Effect of menopausal hormonal therapy on cardiovascular risks in Korean postmenopausal women: A nationwide cohort study.

OBJECTIVE: To evaluate the association between menopausal hormonal therapy (MHT) and the risk of cardiovascular disease (CVD), according to various regimens, dosages, routes of administration and starting ages of MHT. DESIGN: A population-based cohort study using the Korean National Health Insurance Services database. SETTING: Nationwide health insurance database. POPULATION: Women who reported entering menopause at an age of ≥40 years with no history of CVD in the national health examination. METHODS: The study population comprised 1 120 705 subjects enrolled between 2002 and 2019, categorised according to MHT status (MHT group, n = 319 007; non-MHT group, n = 801 698). MAIN OUTCOME MEASURES: Incidence of CVD (a composite of myocardial infarction and stroke). RESULTS: The incidence of CVD was 59 266 (7.4%) in the non-MHT group and 17 674 (5.5%) in the MHT group. After adjusting for confounding factors, an increased risk of CVD was observed with the administration of tibolone (hazard ratio, HR 1.143, 95% CI 1.117-1.170), oral estrogen (HR 1.246, 95% CI 1.198-1.295) or transdermal estrogen (HR 1.289, 95% CI 1.066-1.558), compared with the non-MHT group; the risk was based on an increased risk of stroke. The risk trends were consistent regardless of the age of starting MHT or the physicians' specialty. Among tibolone users, a longer period from entering menopause to taking tibolone and the use of any dosage (1.25 or 2.5 mg) were linked with a higher risk of CVD, compared with non-MHT users. CONCLUSIONS: This nationwide cohort study demonstrated an increased risk of CVD, driven mainly by an increased risk of stroke, among tibolone and oral or transdermal estrogen users, compared with that of non-MHT users.

Relationship between menopausal hormone therapy and incidence of fractures in postmenopausal women.

OBJECTIVE: Long-term protective effects of menopausal hormone therapy (MHT) at fractures with different doses and components are controversial. We analyzed the effect of MHT on the incidence of spine and femur fractures according to MHT type, age at commencement, duration and dose of hormones in Korean women. METHOD: This retrospective study evaluated propensity score-matched patients with MHT from the Korean National Health Insurance Service database. Among women aged ≥50 years with menopause between 2004 and 2007, spine and femur fracture incidence until 2017 was analyzed in 36,446 women who had received MHT for >1 year. Estrogen-progesterone therapy (EPT), estrogen-only therapy (ET) or tibolone therapy was conducted. RESULTS: EPT significantly lowered the incidence of spine and femur fractures with a conventional dose, but not with a low dose. Tibolone significantly decreased the incidence of spine fractures in women aged 50-59 years when used for >5 years, and the incidence of femur fractures in women older than 60 years when used for >3 years. ET significantly lowered the risk of femur fractures when estradiol was used for >5 years. CONCLUSION: In menopausal women, all MHT including conventional-dose EPT, ET and tibolone tended to lower the incidence of fractures. The effects, however, varied with the type of fracture and type of MHT.

Postmenopausal hormone therapy in prior pre-eclamptic women: a nationwide cohort study in Finland.

OBJECTIVE: We compared the trends of hormone therapy (HT) use among women with and without a history of pre-eclampsia. METHODS: This national cohort study consisted of women with a pre-eclamptic pregnancy (n = 31,688) or a normotensive pregnancy (n = 91,726) (controls) during 1969-1993. The data on their use of HT during 1994-2019 were traced from the National Medicine Reimbursement Register. RESULTS: Both women with a history of pre-eclampsia and controls initiated HT at a mean age of 49.9 years. Cumulative HT™ use during the total follow-up did not differ between the groups (31.1% vs. 30.6%, p = 0.066). However, HT use in previously pre-eclamptic women was less common in 1994-2006 (20.2% vs. 22.4%, p < 0.001) and more common in 2007-2019 (22.1% vs. 21.1%, p < 0.001) than in controls. This trend was also seen in the annual changes of HT starters. Women with a history of pre-eclampsia used HT for a shorter time (6.3 vs. 7.1 years, p < 0.001). CONCLUSIONS: In contrast to controls, HT use in previously pre-eclamptic women increased during the last half of the follow-up. This may reflect the changes in the international recommendations, the increased awareness of pre-eclampsia-related cardiovascular risk later in life and the aim to diminish this risk with HT.

