Oral Conjugated Equine Estrogens Research Articles

Real-world practice of estrogen and progestogen prescriptions in menopausal women in Japan: A descriptive study using a Japanese claims database.

This study aimed to investigate the real-world clinical practice of estrogen and progestogen prescriptions for menopausal women. Using a health care database in Japan, we conducted a cross-sectional study on estrogen prescriptions and detailed analyses of newly initiated estrogens and concomitant prescriptions of progestogens. Data between January 2005 and December 2021 were analyzed. In 2021, the proportion of women aged 45-49 years receiving estrogens was 25.8 [95% confidence interval (CI): 25.3, 26.3] per 1000 women, while it was 6.4 [95% CI: 6.0, 6.7] for those aged ≥60 years. The prescription of estrogens gradually increased in women aged 50-59 years after 2009. In women without a history of hysterectomy, transdermal estradiol was the primary form of estrogens prescribed for ≥180 days, in women aged <60 years. The proportion of transdermal estradiol gradually increased each year, whereas that of oral-conjugated equine estrogens decreased. Among progestogen, the proportions of dydrogesterone and transdermal norethisterone acetate increased over time, while that of medroxyprogesterone acetate decreased. Approximately 30% of women prescribed estrogens for ≥180 days did not initiate progestogen concurrently. In women undergoing hysterectomy, progestogen was not initiated in >90% of cases, and transdermal estradiol was prescribed in approximately 80% of cases in 2021. This study reviewed the prescription of estrogens in menopausal women in Japan. A considerable number of women with a uterus are receiving estrogen therapy rather than estrogen-progestogen therapy (EPT), despite the guidelines recommending the use of EPT in these women.

Associations between pituitary-ovarian hormones and cognition in recently menopausal women independent of type of hormone therapy

ObjectivesTo examine associations of pituitary-ovarian hormone levels with cognition before and after different formulations of hormone therapy (HT) or placebo independent of treatment group. MethodsRecently menopausal, healthy women were randomized to 0.45 mg/day oral conjugated equine estrogens (o-CEE, n = 109), 50 μg/day transdermal 17β (tE2, n = 107) or placebo pills and patches (n = 146); women on active treatment received oral 200 mg/day micronized progesterone for 12 days per month. Levels of estrone, 17β-estradiol, follicle stimulating hormone, luteinizing hormone, androstenedione, and testosterone were determined prior to and after 48 months of study participation. Neuropsychological testing was administered at baseline, and months 18, 36 and 48. Latent growth curve models controlling for education level, age, APOE allele status, waist circumference, and treatment examined the trajectories of each cognitive domain after accounting for the effect of hormone levels at baseline and months 18, 36 and 48. A linear multivariate mixed model examined the effect of changes in hormone levels on changes in trajectories of complex attention tasks with varying degrees of difficulty. ResultsAll women were adherent to treatment at month 48. Higher baseline estrone levels were associated with poorer global cognition, auditory attention and working memory, visual attention, and executive function, but not working memory. Higher levels of baseline 17β-E2 were associated with poorer cognitive performance, with marginal significance at baseline in speeded language and mental flexibility (p = 0.013). Other hormone levels were not associated with cognition. Controlling for all treatments, hormone levels at baseline and at month 48 did not have any significant correlation with cognitive trajectories over time. SummaryIn healthy, recently menopausal women, baseline estrone levels were inversely associated with selected cognitive factors independent of two types of HT or placebo during 4 years of follow-up. Baseline levels of the other pituitary-ovarian hormones studied were not associated with baseline cognition, nor were changes in any hormones associated with changes in cognition during the study. The marginal association between estradiol levels and cognitive factors warrants further investigation. ClinicalTrials.gov numbersNCT00154180, NCT00623311.

Coronary artery calcium and bone mineral density by serial CTA: Does menopausal hormone therapy modify the association?

