Effect Of Menopausal Hormone Therapy Research Articles

Effect of Prior Use Menopausal Hormone Therapy on Blood Pressure Responses in Women

Cerebrovascular reactivity to hypercapnia is higher in women receiving menopausal hormone therapy (MHT) compared with controls, and this may persist after cessation of MHT. We hypothesized that the effect of MHT may be influenced by mean arterial pressure (MAP). Therefore, we examined both middle cerebral artery velocity (MCAv) and MAP responses to stepped hypercapnia in 60 postmenopausal women who were previously randomized to receive oral conjugated equine estrogen (oCEE, n=15), transdermal 17β estradiol (tE2, n=22), or placebo (PLA, n=23) for 4 years. After a 3 year washout period, reactivity was calculated from the slope of the relationship between MCAv or MAP and end‐tidal CO2. MCAv reactivity was higher in the oCEE group compared with the PLA group (1.6±0.2 vs. 1.1±0.1 cm/s/mmHg; oCEE vs. PLA, respectively, p<0.05), but similar between the tE2 and PLA group (1.3±0.2 vs. 1.1±0.1 cm/s/mmHg; tE2 vs. PLA, respectively, p>0.05). There were no significant differences in MAP reactivity (1.0±0.2, 0.6±0.1, 0.7±0.2 mmHg/mmHg of CO2, oCEE vs. tE2 vs. PLA, respectively, p>0.05) among the groups. However, in the combined MHT group, MAP reactivity was positively correlated with MCAv reactivity (r=0.58, p<0.001), such that women with higher MAP responses demonstrate greater MCAv responses to hypercapnia. In conclusion, there were no differences in MAP reactivity 3 years after cessation of MHT. In addition, our results suggest that greater cerebrovascular reactivity in postmenopausal women who received MHT may be driven by augmented blood pressure responses to hypercapnia. Funding: K99 HL 118164, AG 044170 and HL 83947.

Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats

The neuroprotective effects of menopausal hormonal therapy in Parkinson's disease have not yet been clarified, and it is not known whether there is a critical period. Estrogen induced significant protection against 6-hydroxydopamine-induced dopaminergic degeneration when administered immediately or 6 weeks, but not 20 weeks after ovariectomy. In the substantia nigra, ovariectomy induced a decrease in levels of estrogen receptor-α and increased angiotensin activity, NADPH-oxidase activity, and expression of neuroinflammatory markers, which were regulated by estrogen administered immediately or 6 weeks but not 20 weeks after ovariectomy. Interestingly, treatment with angiotensin receptor antagonists after the critical period induced a significant level of neuroprotection. In cultures, treatment with 1-methyl-4-phenylpyridinium induced an increase in astrocyte-derived angiotensinogen and dopaminergic neuron death, which were inhibited by estrogen receptor α agonists. In microglial cells, estrogen receptor β agonists inhibited the angiotensin-induced increase in inflammatory markers. The results suggest that there is a critical period for the neuroprotective effect of estrogen against dopaminergic cell death, and local estrogen receptor α and renin-angiotensin system play a major role.

Menopausal Hormonal Therapy and Cardiovascular Disease

Cardiovascular disease is the leading cause of death in women. Older observational studies suggested a significant protective effect of menopausal hormone therapy (MHT) for coronary heart disease (CHD) when prescribed for women at the onset of menopause; and this also translated into a significant reduction in mortality as well. Multiple mechanisms have been found to support these findings. Various secondary prevention trials and the use of hormones in older women have shown negative findings and a trend for more coronary events in these women with atherosclerotic plaque. Data from the Women’s Health Initiative in younger women confirm the data in the observational studies showing a protective effect on CHD and mortality for conjugated equine estrogens (CEE) alone, whereas the data with CEE and medroxyprogesterone acetate do not show as positive an effect. Recent trials testing the “timing” hypothesis also have confirmed these data for benefit in younger women, but not in older women. Because prevention of diseases after menopause should be a major goal of providers of health care for women, the consideration of using MHT, particularly the use of estrogen, may once again be considered as part of this prevention strategy.

Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease

Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and ‘timing’ could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD.