Menopausal hormone therapy and the risk of cataracts in postmenopausal women in South Korea.

PURPOSE: Postmenopausal women have a higher prevalence of cataracts than men of a similar age. This study aimed to evaluate the effects of menopausal hormone therapy (MHT) on lens opacities in postmenopausal women. METHODS: This retrospective cohort study analysed population-based health insurance data in South Korea collected from 2002 to 2019. To determine the risk factors associated with cataract, postmenopausal women (N = 2,506,271) were grouped according to post-MHT use. The treatment group was further divided into the following subgroups: tibolone, combined oestrogen plus progestin by manufacturer, oral oestrogen, combined oestrogen plus progestin by physician and topical oestrogen groups. The main outcome measure was the prevalence of cataracts. RESULTS: The control group comprised 463,151 postmenopausal women who had never used MHT after menopause, while the treatment group included 228,033 postmenopausal women who had used MHT continuously for at least 6 months. The treatment group had a higher incidence of cataracts than the control group based on Cox proportional hazards ratio analysis. Low socioeconomic status and high parity were identified as risk factors for cataracts, and reduced risk of cataracts was associated with living in rural areas and drinking alcohol. CONCLUSIONS: Women undergoing post-MHT, including tibolone, had a higher incidence of cataracts. Cataract development should be a concern when examining postmenopausal patients using MHT.

Effect of tibolone versus hormone replacement therapy on lower urinary tract symptoms and sexual function.

BACKGROUND: Few studies have compared the effects of tibolone versus hormone replacement therapy (HRT) on lower urinary tract symptoms and female sexual function. The current study aimed to compare these treatments. METHODS: Women with climacteric symptoms were recruited consecutively and allocated to receive tibolone (2.5 mg) or estradiol valerate (1 mg) and medroxyprogesterone acetate (2.5 mg). Patients were followed up at 4 weeks and 12 weeks after treatment. RESULTS: Overall, there were no significance of improvement in the International Prostate Symptoms Score (IPSS) scores in the HRT group. However, nocturia and the IPSS storage score improved after tibolone treatment. In addition, orgasm, satisfaction and pain improved after HRT. However, desire, lubrication, and Female Sexual Function Index (FSFI) total scores improved after tibolone treatment. There was a between-group difference in the change from baseline in the nocturia score after 4 weeks of treatment (0.1 ± 0.9 for HRT vs. -0.4 ± 1.2 for tibolone, p = 0.02). Nonetheless, there were no significant differences of the changes from baseline in the other IPSS and FSFI domains between the tibolone and HRT groups. CONCLUSIONS: Despite the limited effect, tibolone seems to have more benefit in nocturia than HRT. In addition, tibolone seems to have benefits on overall low urinary tract storage symptoms; and both tibolone and HRT seem to have beneficial effects on female sexual function, despite there were no significant differences between tibolone and HRT.

Tibolone Improves Locomotor Function in a Rat Model of Spinal Cord Injury by Modulating Apoptosis and Autophagy.

Spinal cord injury (SCI) harms patients' health and social and economic well-being. Unfortunately, fully effective therapeutic strategies have yet to be developed to treat this disease, affecting millions worldwide. Apoptosis and autophagy are critical cell death signaling pathways after SCI that should be targeted for early therapeutic interventions to mitigate their adverse effects and promote functional recovery. Tibolone (TIB) is a selective tissue estrogen activity regulator (STEAR) with neuroprotective properties demonstrated in some experimental models. This study aimed to investigate the effect of TIB on apoptotic cell death and autophagy after SCI and verify whether TIB promotes motor function recovery. A moderate contusion SCI was produced at thoracic level 9 (T9) in male Sprague Dawley rats. Subsequently, animals received a daily dose of TIB orally and were sacrificed at 1, 3, 14 or 30 days post-injury. Tissue samples were collected for morphometric and immunofluorescence analysis to identify tissue damage and the percentage of neurons at the injury site. Autophagic (Beclin-1, LC3-I/LC3-II, p62) and apoptotic (Caspase 3) markers were also analyzed via Western blot. Finally, motor function was assessed using the BBB scale. TIB administration significantly increased the amount of preserved tissue (p < 0.05), improved the recovery of motor function (p < 0.001) and modulated the expression of autophagy markers in a time-dependent manner while consistently inhibiting apoptosis (p < 0.05). Therefore, TIB could be a therapeutic alternative for the recovery of motor function after SCI.