IntroductionBoth osteoporosis and cardiovascular disease (CVD) increase in women after menopause. Estrogen deficiency is thought to be an underlying mechanism for both these conditions. MethodsHealthy menopausal women (n = 374, age 42–58 years) underwent cardiac CT scans over four years as participants in the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, controlled trial to Women randomized to either oral conjugated equine estrogens (o-CEE, n = 104), transdermal 17β-estradiol (t-E2, n = 119) or placebo (n-115). CAC (Agatston units, AU), and BMD (mg/cm3) were measured from thoracic vertebrae at baseline and at the 4 years of the study using validated software. ANOVA and multiple linear regression analyzed the association between incident CAC or progression of CAC and BMD among the treatment groups. ResultsAt baseline 374 women, 40 participants with CAC >0 had greater decrements in BMD than the 334 participants with CAC = 0 at baseline, The average change in BMD in o-CEE group with CAC was −9.6 ± 13.3 versus −3.1 ± 19.5 in those with zero CAC, p = 0.0018. With t-E2, BMD changed by −11.7 ± 26.2 in those with CAC versus +5.7 ± 26.2 in the zero CAC group, p ≤ 0. 0001. Similarly in the 66 participants that showed progression of CAC >1, had more BMD loss, than those with stable CAC regardless of the treatment. ConclusionProgression of bone loss is reduced among women treated with o-CEE or t-E2. Progression of CAC is associated with greater BMD loss, a relationship that is differentially modified by t-E2 and o-CEE.

Comparative venous thromboembolic safety of oral and transdermal postmenopausal hormone therapies among women Veterans.

Hormone therapy (HT) is used by menopausal women to treat vasomotor symptoms. Venous thromboembolism (VTE) is an important risk of HT use, and more knowledge on the comparative safety of different estrogenic compounds is useful for women who use HT for these symptoms. The objective was to compare the risk of VTE among users of oral conjugated equine estrogen (CEE), oral estradiol (E2), and transdermal E2, in a cohort of women veterans. This retrospective cohort study included all women veterans aged 40 to 89 years, using CEE or E2, without prior VTE, between 2003 and 2011. All incident VTE events were adjudicated. Time-to-event analyses using a time-varying HT exposure evaluated the relative VTE risk between estrogen subtypes, with adjustment for age, race, and body mass index, with stratification for prevalent versus incident use of HT. Among 51,571 users of HT (74.5% CEE, 12.6% oral, and 12.9% transdermal E2 at cohort entry), with a mean age of 54.0 years, the incidence of VTE was 1.9/1,000 person-years. Compared with CEE use, in the multivariable regression model, there was no difference in the risk of incident VTE associated with oral E2 use (hazard ratio 0.96, 95% CI 0.64-1.46) or with transdermal E2 use (hazard ratio 0.95, 95% CI 0.60-1.49). Results were unchanged when restricting to incident users of HT. Among women veterans, the risk of VTE was similar in users of oral CEE, oral E2, and transdermal E2. These findings do not confirm the previously observed greater safety of transdermal and oral E2 over CEE.

Conjugated equine estrogen used in postmenopausal women associated with a higher risk of stroke than estradiol

This study aimed to evaluate the risk of ischemic stroke (IS) in hormone therapy (HT) with oral conjugated equine estrogen (CEE) and estradiol (E2) in postmenopausal women in Taiwan. A retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database, a population-based healthcare claims dataset. Eligible women, aged 40–65 years, who received HT with E2 and CEE orally were enrolled. The primary outcome was IS. Propensity score matching with menopausal age and comorbidities was used. Cox proportional hazard regression models were used to calculate the incidence and hazard ratios (HRs) for IS. The mean menopausal ages of the E2 and CEE groups were 50.31 ± 4.99 and 50.45 ± 5.31 years, respectively. After adjusting for age and comorbidities, the incidence of IS was 1.17-fold higher in the women treated with CEE than in those treated with E2 (4.24 vs. 3.61/1000 person-years), with an adjusted HR (aHR) of 1.23 (95% confidence interval [CI] 1.05–1.44). Moreover, HT with CEE initiated within 5 years of menopause had a higher HR than E2 (aHR = 1.20; 95% CI 1.02–1.42). In conclusion, HT with oral CEE might be associated with a higher risk of IS than E2 in postmenopausal Taiwanese women. The use of HT with CEE should be cautioned with the risk of IS.

Cardiovascular disease (CVD) risk scores, age, or years since menopause to predict cardiovascular disease in the Women's Health Initiative.