Menopausal hormone therapy and breast cancer

Observational and randomized controlled trial data have extensively examined the relationship between menopausal hormone therapy (MHT) and risk of developing breast cancer. A highly influential study from the Women's Health Initiative (WHI) in 2002 reported that a MHT regimen of conjugated equine estrogens and medroxyprogesterone acetate increased the risk of breast cancer by 26%. Later reports from the WHI indicated that a MHT regimen with conjugated equine estrogens alone decreased the risk of breast cancer by 23%. Critical re-examination of the WHI study noted that the average participant age was 63, that few women had symptoms, and that the WHI results might not apply to younger, symptomatic women shortly after menopause. Since the original publications, several post hoc analyses and observational studies have stimulated reconsideration of the WHI findings. Emphasis has been directed toward risks in younger women just entering the menopause, the subgroup who are most likely to be considering MHT use.The goal of this treatise is to integrate available mechanistic and clinical information related to the use of estrogen alone or estrogen plus a progestogen for five years or less. These data suggest that estrogen alone neither decreases nor increases risk in younger women initiating therapy close to the time of menopause but decreases risk in older women. Both younger and older women experience an excess risk with estrogen plus a progestogen. The attributable risk in younger women is less in those with a low underlying Gail Model risk score. Effects of MHT on risk largely reflect actions on pre-existing, occult, undiagnosed breast cancers. Tumor kinetic models suggest that the pro-proliferative effects of estrogen plus a progestogen on occult tumors provide a mechanistic explanation for the increased risk with this therapy. Pro-apoptotic effects of estrogen alone may explain the reduction of breast cancer in women starting this therapy at an average age of 63 as reported in the WHI study.This article is part of a Special Issue entitled ‘Menopause’.

Effects of menopausal hormone treatments on prostanoid levels and platelet sensitivity to cyclic AMP activation in healthy, recently menopausal women

Estrogen modulates the prostanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) which contribute to vascular hemostasis in endothelium and platelets. Estrogen decreases in women at menopause, and menopausal hormone therapy (MHT) may increase risk of thrombosis. This study aimed to determine effects of MHT on serum prostanoid levels and on prostanoid‐related platelet functions in healthy, recently‐menopausal women. Women (age 52.3±2.3 yrs; n=115) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) were randomized to either: 1) oral conjugated equine estrogen, 2) transdermal 17β estradiol each with intermittent oral progesterone or 3) placebo, for 48 months. Serum PGI2 and TXA2 levels were assessed by quantification (ng/ml) of their stable metabolites 6‐k‐PGF1α and TXB2, respectively. Initial TXB2 levels (46.9±7.5) were unchanged (P>; 0.05) after 48 months in each treatment group. However, 6‐k‐PGF1α decreased from 2.1±0.2 to 1.4±0.1 at 48 months in combined groups, but was statistically significant (1.5±0.3) only in the transdermal group. Inhibition of platelet ATP secretion by PGE1 did not correlate with serum 6‐k‐PGF1α levels. These results suggest that serum PGI2 levels decrease with age in menopausal women and are unaffected by MHT. Factors other than changes in serum prostanoids may impose thrombotic risk associated with MHT. (Supported by the Aurora Fnd, NIH HL88988 and Mayo Clinic).