Relationship between the type of hormone replacement therapy and incidence of breast cancer in Korea.

OBJECTIVE: This study aimed to investigate the relationship between hormone replacement therapy (HRT) types and breast cancer (BC) incidence in postmenopausal women in Korea. METHODS: The nested case-control study used data from the National Health Insurance Service database. Among the women aged ≥50 years who menopaused between 2004 and 2007, BC incidence up to 2017 was analyzed in 36,446 women using or having used HRT for >1 year and in 36,446 women who did not use any HRT for more than 1 year. HRT types and duration were classified into three categories. RESULTS: BC risk (BCR) decreased with tibolone use for all ages. With HRT initiation in women aged ≥50 years, BCR was lower with tibolone and estrogen-progestogen therapy. HRT for <3 years showed lower BCR with tibolone, while higher BCR was observed with estrogen-only therapy. BCR was lower in women of all ages on HRT for >5 years than in the control group. CONCLUSIONS: For women in their 50s, tibolone use lowers BCR; for all ages, the use of any HRT for >5 years showed lower BCR in Korea. These divergent results from western countries could be associated with the specific characteristics of BC in Korea.

Integrated Metabolomics and Lipidomics Reveal High Accumulation of Glycerophospholipids in Human Astrocytes under the Lipotoxic Effect of Palmitic Acid and Tibolone Protection.

Lipotoxicity is a metabolic condition resulting from the accumulation of free fatty acids in non-adipose tissues which involves a series of pathological responses triggered after chronic exposure to high levels of fatty acids, severely detrimental to cellular homeostasis and viability. In brain, lipotoxicity affects both neurons and other cell types, notably astrocytes, leading to neurodegenerative processes, such as Alzheimer (AD) and Parkinson diseases (PD). In this study, we performed for the first time, a whole lipidomic characterization of Normal Human Astrocytes cultures exposed to toxic concentrations of palmitic acid and the protective compound tibolone, to establish and identify the set of potential metabolites that are modulated under these experimental treatments. The study covered 3843 features involved in the exo- and endo-metabolome extracts obtained from astrocytes with the mentioned treatments. Through multivariate statistical analysis such as PCA (principal component analysis), partial least squares (PLS-DA), clustering analysis, and machine learning enrichment analysis, it was possible to determine the specific metabolites that were affected by palmitic acid insult, such as phosphoethanolamines, phosphoserines phosphocholines and glycerophosphocholines, with their respective metabolic pathways impact. Moreover, our results suggest the importance of tibolone in the generation of neuroprotective metabolites by astrocytes and may be relevant to the development of neurodegenerative processes.

Respirasome Proteins Are Regulated by Sex-Hormone Interactions in the Brain.

The existence of sex differences in disease incidence is attributed, in part, to sex differences in metabolism. Uncovering the precise mechanism driving these differences is an extraordinarily complex process influenced by genetics, endogenous hormones, sex-specific lifetime events, individual differences and external environmental/social factors. In fact, such differences may be subtle, but across a life span, increase susceptibility to a pathology. Whilst research persists in the hope of discovering an elegant biological mechanism to underpin sex differences in disease, here, we show, for the first time, that such a mechanism may be subtle in nature but influenced by multiple sex-specific factors. A proteomic dataset was generated from a gonadectomized mouse model treated with Tibolone, a menopausal hormone therapy. Following functional enrichment analysis, we identified that Alzheimer's disease and the electron transport chain-associated pathways were regulated by sex-hormone interactions. Specifically, we identified that the expression of three respirasome proteins, NDUFA2, NDUFA7 and UQCR10, is significantly altered by compounding factors that contribute to sex differences. These proteins function in bioenergetics and produce reactive oxygen species, which are each dysregulated in many diseases with sex differences in incidence. We show sex-specific reprogrammed responses to Tibolone following gonadectomy, which primarily influence the expression of proteins contributing to metabolic pathways. This further infers that metabolic differences may underpin the observed sex differences in disease, but also that hormone therapy research now has potential in exploring sex-specific interventions to produce an effective method of prevention or treatment.

Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis.

Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.

The effect of tibolone treatment on lipid profile in women: A systematic review and dose-response meta-analysis of randomized controlled trials.

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/m2versus 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.

Association of tibolone and dementia risk: a cohort study using Korean claims data.

OBJECTIVE: Few studies have examined whether tibolone (TIB), a type of hormone replacement therapy widely used in Asia and Europe, affects dementia risk in postmenopausal women. Our study aims to investigate the association of TIB and dementia risk in Korean women aged 50-80 years. METHODS: A population-based longitudinal study was conducted using the Korean National Health Insurance Service claims database merged with national health examination data from 2002 to 2015. Among 13,110 participants, exposure to TIB was determined using the standardized defined daily dose (DDD) system from 2003 to 2007. Starting from 2007, participants were followed up for overall dementia, Alzheimer's disease (AD) and vascular dementia (VD) until 2015. Cox proportional hazards regression was used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of dementia according to TIB use. RESULTS: TIB use was not significantly associated with the risk of total dementia (aHR = 1.040; 95% CI = 0.734-1.472; p = .827), AD (aHR = 0.949; 95% CI = 0.652-1.381; p = .785) and VD (aHR = 1.245; 95% CI = 0.631-2.457; p = .528). CONCLUSIONS: Our results suggest that TIB use does not have a significant association with dementia risk. Further randomized controlled trials are necessary to elucidate the role of exogenous hormones in the development of dementia.

The synthetic steroid tibolone exerts sex-specific regulation of astrocyte phagocytosis under basal conditions and after an inflammatory challenge.

BACKGROUND: Tibolone is a synthetic steroid used in clinical practice for the treatment of climacteric symptoms and osteoporosis. Active metabolites of tibolone, generated in target tissues, have an affinity for estrogen and androgen receptors. Astrocytes are direct targets for estrogenic compounds and previous studies have shown that tibolone protects brain cortical neurons in association with a reduction in reactive astrogliosis in a mouse model of traumatic brain injury. Since phagocytosis is a crucial component of the neuroprotective function exerted by astrocytes, in the present study, we have assessed whether tibolone regulates phagocytosis in primary astrocytes incubated with brain-derived cellular debris. METHODS: Male and female astrocyte cell cultures were obtained from newborn (P0-P2) female and male Wistar rats. Astrocytic phagocytosis was first characterized using carboxylate beads, Escherichia coli particles, or brain-derived cellular debris. Then, the effect of tibolone on the phagocytosis of Cy3-conjugated cellular debris was quantified by measuring the intensity of Cy3 dye-emitted fluorescence in a given GFAP immunoreactive area. Before the phagocytosis assays, astrocytes were incubated with tibolone in the presence or absence of estrogen or androgen receptor antagonists or an inhibitor of the enzyme that synthesizes estradiol. The effect of tibolone on phagocytosis was analyzed under basal conditions and after inflammatory stimulation with lipopolysaccharide. RESULTS: Tibolone stimulated phagocytosis of brain-derived cellular debris by male and female astrocytes, with the effect being more pronounced in females. The effect of tibolone in female astrocytes was blocked by a selective estrogen receptor ß antagonist and by an androgen receptor antagonist. None of these antagonists affected tibolone-induced phagocytosis in male astrocytes. In addition, the inhibition of estradiol synthesis in the cultures enhanced the stimulatory effect of tibolone on phagocytosis in male astrocytes but blocked the effect of the steroid in female cells under basal conditions. However, after inflammatory stimulation, the inhibition of estradiol synthesis highly potentiated the stimulation of phagocytosis by tibolone, particularly in female astrocytes. CONCLUSIONS: Tibolone exerts sex-specific regulation of phagocytosis in astrocytes of both sexes, both under basal conditions and after inflammatory stimulation.