To assess the utility of cardiovascular disease (CVD) risk scores compared to age or years since menopause for prediction of CVD events in the WHI clinical trials. Briefly, in the randomized clinical trial 27,347 postmenopausal women age 50 to 79 years entered from 1993 to 1998. Women with a uterus (16,608) were randomized to receive daily oral conjugated equine estrogen (CEE) (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) (5.7 years or placebo), while women with a hysterectomy (10,739) were randomized to receive daily oral CEE (0.625 mg) alone or placebo (7.2 y). CVD risk scores were assessed at baseline and CVD events were adjudicated throughout the follow-up period to the end of the main study phase and to the end of cumulative follow-up. The median follow-up time after the start of the randomized clinical trial to the end of the main study phase was 8.2 years. The median follow-up time to the end of cumulative follow-up was 17.6 years. We compared The American Heart Association/American College of Cardiology (AHA/ACC) and Framingham Heart Study risk scores to age or years since menopause all obtained at baseline to predict subsequent CVD events. The absolute event rates, hazard ratios, and C-statistics (Uno Concordance from Cox proportional models) were compared. Overall, the hazard ratios for CVD events were highest with calculated CVD scores calculated at trial onset both at the end of the main study (ranging from 2.02 to 10.8 for Q2-Q5, compared to Q1) and at cumulative follow-up (ranging from 1.76 to 8.86 for Q2-Q5, compared to Q1). While older age and years since menopause at baseline were also associated with higher CVD event rates, better risk prediction was accomplished by using CVD risk scores. The Framingham Heart Study BMI score had the highest C-statistic at the end of the main study (0.711) and after 17.6 years through the end of follow-up (0.689). CVD risk scores can help identify postmenopausal women at higher risk for CVD beyond age or time since menopause. Risk scoring that better estimates vascular aging may facilitate CVD risk prevention. When performed prior to initiation of menopausal hormone therapy, scores can better inform HT risk/benefit discussions.

Peripheral Markers of Neurovascular Unit Integrity and Amyloid-β in the Brains of Menopausal Women.

Background:The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer’s disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers.Objective:This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women.Methods:A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1–42 (Aβ1–42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs.Results:Only the number of microvesicles positive for Aβ1–42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045).Conclusion:Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.

Preservation of white matter integrity on DTI 3 years after early menopausal hormone therapies

AbstractBackgroundThe critical‐period theory of menopausal hormone therapy (mHT) suggests that if menopausal hormone therapy begins shortly after menopause, it may have beneficial effects on brain structure and cognitive health. We investigated white matter integrity with diffusion tensor MRI (DTI) 3 years after the end of mHT trial in recently menopausal women who were randomized shortly after menopause.MethodParticipants of this study were enrolled in the Kronos Early Estrogen Prevention Study (aged 42–56 years; 5–36 months past menopause). Participants received the following treatments: 0.45 mg/d oral conjugated equine estrogen (oCEE, n=19); 50 μg/d transdermal 17β‐estradiol (tE2, n=22); or placebo (n=33) for 4 years. Oral progesterone (200 mg/d) was given to hormone therapy groups for 12 days each month. DTI was performed 3 years after the end of 4 years of hormone therapy (n=75), which corresponded to 7 years after randomization. Voxel‐based analysis was performed on DTI to evaluate fractional anisotropy (FA) and mean diffusivity (MD) differences between treatment groups (uncorrected p&lt;0.001).ResultVoxel based analysis showed higher FA, a measure of white matter integrity, in the superior corona radiata, anterior limb of the internal capsule and splenium of the corpus callosum of participants treated with oCEE compared to placebo (p &lt;0.001, Figure 1A). Furthermore, higher FA was observed in the superior corona radiata, anterior limb of internal capsule and thalamus in participants treated with tE2 compared to placebo (p &lt;0.001, Figure 1B). There were no differences in FA findings between oCEE and tE2 groups, and no MD differences between treatments groups.ConclusionA relatively higher FA in a variety of white matter regions in the oCEE and tE2 groups compared to placebo suggest that mHT may have long‐term protective effects on white matter integrity. Previously, we had shown that women in the tE2 group preserved their dorsolateral prefrontal cortex volumes better than the placebo group over 7 years. Our findings suggest that the tracts that connect the dorsolateral prefrontal cortex and the thalamus such as the superior corona radiata and the anterior limb of internal capsule may particularly benefit from mHT.

Associations of pituitary-ovarian hormones and white matter hyperintensities in recently menopausal women using hormone therapy.