Role of Estrogen in the Age-Related Decline in Bone Microstructure

The effects of estrogen deficiency on bone mineral density (BMD) are well described. At the menopause, there is an accelerated phase of bone loss, and this can be prevented by the administration of menopausal hormonal therapy (MHT). There has recently been a technical advance that allows us to observe the effect of estrogen deficiency and replacement on bone microstructure, namely high-resolution peripheral quantitative computed tomography (HR-pQCT). Quantitative computed tomography (QCT) allows the study of bone in 3 dimensions and hence allows us to study the 2 major types of bone (cortical and trabecular) separately. This contrasts with the most commonly used method for studying bone, dual-energy x-ray absorptiometry, which allows the study of bone in 2 dimensions and so provides no separation of the 2 bone types. QCT methods have advanced and now have higher resolution, and dedicated devices are available that allow the measurement of the peripheral skeleton (radius and tibia) at high resolution (voxel size, 82 m). This allows us to study bone microstructure measures such as cortical thickness and trabecular number. In this issue of the JCEM, Farr et al (1) report on the changes in bone microstructure in response to MHT in women shortly after the menopause. They measured the radius using HR-pQCT over 4 years of treatment with MHT or placebo. They report significant effects of MHT (as compared to placebo) on volumetric BMD of the radius, significant for the cortical but not trabecular bone. The relative increase in cortical volumetric bone density was accompanied by a relative decrease in cortical porosity but no change in cortical thickness. The predominant effect of MHT on cortical bone was somewhat surprising because the fractures that result from postmenopausal osteoporosis usually occur at sites rich in trabecular bone, and estrogen deficiency is considered to be the principal cause of this trabecular bone loss. The introduction of HR-pQCT has extended our knowledge about bone modeling and bone loss across life and has given new insights into the basis of bone fragility. Particularly, these studies have shown that trabecular and cortical bone compartments behave differently during skeletal development and during aging. During skeletal development, trabecular modeling of the radius is completed at around the end of longitudinal growth at the end of puberty, but the cortex is still porous at the end of linear growth (ages 15–17 y). There is a significant decrease in radial cortical porosity between the end of adolescence and the end of the third decade (2). Cortical bone density remains stable from skeletal maturity to middle age, but there is some evidence that trabecular bone loss may begin in young adulthood, soon after skeletal maturity (thus before the menopause) (3). Trabecular bone at the radius is lost with aging, and the patternof lossdiffersbetweenmenandwomen.Menshow a decrease in trabecular thickness, and women show a decrease in trabecular number (3, 4). This may represent a greater rate of trabecular perforation in women. Trabecular microstructural properties in older women are associated with circulating estrogen levels (5). The extension of HR-pQCT to the study of cortical microstructure has demonstrated the importance of cortical bone loss in ageand menopause-related decrease in bone strength. At the radius, cortical porosity increases and cortical BMD decreases with age in men and women. However, the bone loss is more rapid in women than in

Effects of menopausal hormone therapy on ductal carcinoma in situ of the breast

Post-menopausal hormone therapy with estrogen plus progestin is consistently reported to be associated with an increased risk of invasive breast cancer. However, findings on an association between hormone use and ductal carcinoma in situ of the breast (DCIS), a possible precursor lesion of invasive breast cancer, are sparse and inconsistent. Women's Health Initiative data were used to assess the effects of hormone therapy on the risk of DCIS in two clinical trials of hormone therapy (16,276 women enrolled in the trial of daily conjugated equine estrogens plus medroxyprogesterone acetate (CEE+MPA) vs placebo; 10,187 women enrolled in the trial of CEE-alone vs placebo). The effects of hormone therapy on DCIS in clinical trial participants were assessed during the intervention, post-intervention, and entire followup periods, and in the observational study (OS; 30,421 CEE+MPA users and non-users and 18,657 CEE-alone users and non-users who met eligibility criteria similar to the clinical trial). Compared to placebo, CEE+MPA was non-significantly associated with higher risk of DCIS over approximate average of 11years of follow-up (HR=1.23; 95% CI: 0.91-1.64). No statistical difference was detected between intervention and post-intervention phases (p=0.32). Corresponding OS results supported an increased risk for DCIS in CEE+MPA users compared to women who were non-users (HR=1.65; 95% CI: 1.25-2.19) after adjusting for potential confounders. There was no clear association between CEE-alone use and risk of DCIS. CEE-alone trial data showed that the risk of DCIS was non-significantly lower in the treatment than in the placebo group, while analysis of the corresponding OS showed a non-significantly higher risk of DCIS in the CEE-alone users than non-users. Our analysis suggests that combined estrogen plus progestin use in post-menopausal women may increase risk of DCIS. Whether estrogen-alone use is associated with DCIS requires further investigation.

Effects of menopausal hormone therapy on uterine myoma in menopausal women.

ObjectivesThe aim of the present study is to evaluate the long term effects of estrogen-progestogen therapy (EPT) on uterine myomas volume in postmenopausal women.MethodsWe performed a retrospective analysis on postmenopausal women with asymptomatic uterine myoma during the period between April, 2008 and September, 2012. Postmenopause was defined as amenorrhea for longer than a year or serum follicle stimulating hormone levels higher than 40 IU/L. The volume of the myoma was assessed by transvaginal ultrasonography for every 6 months after administration of EPT.ResultsThirty-eight women were included in the study, with 32 in the EPT group and 6 in the control group. Overall, uterine myoma volume (mean ± standard deviation, cm3) in the EPT group was 19.5 ± 24.6 at baseline, and those at 6 and 12 months were 24.7 ± 35.1 and 28.5 ± 56.4, respectively. Myoma volume did not change significantly with EPT, and these changes were not significantly different from the control group. Myoma volume changes were not significantly different in the subgroups according to the route of estrogen administrations and the method of progestogen administrations. Clinically significant volume increases during one year of EPT was noted in 28.1% (9/32), however, only one showed transient increases.ConclusionOur results suggest that treating postmenopausal woman with EPT on a long-term basis does not increase the volume of uterine myomas.

