some 1300 additional ovarian cancers and 1000 additional deaths from the malignancy in the UK.
Article
Objective: To compare the effectiveness of tibolone and 17β-estradiol on climacteric symptoms, lipid and biochemical parameters in women with surgical menopause. Methods: In a prospective randomised clinical trial group comparative study, the effects on the aforementioned parameters, as well as treatment compliance and side effects were studied with oral tibolone 2.5 mg per day and with transdermic 17β-estradiol at 50 μg per day for a period of 12 months. Statistical analysis was carried out using the Fisher-test, analysis of the variance (ANOVA) for the two factors and the Bouferoni test. Results: Lipid metabolism analysis showed lower levels of HDL and triglycerides in the tibolone group. Other biochemical parameters were not affected. Similar reductions in climacteric symptoms were found in both the groups, but the tibolone group revealed a greater improvement in psychological problems and in sexual behaviour. No differences were observed with respect to compliance and side effects. Conclusions: Tibolone is as effective or more than 17β-estradiol in reducing climacteric symptoms, and shows greater triglyceride and total cholesterol improvements. Tibolone is a good alternative to estrogens in women with surgical menopause.
Article
Objective: This study compared the effects of a continuous-combined regimen of low-dose hormone therapy (LD-HT) versus tibolone and supplemental calcium/vitamin D3 (control) on quality of life (QoL) in symptomatic postmenopausal women. Design: This study was a prospective, randomised, double-blind, comparative trial with a control group. Setting: The study was conducted in a climacteric outpatient clinic in the University Hospital of Federal University of Juiz de Fora, Brazil. Population: A total of 174 postmenopausal women under 60 years of age who attended the climacteric outpatient clinic between June 2009 and June 2011 were recruited. These women complained of moderate or intense vasomotor symptoms and exhibited no contraindications for the use of hormone therapy. Interventions: The patients were randomised into three groups: (1) daily treatment with 2.5mg tibolone (n=64), (2) 50mg calcium carbonate+200 IU vitamin D3 (Ca/Vit D3, n=54) or (3) 1mg oestradiol+0.5mg norethindrone acetate (E2/NETA, n=56) for 12 weeks. Primary outcome measures: The primary outcome was the evaluation of QoL using the Women's Health Questionnaire (WHQ) in all subjects at baseline and after 4, 8 and 12 weeks of treatment. Results: A total of 130 women in the following groups completed the study: tibolone (n=42), Ca/Vit D3 (n=44) and E2/NETA (n=44). An improved QoL based on the WHQ was observed at T0 (80.12±14.04, 77.73±15.3, 77.45±15.4) and T12 (57.0±15.5, 55.7±16.7, 58.4±12.6) for the tibolone, E2+NETA and Ca/Vit D3 groups, respectively (p values <0.05). The three groups exhibited significantly different scores at T12 for sexual behaviour and vasomotor symptoms. The tibolone group exhibited better sexual function compared with the E2/NETA and Ca/Vit D3 groups (4.2±26, 5.6±2.8, 5.4±2.8, respectively, p values <0.05). LD-HT was superior to tibolone and Ca/Vit D3 treatment for improvements in vasomotor symptoms (3.2±1.5, 4.0±1.8, 4.3±2.0, respectively, p values <0.05). Adverse effects were few and mild. Conclusions: An improved QoL was observed in the three study groups. Tibolone primarily improved sexual function, and E2/NETA exhibited a superior response for vasomotor symptoms.
Article
Objective To describe the prevalence of, and degree of distress caused by, 15 symptoms commonly attributed to the menopause among a random sample of women aged 45 to 54, selected from the total population of a geographically defined area.Design Postal questionnaire survey.Setting Grampiane Health Board area.Participants Eight thousand women, aged 45 to 54, randomly selected from the Grampian Community Health Index.Main outcome measures Self-reported symptoms, including depression, and use of hormone replacement therapy (HRT) among women of differing menopausal status.Results The response rate was 78%; 57% of respondents had experienced one or more of the 15 symptoms listed, but only 22% had found such symptoms a problem. Women's experience of classic vasomotor and atrophic symptoms varied according to menopausal status but experience of general somatic and psychological symptoms did not. Users of HRT and women whose menopause was iatrogenic found more symptoms a problem.Conclusions Symptoms attributed to the menopause are common among women in the age group studied but often are not perceived as a problem. Among nonusers of HRT, only vasomotor and atrophic symptoms vary with menopausal status. Other somatic and psychological symptoms experienced by middle-aged women cannot be regarded as part of the same ‘menopausal syndrome’.