Little is known about how menopausal hormone treatment (HT) may influence the development of white matter hyperintensities (WMHs) in the brain. This study evaluated the associations of changes in levels of pituitary-ovarian hormones during HT and changes in WMH. Women (n = 78 adherent to treatment) enrolled in the Kronos Early Estrogen Prevention Study underwent brain magnetic resonance imaging, and blood collection before and after 48 months of randomization to 0.45 mg/d oral conjugated equine estrogen (oCEE) daily, 50 μg/d transdermal 17β estradiol (tE2), or placebo pills and patches. Women in the active treatment groups also received oral 200 mg/d micronized progesterone the first 12 days of the month. Estradiol (E2), estrone (E1), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum by high sensitivity liquid chromatography/mass spectrometry at baseline and following 48 months of HT. Longitudinal change in WMH volume was determined from fluid-attenuated inversion recovery magnetic resonance imaging using a semiautomated image segmentation algorithm. Serum levels of FSH, LH, E1, or E2 did not associate with WMH volume at baseline. After 48 months of treatment, smaller increases in WMH associated with decreases in FSH from baseline in the tE2 group and increases in E1 in both tE2 and oCEE groups. Changes in LH did not associate with changes in WMH in any group. Circulating levels of pituitary-ovarian hormones associate with changes in WMH volume in recently menopausal women using HT. Whether these relationships would be influenced by different doses of tE2 or oCEE remains to be determined. : Video Summary:http://links.lww.com/MENO/A590.

The Women's Health Initiative trials of menopausal hormone therapy: lessons learned.

The Women's Health Initiative (WHI) assessed oral conjugated equine estrogens (CEE) taken with or without medroxyprogesterone acetate (MPA) for prevention of chronic disease in postmenopausal women aged 50-79 years. Women with an intact uterus (n = 16,608) were randomized to CEE+ MPA therapy or placebo for a median of 5.6 years; women with hysterectomy (n = 10,739) were randomized to CEE-alone therapy or placebo for a median of 7.2 years. Both cohorts have been followed for 18 years. In the overall study population (mean age, 63 y), neither estrogen-progestin therapy (EPT) nor estrogen-only therapy prevented coronary heart disease or led to a favorable balance of chronic-disease benefits and risks. Subgroup analyses, however, suggest that timing of hormone therapy (HT) initiation influences the relation between HT and coronary risk, as well as its overall benefit-risk balance, with more favorable effects in women who are younger (age < 60 year) or recently menopausal (within 10 year) than in women who are older or further past the menopausal transition. In younger women who entered the trial of estrogen-only therapy with oophorectomy, the intervention was associated with a significant 32% reduction in all-cause mortality over long-term follow-up. WHI findings indicate important differences in HT-related clinical outcomes by age and time since menopause. Systemic HT has an acceptable safety profile for menopause management when initiated among healthy women who are younger (or recently menopausal) and not at elevated risk for cardiovascular disease or breast cancer. Initiation of treatment in older women who are distant from menopause onset, however, should be avoided. Other HT formulations and routes of delivery warrant further study.(WHI clinicaltrials.gov identifier: NCT00000611).

Heart fat and carotid artery atherosclerosis progression in recently menopausal women: impact of menopausal hormone therapy: The KEEPS trial

Heart fat deposition has been linked to atherosclerosis, and both accelerate after menopause. Hormone therapy (HT) may differentially slow heart fat deposition and progression of atherosclerosis, depending on the specific HT agent or its route of administration. Our objective was to evaluate the effects of different HT agents, oral and transdermal, on associations between heart fat accumulation and atherosclerosis progression, measured by carotid intima-media thickness (CIMT), in recently menopausal women from the Kronos Early Estrogen Prevention Study (KEEPS) trial. KEEPS was a randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens (o-CEE) or 50 mcg/d transdermal 17β-estradiol (t-E2), compared with placebo, on 48 months progression of CIMT. Epicardial adipose tissue (EAT) and paracardial adipose tissue (PAT) volumes were quantified by computed tomography. In all, 467 women (mean age [SD] 52.7 [2.5]; 78.2% White; 30% on o-CEE, 30.8% t-E2, 39.2% placebo) with heart fat volumes and CIMT at baseline and 48 months were included. EAT and PAT changes were not associated with CIMT progression; however, the assigned treatment significantly modified the association between PAT (but not EAT) change and CIMT progression. In the o-CEE group, adjusted CIMT progression was 12.66 μm (95% confidence interval [CI] 1.80, 23.52) lower than in t-E2 group (P = 0.02), and 10.09 μm (95% CI 0.79, 19.39) lower than in placebo group (P = 0.03), as per 1-SD increase in PAT. Compared with t-E2, o-CEE appears to slow down the adverse effect of increasing PAT on progression of atherosclerosis. Whether this beneficial association is specific to CEE or to the oral route of CEE administration is unclear and should be assessed further.