Current Resources for Evidence‐Based Practice January/February 2013

Current Resources for Evidence‐Based Practice January/February 2013

Relationships of Coronary Heart Disease With 27-Hydroxycholesterol, Low-Density Lipoprotein Cholesterol, and Menopausal Hormone Therapy

Menopausal hormone therapy (MHT) increases the risk of coronary heart disease (CHD) in older women with elevated low-density lipoprotein (LDLC) levels. The endogenous estrogen receptor antagonist 27-hydroxycholesterol (27OHC) is correlated with LDLC levels and may block the beneficial effects of estrogen on the cardiovascular system. We conducted a nested case-control study in the Women's Health Initiative trials of 350 CHD cases and 813 matched controls to explore potential mediation by 27OHC of the dependence of the CHD risk elevation with MHT on LDLC. Baseline levels of 27OHC were not associated with CHD risk when LDLC was included in the multivariable models. The odds ratio for CHD associated with increased LDLC was 1.15 (95% confidence interval, 1.08-1.23) and was unchanged at 1.14 (95% confidence interval, 1.07-1.22) when 27OHC was added to the model. Baseline 27OHC did not interact with MHT on CHD risk (P=0.81). In contrast, LDLC levels modified the effect of MHT on CHD risk (P for interaction=0.02), and adding 27OHC did not affect this result. With the use of log scales, the effect of MHT on CHD increased linearly with increasing level of baseline LDLC, with a transition from no risk to increased risk at ≈3.36 mmol/L (130 mg/dL). This study found that 27OHC does not independently increase the risk of CHD, does not modify the increased risk of CHD resulting from MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.

Effects of menopausal hormone therapy (MHT) on vascular reactive molecules in platelets

Activated platelets release mitogenic factors, vascular remodeling enzymes, inflammatory and cellular adhesive molecules into the vascular microenvironment to alter chemotactic and adhesive properties of vascular endothelium. Platelet‐derived growth factor‐BB (PDGF‐BB) and matrix metalloproteinase‐2 (MMP‐2) increased in the platelets following ovariectomy but decreased with estrogen treatment in pigs. Experiments were designed to identify changes in these factors using custom antibody arrays in lysate of platelets collected from women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic. Washed platelets were prepared from anticoagulated blood before (baseline) and 48 months after randomization into either placebo or oral or transdermal MHT. Preliminary analysis shows after 48 months compared to baseline, platelet content of C‐reactive protein, intercellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1), PDGF‐BB, MMP‐2 and transforming growth factor‐beta (TGF‐beta) were lower (20–60%) in two groups but higher (20–74%) in one group. Based on our studies in pigs, it is expected that the two groups showing decreases in platelet proteins would be from women randomized to MHT. However, KEEPS will not be unblinded until February 2012. (Supported by grants from Aurora Foundation, NIH HL90639, 1UL1 RR024150).

Menopausal Hormone Therapy and Risks of Melanoma and Nonmelanoma Skin Cancers: Women’s Health Initiative Randomized Trials

Case-control studies have reported that exogenous estrogen use is associated with increased risk of skin cancer. The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma were evaluated in post hoc analyses of the Women's Health Initiative randomized placebo-controlled hormone therapy trials of combined estrogen plus progestin (E + P) and estrogen only (E-alone). Postmenopausal women aged 50-79 years were randomly assigned to conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo in the E + P trial if they had an intact uterus (N = 16,608) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy (N = 10,739); the mean follow-up was 5.6 and 7.1 years, respectively. Incident nonmelanoma skin cancers (n = 980 [E + P trial]; n = 820 [E-alone trial]) and melanomas (n = 57 [E + P trial]; n =38 [E-alone trial]) were ascertained by self-report. Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records. Incidences of nonmelanoma skin cancer and melanoma were compared between the two randomization groups within each trial using hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) and Wald statistic P values from Cox proportional hazards models. All statistical tests were two-sided. Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone (combined analysis of E + P and E-alone) and placebo groups (nonmelanoma skin cancer: HR = 0.98, 95% CI = 0.89 to 1.07; melanoma: HR = 0.92, 95% CI = 0.61 to 1.37). Results were similar for the E + P and E-alone trials when analyzed individually. Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma. These findings do not support a role of menopausal estrogen, with or without progestin, in the development of skin cancer in postmenopausal women.