Effects of tibolone or continuous combined oestradiol and norethisterone acetate on lipids, high-density lipoprotein subfractions and apolipoproteins in postmenopausal women in a two-year, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the effects of (a) tibolone, (b) continuous combined oestrogen plus progestogen and (c) placebo on plasma lipid and lipoprotein markers of cardiovascular risk in healthy postmenopausal women. STUDY DESIGN: Randomized, single-centre, placebo-controlled, double-blind study. PATIENTS: One hundred and one postmenopausal women were randomized (1:1:1) into one of three groups taking daily 2.5 mg tibolone, continuous oral oestradiol-17ß 2 mg plus norethisterone acetate 1 mg 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 < .001), the greatest effect being in the cholesterol-enriched HDL2 subfraction (-40%, P < .001). Tibolone's effect on HDL concentrations was also apparent in the principal HDL protein component, apolipoprotein AI (-29% at 24 months, P < .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 = .008). E2 /NETA reduced HDL-C to a lesser extent than tibolone (-12% at 24 months, P < .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.

Systemic lupus erythematosus and menopause.

Estrogen has been known for a long time to be a trigger on auto-immunity and may influence the course of lupus. Women experiencing systemic lupus are at high risk for premature ovarian insufficiency if using cyclophosphamide, of osteoporosis, arterial ischemic diseases and venous thrombosis at young age. In about 30% of them, an antiphospholipid/anticoagulant antibody can occur which is associated with very high risk of thrombosis. However, the severity of the disease may vary and some women with lupus could benefit from a menopausal hormone therapy (MHT). As a consequence, management of menopause symptoms needs to evaluate carefully the condition of the patient, her lupus history and cardiovascular risk. We will describe the effect of lupus on menopause, of menopause on lupus and report in detail the literature available on MHT and the risk of lupus or the risk of flares in women with lupus. Some other options than MHT for the management of climacteric symptoms will be discussed.

Microglial and Astrocytic Function in Physiological and Pathological Conditions: Estrogenic Modulation.

There are sexual differences in the onset, prevalence, and outcome of numerous neurological diseases. Thus, in Alzheimer's disease, multiple sclerosis, and major depression disorder, the incidence in women is higher than in men. In contrast, men are more likely to present other pathologies, such as amyotrophic lateral sclerosis, Parkinson's disease, and autism spectrum. Although the neurological contribution to these diseases has classically always been studied, the truth is that neurons are not the only cells to be affected, and there are other cells, such as glial cells, that are also involved and could be key to understanding the development of these pathologies. Sexual differences exist not only in pathology but also in physiological processes, which shows how cells are differentially regulated in males and females. One of the reasons these sexual differences may occur could be due to the different action of sex hormones. Many studies have shown an increase in aromatase levels in the brain, which could indicate the main role of estrogens in modulating proinflammatory processes. This review will highlight data about sex differences in glial physiology and how estrogenic compounds, such as estradiol and tibolone, could be used as treatment in neurological diseases due to their anti-inflammatory effects and the ability to modulate glial cell functions.

Tibolone and risk of gynecological hormone sensitive cancer.

Risk of ovarian cancer with hormone therapy is associated with use of both unopposed estrogen therapy and combined estrogen-progestin therapy, whereas for endometrial cancer addition of continuous progestin decreases the estrogen induced increased risk. Less is known about risk with use of tibolone; a synthetic steroid with estrogenic, progestagenic and androgenic properties. We assessed these associations in a prospective cohort study, including all Danish women 50-79 years of age and followed 1995-2009. National Danish Registers captured individually updated exposure information, cancer cases including histology and confounding factors. Poisson regression analyses provided multiple adjusted incidence rate ratios (IRRs). More than 900,000 women were followed for 9.8 years on average; 4,513 were diagnosed with ovarian cancer and 6,202 with endometrial cancer. Compared to women never on postmenopausal hormone therapy, current users of tibolone had an increased IRR for ovarian cancer (1.42(95% confidence interval [CI], 1.01-2.00) and serous ovarian tumors (2.21(95%CI 1.48-3.32)). The risk increased with duration of use, particularly for serous ovarian tumors. Compared to never users, the IRR of endometrial cancer was 3.56(95%CI 2.94-4.32) among current users of tibolone and 3.80(95%CI 3.08-4.69) of Type I endometrial cancer. The steepest risk increase with duration of use was for Type I tumors. In conclusion, tibolone is associated with increased risk for ovarian and endometrial cancer overall; and particular the risk of serous ovarian tumors and Type I endometrial cancer. Because the associations are stronger with increasing durations of use - and for hormone sensitive tumors - the results seem indicative of causality.