Effects of Hormone Therapy on Heart Fat and Coronary Artery Calcification Progression: Secondary Analysis From the KEEPS Trial.

BackgroundHeart fats (epicardial and paracardial adipose tissue [PAT]) are greater after menopause. Endogenous estrogen may regulate these fat depots. We evaluated the differential effects of hormone therapy formulations on heart fat accumulations and their associations with coronary artery calcification (CAC) progression in recently menopausal women from KEEPS (Kronos Early Estrogen Prevention Study).Methods and Results KEEPS was a multicenter, randomized, placebo‐controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens and 50 µg/d transdermal 17β‐estradiol, compared with placebo, on 48‐month progression of subclinical atherosclerosis among 727 early menopausal women. CAC progression was defined if baseline CAC score was 0 and 48‐month CAC score was >0 or if baseline CAC score was >0 and <100 and annualized change in CAC score was ≥10. Of 727 KEEPS participants, 474 (mean age: 52.7 [SD: 2.6]; 78.1% white) had computed tomography–based heart fat and CAC measures at both baseline and 48 months. Compared with women on placebo, women on oral conjugated equine estrogens were less likely to have any increase in epicardial adipose tissue (odds ratio for oral conjugated equine estrogens versus placebo: 0.62 [95% CI, 0.40–0.97]; P=0.03). PAT did not change in any group. Changes in epicardial adipose tissue and PAT did not differ by treatment group. CAC increased in 14% of participants. The assigned treatment modified the association between PAT changes and CAC progression (P=0.02) such that PAT increases were associated with CAC increases only in the transdermal 17β‐estradiol group.ConclusionsIn recently menopausal women, oral conjugated equine estrogens may slow epicardial adipose tissue accumulation, whereas transdermal 17β‐estradiol may increase progression of CAC associated with PAT accumulation.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00154180.

Changes in carotid artery intima-media thickness 3 years after cessation of menopausal hormone therapy: follow-up from the Kronos Early Estrogen Prevention Study.

Little is known regarding the progression of preclinical atherosclerosis upon cessation of menopausal hormone therapy (MHT). This study evaluated changes in carotid artery intima-media thickness (CIMT) in a subgroup of participants during 4 years and 3 years after the Kronos Early Estrogen Prevention Study (KEEPS). Of the women enrolled in KEEPS at Mayo Clinic (n = 118), a subset (n = 76) agreed to participate in this follow-up study. KEEPS MHT assignments were placebo (PBO), n = 33; transdermal 17β-estradiol (tE2), n = 23; and oral conjugated equine estrogens group (oCEE), n = 20. CIMT was measured by B-mode ultrasonography. Longitudinal analysis of CIMT was performed using all available data from pre-, on-, and post-treatment periods. At 7 years, median age of participants was 60.2 years; median time since menopause was 8.5 years. The mean difference in rates of increase was significantly greater over the post- than on-treatment period within the oCEE group (0.010 [0.002-0.017] mm/y), but not within the PBO (0.006 [-0.001 to 0.012] mm/y; P = 0.072) or tE2 (0.002 [-0.005 to 0.010] mm/y; P = 0.312) groups. There were, however, no significant treatment differences in the linear trends over those intervals (P = 0.524). Cessation of MHT at the lower doses and formulations used in KEEPS did not appear to alter the trajectory of CIMT over a 3-year follow-up period. CIMT, however, increased in all groups over the entire 7-year timeframe as expected with age and timing of menopause possibly key contributors.

Estrogen-alone therapy and invasive breast cancer incidence by dose, formulation, and route of delivery: findings from the WHI observational study.