Risk of Osteoporotic Fractures After Discontinuation of Menopausal Hormone Therapy: Results From the E3N Cohort

While current use of menopausal hormone therapy (MHT) reduces the risk of osteoporotic fractures, epidemiologic studies suggest that protection wears off rapidly after discontinuation of treatment. The authors identified 5,589 first osteoporotic fractures (2,235 major osteoporotic fractures) among 70,182 postmenopausal women from the French E3N cohort (1992-2008) and used Cox multivariate proportional hazards regression models to estimate hazard ratios. Persistence of protection against major osteoporotic fractures after MHT discontinuation was only observed when MHT had been used for at least 5 years, with a slightly more important decrease within the 5 years after discontinuation (compared with never use of MHT, hazard ratio = 0.68, 95% confidence interval: 0.50, 0.92) than beyond 5 years (hazard ratio = 0.83, 95% confidence interval: 0.69, 0.99); the P value for homogeneity between the 2 estimates was not significant. Oral estrogen use and transdermal estrogen use conveyed similar estimates in past users. Among current users, the authors confirmed a protective effect of MHT against risk of osteoporotic fractures. These findings, which relied on a number of MHT combinations, suggested that such therapies should be used for 5 years or more for reducing risk of fracture after treatment discontinuation.

Health-related quality of life during hormone therapy after breast cancer: a randomized trial

Aim To study the effects of menopausal hormone therapy (HT) on health-related quality of life in women after breast cancer.Patients and methods In the Stockholm trial, breast cancer survivors were randomized to HT (estradiol and progestogen) or to a control group (no treatment). A subgroup of 75 women was studied (38 with HT, 37 controls). Fifty patients were on concomitant tamoxifen. Patients completed three questionnaires (EORTC QLQ C-30, EORTC QLQ-BR 23 and the Hospital Anxiety and Depression Scale (HADS)) during 1 year of treatment.Results A significant group-by-time interaction was found for improvement of insomnia in the HT group (p < 0.001). Within the HT group, but not in the control group, there was significant improvement for HADS anxiety, HADS depression, emotional, cognitive, and social functions and global quality of life. When HT was added to tamoxifen, the increase in global quality of life was significant (p < 0.01).Conclusion The effects of HT on quality of life in breast cancer survivors have not previously been reported. The present data suggest that this controversial treatment may improve quality of life after breast cancer.

Impact of Sex Hormone Metabolism on the Vascular Effects of Menopausal Hormone Therapy in Cardiovascular Disease

Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to agerelated changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.

Hemorheologic profile in healthy women undergoing controlled ovarian stimulation

We investigated the hemorheologic profile in 110 women undergoing controlled ovarian stimulation and provide evidence that smokers and women with body mass index>25 kg/m2 exhibit alterations of rheologic profile. A progressive increase of whole-blood viscosity throughout the ovarian stimulation cycle was observed; deformability and aggregation of erythrocytes decreased from baseline to the beginning of recombinant FSH administration, then remained unchanged throughout the next days; hematocrit mildly decreased during the last days of recombinant FSH administration; and fibrinogen and cholesterol levels decreased and increased, respectively, throughout the stimulation cycle.

Genetic modifiers of the effect of menopausal hormone therapy on breast cancer risk – A meta-analysis of four genome-wide association studies