Article
Objective: To compare the effects of two postmenopausal regimens on menopausal symptoms, bleeding episodes, side effects and acceptability. Design: Double-blind, randomised controlled trial. Setting: Twenty-nine sites in Denmark, nine in Norway and six in Sweden. Participants: Four hundred and thirty-seven postmenopausal women with menopausal complaints. None of these women had had a hysterectomy. Interventions: Daily treatment with tibolone 2.5 mg (n = 218) or 17beta-oestradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA) (n = 219). Main outcome measures: Hot flushes, sweating episodes, vaginal dryness, assessment of sexual life and bleeding patterns; at baseline and after 4, 12, 24 and 48 weeks. Results: Treatment with either preparation significantly reduced mean scores for hot flushes, sweating episodes and vaginal dryness. The overall discontinuation rate was 28% (tibolone 25%, E2/NETA 31%; P = 0.14), mostly during the first six months. There was a markedly lower cumulative incidence of bleeding or spotting episodes with tibolone compared with E2/NETA (P < 0.0001), mainly during the first six treatment cycles. Conclusions: Both tibolone and E2/NETA effectively alleviate menopausal symptoms. However, tibolone caused significantly fewer bleeding or spotting episodes, which were reflected by lower overall rates of bleeding, as well as lower drop-out rates due to bleeding.
Article
Objective To examine the effects of tibolone on bone mineral density and its concurrent safety and subject acceptability. Design Prospective randomised controlled study. Setting Centre for Metabolic Bone Disease, Hull. Population Forty-seven healthy post-menopausal women aged 50–57 years with normal bone mineral density at lumbar spine. Methods Bone mineral density was assessed every 24 weeks at lumbar spine and proximal femur using dual energy X-ray absorptiometry. Results The bone mineral density of the tibolone treated subjects tended to increase while those of the controls tended to fall. The higher densities in the tibolone group were significant at lumbar spine from week 24 (P= 0.002) and at the trochanter from week 72 (P= 0.014). The lower bone densities in the controls were significant at Ward's Triangle and femoral neck at week 96 (P < 0.0001), and at lumbar spine from week 24 onwards (P < 0.05). Between-treatment analysis indicated that, by the 96th week, the bone densities at all sites in the tibolone group were significantly different from those in the control group. At the lumbar spine the differences were highly significant throughout the study (P < 0.0004). Four women receiving tibolone withdrew from the study due to unacceptable adverse events. Two women withdrew from the control group. There was no significant difference between the groups in the number of subjects suffering adverse experiences. Vaginal bleeding occurred in seven women, all from the tibolone treated group, resulting in one withdrawal from the study. Conclusion Tibolone is thus an effective and well-tolerated alternative to oestrogen in the prevention of osteoporosis with its beneficial effects being most apparent at the lumbar spine.
Article
For many years, hormone replacement therapy (HRT) was the mainstay for osteoporosis prevention in postmenopausal women until a large randomized clinical trial raised serious safety concerns. This resulted in a big drop in HRT use and its demotion by regulatory authorities to second-line treatment. Many clinicians now feel that HRT is not safe to use, and recommend various alternatives for the treatment of osteoporosis. But how effective are these alternative therapies, are they any safer than HRT, and how do their costs compare? This review questions the validity of the safety concerns about HRT, and highlights the safety concerns about alternative therapies. It concludes that HRT is as safe as the other treatment options, and its efficacy and low cost demand that it be restored as a first-line treatment for the prevention of postmenopausal osteoporosis. Other therapies are available for use in osteoporosis, and the bisphosphonates are particularly effective for the treatment of the established disease. However, they must be used selectively and with caution, and are best restricted to those patients who are elderly or have severe disease. New treatments are emerging, but again caution must be taken until any long-term adverse effects have been identified.
Article
To evaluate the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) vs. tibolone and placebo for menopausal vasomotor symptoms and the incidence of uterine bleeding. This 12-week, double-blind, randomized, controlled trial was conducted at 35 sites in Europe, two sites in South Africa, and one site in Mexico. Postmenopausal women with ≥50 moderate or severe hot flushes per week (n = 485) were randomized to desvenlafaxine 100 mg/day, tibolone 2.5 mg/day, or placebo. Reduction in the average daily number of moderate and severe hot flushes at weeks 4 and 12 (primary endpoint) was evaluated using analysis of covariance. Safety assessments included incidence of uterine bleeding, adverse events, laboratory values, and vital signs. At week 12, no statistically significant difference was observed in reduction of the average daily number of moderate and severe hot flushes for desvenlafaxine (-5.78) vs. placebo (-5.82; p = 0.921), although time to 50% reduction was significantly less than placebo (13 vs. 26 days, p = 0.006). Hot flush reduction with tibolone (-8.21) was significantly greater than placebo (p < 0.001). Nausea was the most common adverse event with desvenlafaxine, was generally mild to moderate, and resolved within the first 2 weeks. Significantly more subjects experienced bleeding with tibolone (23%) vs. desvenlafaxine (12%; p < 0.024) or placebo (9%; p < 0.001). Desvenlafaxine did not separate from placebo in reducing the number of moderate to severe hot flushes at week 12, although it did allow women to achieve 50% reduction sooner than placebo. Tibolone did separate from placebo, but with smaller than expected effect. The placebo effect was high (57%). Adverse drug reactions were consistent with the known safety profile of desvenlafaxine, and significantly more women who received tibolone experienced episodes of bleeding compared with women who received desvenlafaxine or placebo.