Research on the relationships between different hormone therapy doses, formulation and routes of delivery, and subsequent breast cancer incidence has been limited. This study directly compared different estrogen doses, formulations, and route of delivery of estrogen alone among women with a hysterectomy in relation to invasive breast cancer incidence. The Women's Health Initiative Observational Study is a large multicenter prospective cohort study conducted at 40 US sites. Analyses included 26,525 postmenopausal women with a hysterectomy, aged 50 to 79 years, at study entry, recruited between September, 1993 and December, 1998, with annual follow-up through September 12, 2005. Average follow-up was 8.2 years. For conjugated equine estrogen (CEE) users, no difference was observed between low-dose CEE (<0.625 mg) compared with conventional-dose CEE (0.625 mg) for breast cancer (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.65, 1.48)]. Compared with conventional-dose CEE, transdermal estrogen was associated with a nonsignificant lower risk of invasive breast cancer (HR 0.75, 95% CI 0.47, 1.19). The low prevalence of transdermal use likely limited power for this comparison, and for a comparison of oral estradiol to conventional-dose CEE (HR 1.20, 95% CI 0.84, 1.39). Our results indicate that invasive breast cancer risk did not differ appreciably in women with a hysterectomy using estrogen-alone when directly comparing different doses, formulations, and routes of delivery to the conventional oral CEE. These findings suggest that the lower breast cancer risk found in the WHI estrogen-alone trial may extend to lower doses of CEE. Additional research is needed to confirm these hypotheses.

Racial Differences in the Effects of Hormone Therapy on Incident Open-Angle Glaucoma in a Randomized Trial

We conducted a secondary analysis of a randomized, placebo-controlled trial to test if hormone therapy (HT) altered the risk of open-angle glaucoma (OAG), and if the risk reduction varied by race. Secondary analysis of randomized controlled trial data. We linked Medicare claims data to 25 535 women in the Women's Health Initiative. Women without a uterus were randomized to receive either oral conjugated equine estrogens (CEE 0.625mg/day) or placebo, and women with a uterus received oral CEE and medroxyprogesterone acetate (CEE 0.625mg/day+ MPA 2.5mg/day) or placebo. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence interval. After exclusion of women with prevalent glaucoma or without claims for eye care provider visits, the final analysis included 8102 women (mean age= 68.5 ± 4.8 years). The OAG incidence was 7.6% (mean follow-up= 11.5 ± 5.2 years; mean HT duration= 4.4 ± 2.3 years). Increased age (P trend= .01) and African-American race (HR= 2.69, 95% CI= 2.13-3.42; white as a reference) were significant risk factors for incident OAG. We found no overall benefit of HT in reducing incident OAG (HR= 1.01, 95% CI= 0.79-1.29 in the CEE trial, and HR= 1.05, 95% CI= 0.85-1.29 in the CEE+ MPA trial). However, race modified the relationship between CEE use and OAG risk (P interaction= .01), and risk was reduced in African-American women treated with CEE (HR= 0.49, 95% CI= 0.27-0.88), compared to placebo. Race did not modify the relation between CEE+ MPA use and OAG risk (P interaction= .68). Analysis suggests that HT containing estrogen, but not a combination of estrogen and progesterone, reduces the risk of incident OAG among African-American women. Further investigation is needed.

Association between Cerebrovascular Reactivity and Intravascular Cellular Activation in Postmenopausal Women Following Use of Menopausal Hormone Treatments

Cerebrovascular reactivity to hypercapnia, an estimate of microvascular responses in the brain, is increased during menopausal hormone treatment (MHT) in postmenopausal women. It is unclear whether this effect of MHT continues beyond the treatment period. We hypothesized that prior MHT use would not affect cerebrovascular reactivity 3 years after treatment. In addition, we have previously shown that cerebrovascular reactivity is associated with vascular activation in postmenopausal women with elevated cardiovascular risk. We hypothesized that cerebrovascular reactivity is not associated with markers of intravascular cellular activation in postmenopausal women with low cardiovascular risk who are within 10 years of menopause. Cerebrovascular reactivity to hypercapnia was measured in 58 postmenopausal women from the Kronos Early Estrogen Prevention Study at Mayo Clinic 3 years after the cessation of MHT [oral conjugated equine estrogen (oCEE), n=15; transdermal 17β‐estradiol (tE2, n=22); or placebo (PLA, n=23)]. Cerebrovascular reactivity was estimated from the middle cerebral artery flow velocity (MCAv) response to hypercapnia. Mean arterial blood pressure (MAP) was measured continuously throughout the protocol. Fasting blood was analyzed for a set of 14 activation markers of platelet and endothelial cells, inflammation and thrombogenicity. Principal components (PC) analysis was used to reduce these measures to fewer dimensions on which the associations of intravascular cellular activation with cerebrovascular reactivity could be based. Women were 60±3 years of age with a body mass index of 28±4 Kg/m2. MAP (99±14 mmHg in PLA, 97±7 mmHg in tE2, 98±9 mmHg in oCEE; p&gt;0.90) and MCAv (60±14 cm/s in PLA, 68±20 cm/s in tE2, 71±18cm/s in oCEE; p&gt;0.16) did not differ among groups. Cerebrovascular reactivity did not differ among women based on previous MHT randomization (1.2±0.7 cm/s/mmHg in PLA, 1.4±1.0 cm/s/mmHg in tE2 and 1.7±1.0 cm/s/mmHg in oCEE; p&gt;0.17). The 14 markers of intravascular cellular activation were reduced to five PC that did not differ based on prior MHT assignment. There was no overall association of cellular activation PC with cerebrovascular reactivity. Effects of MHT on cerebral microvascular reactivity do not extend beyond the time of menopausal hormone treatment. Intravascular cellular activation does not alter cerebrovascular reactivity to hypercapnia in postmenopausal women with low cardiovascular risk profiles 3 years after the cessation of MHT.Support or Funding InformationNIH grant P50 AG44170This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Prior Menopausal Hormone Treatments And Association of Peripheral Markers of Neurovascular Unit Integrity And β‐amyloid in The Brains of Menopausal Women