Migraine, hormones and the menopausal transition.

Migraine is a common, disabling and incapacitating headache disorder that may be triggered by many factors, such as hormones especially during the perimenopausal period, where large alterations in estradiol levels can occur. The evidence implies that hormonal fluctuations are one of the important triggers of migraine. During reproductive life and during hormonal contraception, the course of migraine can be impacted. Different types of migraine with and without aura can be variously influenced by hormones. Migraine can constitute a risk factor for stroke and this must be taken in account for menopause hormone therapy. Hormone therapy is a possible approach to prevent migraine that happens during the menopause transition. Scarce data on the various regimens and types of hormone therapy are available. Transdermal estradiol displays a more favorable profile on migraine than oral estrogens because it may provide more constant levels of estrogens.

Effects of tibolone on fibrinogen and antithrombin III: A systematic review and meta-analysis of controlled trials.

Tibolone is a synthetic steroid with estrogenic, androgenic and progestogenic activity, but the evidence regarding its effects on fibrinogen and antithrombin III (ATIII) has not been conclusive. We assessed the impact of tibolone on fibrinogen and ATIII through a systematic review and meta-analysis of available randomized controlled trials (RCTs). The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2016) to identify controlled clinical studies investigating the effects of oral tibolone treatment on fibrinogen and ATIII. Overall, the impact of tibolone on plasma fibrinogen concentrations was reported in 10 trials comprising 11 treatment arms. Meta-analysis did not suggest a significant reduction of fibrinogen levels following treatment with tibolone (WMD: -5.38%, 95% CI: -11.92, +1.16, p=0.107). This result was robust in the sensitivity analysis and not influenced after omitting each of the included studies from meta-analysis. When the studies were categorized according to the duration of treatment, there was no effect in the subsets of trials lasting either <12months (WMD: -7.64%, 95% CI: -16.58, +1.29, p=0.094) or ≥12months (WMD: -0.62%, 95% CI: -8.40, +7.17, p=0.876). With regard to ATIII, there was no change following treatment with tibolone (WMD: +0.74%, 95% CI: -1.44, +2.93, p=0.505) and this effect was robust in sensitivity analysis. There was no differential effect of tibolone on plasma ATIII concentrations in trials with either <12months (WMD: +2.26%, 95% CI: -3.14, +7.66, p=0.411) or≥12months (WMD: +0.06%, 95% CI: -1.16, +1.28, p=0.926) duration. Consistent with the results of subgroup analysis, meta-regression did not suggest any significant association between the changes in plasma concentrations of fibrinogen (slope: +0.40; 95% CI: -0.39, +1.19; p=0.317) and ATIII (slope: -0.17; 95% CI: -0.54, +0.20; p=0.374) with duration of treatment. In conclusion, meta-analysis did not suggest a significant reduction of fibrinogen and ATIII levels following treatment with tibolone.

Use of hormone therapy for menopausal symptoms and quality of life in breast cancer survivors. Safe and ethical?

Breast cancer is the most prevalent cancer in women and presently, the breast cancer survivors are an important group of women that faced the several consequences of estrogen deficiency, which is especially common in women after chemotherapy. The most bothersome is the vasomotor symptoms, which are effectively relieved by hormonal therapy (HT). Also, the increased risk of osteoporosis and coronary artery disease is major problem to be resolved in pos of maintaining a good quality of life. Fearing cancer recurrence, most physicians do not offer HT to women with a history of breast cancer. Over this issue reviews the available evidence of the use of HT and tibolone in women treated for breast cancer.