Hormone therapy (HT) is associated with an elevated risk of breast cancer (BC) in postmenopausal women. Only limited studies have examined whether BC risk after HT exposure varies by individual susceptibility. To identify loci that modify HT related BC risk, four genome-wide case-only studies were analysed separately and combined in a meta-analysis. We included data from the genome-wide association studies HEBCS (Finland), MARIE (Germany), NHS (USA) and SASBAC (Sweden) which yielded 344, 742, 1,090 and 773 female, postmenopausal BC cases, respectively. Recruitment was hospital-based for HEBCS and population-based for MARIE, SASBAC and NHS. The available SNPs (genotyped using the Illumina 370k array in MARIE and 550 k in HEBCS, NHS and SASBAC) were used to impute additional SNPs (software: MACH) which resulted in up to 2,800,000 SNPs in total per study. The case-only approach is more powerful to detect gene-environment interactions than the case-control approach if the assumption of gene-environment independence is valid. We performed case-only logistic regression analysis for each study separately (outcome: current versus never/past HT use) using the software ProbABEL that takes into account the uncertainty introduced by imputation, i.e. the probabilities of each genotype per SNP and individual are used rather than the most likely genotype. A log-additive mode of inheritance is employed. The meta-analyses will be conducted assuming fixed effects (software: Plink). Our study has 80% power to detect an interaction effect of 1.25 assuming genetic and environmental main effects of 1.15, a moderate risk allele frequency of 0.10 and a prevalence of the environmental exposure of 0.50, Currently, analyses are ongoing and results will be presented at the conference. The most significant results will be replicated in independent case-control studies from the Breast Cancer Association Consortium (BCAC). We will thus rule out false positives due to possible gene-HT dependencies.

Potential Approaches to Enhance the Effects of Estrogen on Senescent Blood Vessels and Postmenopausal Cardiovascular Disease

Cardiovascular disease (CVD) is more common in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Vascular estrogen receptors ERalpha, ERbeta and a transmembrane estrogen-binding protein GPR30 have been described. Also, experimental studies have demonstrated vasodilator effects of estrogen on the endothelium, vascular smooth muscle and extracellular matrix. However, randomized clinical trials have not supported vascular benefits of menopausal hormone therapy (MHT), possibly due to the subjects' advanced age and age-related changes in estrogen synthesis and metabolic pathways, the vascular ERs number, distribution and integrity, and the post-ER vascular signaling pathways. Current MHT includes natural estrogens such as conjugated equine estrogen, as well as synthetic and semi-synthetic estrogens. New estrogenic formulations and hormone combinations have been developed. Phytoestrogens is being promoted as an alternative MHT. Specific ER modulators (SERMs), and selective agonists for ERalpha such as PPT, ERbeta such as DPN, and GPR30 such as G1 are being evaluated. In order to enhance the vascular effectiveness of MHT, its type, dose, route of administration and timing may need to be customized depending on the subject's age and pre-existing CVD. Also, the potential interaction of estrogen with progesterone and testosterone on vascular function may need to be considered in order to maximize the vascular benefits of MHT on senescent blood vessels and postmenopausal CVD.

Vascular Sex Hormone Receptors and their Specific Modulators in the Management of Postmenopausal Cardiovascular Disease

Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Studies on the vasculature have identified estrogen receptors ERα, ERβ and a novel estrogen binding membrane protein GPR30, that mediate genomic and/or non-genomic effects. Estrogen promotes endothelium-dependent relaxation by inducing the production/activity of nitric oxide, prostacyclin, and hyperpolarizing factor, and inhibits the mechanisms of vascular smooth muscle contraction including [Ca(2+)](i), protein kinase C, Rho kinase and mitogen-activated protein kinase. Additional effects of estrogen on the cytoskeleton, matrix metalloproteinases and inflammatory factors contribute to vascular remodeling. However, the experimental evidence did not translate into vascular benefits of menopausal hormone therapy (MHT), and the HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events. The discrepancy has been partly related to delayed MHT and potential changes in the vascular ER amount, integrity, affinity, and downstream signaling pathways due to the subjects' age and preexisting CVD. The adverse vascular effects of MHT also highlighted the need of specific modulators of vascular sex hormone receptors. The effectiveness of MHT can be improved by delineating the differences in phramcokinetics and pharmacodynamics of natural, synthetic, and conjugated equine estrogens. Estriol, "hormone bioidenticals" and phytoestrogens are potential estradiol substitutes. The benefits of low dose MHT, and transdermal or vaginal estrogens over oral preparations are being evaluated. Specific ER modulators (SERMs) and ER agonists are being developed to maximize the effects on vascular ERs. Also, the effects of estrogen are being examined in the context of the whole body hormonal environment and the levels of progesterone and androgens. Thus, the experimental vascular benefits of estrogen can be translated to the outcome of MHT in postmenopausal CVD, as more specific modulators of sex hormone receptors become available and are used at the right dose, route of administration and timing, depending on the subject's age and preexisting cardiovascular condition.