BackgroundBreak down of the blood brain barrier and activation of brain cells are implicated in progression of deposition of β‐amyloid that is associated with the pathophysiology of Alzheimer's disease. A previous study from our group indicated that deposition of β‐amyloid may be reduced in the brains of menopausal women treated with transdermal 17β‐estradiol. This study aimed to determine the association of peripheral microvesicles carrying markers of cells of the neurovascular unit with β‐amyloid in the brains of menopausal women and if the association was affected by prior menopausal hormone treatments (MHT).MethodsMenopausal women previously enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic underwent β‐amyloid positron emission tomography (PET) imaging of their brains 3 years following treatment with either placebo (PL, n=29), transdermal 17β‐estradiol (tE2; n=21), or oral conjugated equine estrogen (oCEE; n=17) for 4 years. Microvesicles (MV) were isolated from peripheral venous blood by differential centrifugation and analyzed by flow cytometry using fluorophore conjugated antibodies directed toward total tau, β‐amyloid 1‐42 (Ab1‐42), neuron specific class III β‐tubulin (Tuj1), microglia ionized calcium adaptor molecule 1(Iab‐1), glial fibrillar acid protein (GFAP), and low density lipoprotein receptor‐related protein 1. Principal components analysis was used to reduce the dimensionality of the 6 brain markers to 2 principal components (PCs). Proportional odds ordinal logistic regression analysis was used to regress deposition of β‐amyloid on the 2 PCs with and without adjustment for MHT group.ResultsNumber of blood MV positive for Ab1‐42 differed significantly among MHT groups (median [IQR]: 6.06 [2.11, 12.55] in the PL; 2.49 [0.73, 3.59] in the tE2 and 4.96 [0.83, 10.31] in the oCEE; P=0.036). The first 2 PCs explain 58% of the variance of the 6 markers. PC#1 represented a contrast between MV‐Iab‐1 and the MV‐GFAP and MV‐Tuj1. In multivariable models, brain β‐amyloid load positively associated with the first PC after adjustment for MHT (P= 0.006).ConclusionMV derived from cells of the neurovascular unit can be detected in peripheral blood, and, when combined into summary scores, showed an association with deposition of β‐amyloid in the brain that is independent of MHT.Support or Funding InformationSupported by grants from NIH P50 AG044170 and the Mayo FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Brain structure and cognition 3 years after the end of an early menopausal hormone therapy trial.

ObjectiveThe effects of 2 frequently used formulations of menopausal hormone therapy (mHT) on brain structure and cognition were investigated 3 years after the end of a randomized, placebo-controlled trial in recently menopausal women with good cardiovascular health.MethodsParticipants (aged 42–56 years; 5–36 months past menopause) were randomized to one of the following: 0.45 mg/d oral conjugated equine estrogen (oCEE); 50 μg/d transdermal 17β-estradiol (tE2); or placebo pills and patch for 4 years. Oral progesterone (200 mg/d) was given to mHT groups for 12 days each month. MRIs were performed at baseline, at the end of 4 years of mHT, and 3 years after the end of mHT (n = 75). A subset of participants also underwent Pittsburgh compound B–PET (n = 68).ResultsVentricular volumes increased more in the oCEE group compared to placebo during the 4 years of mHT, but the increase in ventricular volumes was not different from placebo 3 years after the discontinuation of mHT. Increase in white matter hyperintensity volume was similar in the oCEE and tE2 groups, but it was statistically significantly greater than placebo only in the oCEE group. The longitudinal decline in dorsolateral prefrontal cortex volumes was less in the tE2 group compared to placebo, which correlated with lower cortical Pittsburgh compound B uptake. Rates of global cognitive change in mHT groups were not different from placebo.ConclusionsThe effects of oCEE on global brain structure during mHT subside after oCEE discontinuation but white matter hyperintensities continue to increase. The relative preservation of dorsolateral prefrontal cortical volume in the tE2 group over 7 years indicates that mHT may have long-term effects on the brain.Classification of evidenceThis study provides Class III evidence that the rates of change in global brain volumes and cognitive function in recently menopausal women receiving mHT (tE2 or oCEE) were not significantly different from women receiving placebo, as measured 3 years after exposure to mHT.

Long-Term Effects of Gonadotropin-Releasing Hormone Agonists and Add-Back in Adolescent Endometriosis.

To explore the potential occurrence of long-term side effects and tolerability of gonadotropin-releasing hormone agonist (GnRHa) plus 2 different add-back regimens in adolescent patients with endometriosis. Follow-up questionnaire sent in 2016 to patients who participated in a drug trial between 2008 and2012. Tertiary care center in Boston, Massachusetts. Female adolescents with surgically confirmed endometriosis (n=51) who enrolled in a GnRHa plus add-back trial as adolescents. Leuprolide depot 11.25mg intramuscular injection every 3months, plus oral norethindrone acetate 5mg daily or oral norethindrone acetate 5mg daily and oral conjugated equine estrogens 0.625mg daily. Side effects during and after treatment, irreversible side effects, changes in pain, overall satisfaction. The response rate was 61% (25 of 41; 10 subjects could not be located). Almost all (24 of 25) reported side effects during treatment; 80% (16 of 21) reported side effects lasting longer than 6months after stopping treatment. Almost half (9 of 20) reported side effects they considered irreversible, including memory loss, insomnia, and hot flashes. Despite side effects, participants rated GnRHa plus add-back as the most effective hormonal medication for treating endometriosis pain; two-thirds (16 of 25) would recommend it to others. More participants who received a modified 2-drug add-back regimen vs standard 1-drug add-back would recommend GnRHa and believed it was the most effective hormonal medication. Subjects believed that GnRHa used with add-back was effective and would recommend it to others, despite significant side effects. Those who received 2-drug add-back reported more success than those who received standard add-back. A subset of patients reported side effects they consider to be irreversible.

Estrogen-based hormone therapy in women with primary ovarian insufficiency: a systematic review.

Sex hormones play a role in bone density, cardiovascular health, and wellbeing throughout reproductive lifespan. Women with primary ovarian insufficiency (POI) have lower estrogen levels requiring hormone therapy (HT) to manage symptoms and to protect against adverse long-term health outcomes. Yet, the effectiveness of HT in preventing adverse outcomes has not been systematically assessed. We summarize the evidence regarding effects of HT on bone and cardiovascular health in women with POI. A comprehensive search of the electronic databases MEDLINE, EMBASE, and Scopus was conducted by a medical reference librarian from database inception to January 2016. Randomized trials and observational cohort studies with an estrogen-based HT intervention in women with POI under the age of 40 were included. Reviewers worked independently and in duplicate to assess eligibility and risk of bias, and extract data of interest from each study. The search identified 1670 articles; 12 met inclusion criteria. Four randomized clinical trials and eight cohort studies at high risk of bias enrolled 806 women with POI. The most common HT formulations were transdermal estradiol and oral conjugated equine estrogen combined with medroxyprogesterone acetate. Bone mineral density was the most frequent outcome, with three out of eight studies showing HT associated increase benefits. Only one study reported effects on fractures or vasomotor symptoms and none on cardiovascular mortality. Results regarding lipid profiles were inconsistent. Evidence supporting bone and cardiovascular benefits of HT in women with POI is limited by high risk of bias, reliance on surrogate outcomes, and heterogeneity of trials regarding the formulation, dose, route of administration, and regimen of HT. Further research addressing patient important outcomes such as fractures, stroke, and cardiovascular mortality are crucial to optimize benefits of this therapy.