Effect Of Postmenopausal Hormone Therapy Research Articles

Effect of Postmenopausal Hormone Therapy on Glucose Regulation in Women With Type 1 or Type 2 Diabetes: A Systematic Review and Meta-analysis.

Blood glucose regulation in women with diabetes may change during and after menopause, which could be attributed, in part, to decreased estrogen levels. To determine the effect of postmenopausal hormone therapy (HT) on HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering drugs in women with type 1 and women with type 2 diabetes. We conducted a systematic search of MEDLINE, Embase, Scopus, the Cochrane Library, and the ClinicalTrials.gov registry to identify randomized controlled trials (RCTs). We selected RCTs on the effect of HT containing estrogen therapy in postmenopausal women (≥12 months since final menstrual period) with type 1 or type 2 diabetes. Data were extracted for the following outcomes: HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering medication. Nineteen RCTs were included (12 parallel-group trials and 7 crossover trials), with a total of 1,412 participants, of whom 4.0% had type 1 diabetes. HT reduced HbA1c (mean difference -0.56% [95% CI -0.80, -0.31], -6.08 mmol/mol [95% CI -8.80, -3.36]) and fasting glucose (mean difference -1.15 mmol/L [95% CI -1.78, -0.51]). Of included studies, 50% were at high risk of bias. When postmenopausal HT is considered for menopausal symptoms in women with type 2 diabetes, HT is expected to have a neutral-to-beneficial impact on glucose regulation. Evidence for the effect of postmenopausal HT in women with type 1 diabetes was limited.

Association Between the Route of Administration and Formulation of Estrogen Therapy and Hypertension Risk in Postmenopausal Women: A Prospective Population-Based Study.

Hypertension is the leading global cause of cardiovascular disease and premature mortality in women. The effects of postmenopausal hormone therapy (HT) on blood pressure are uncertain but may be related to route of estrogen administration and formulation of estrogen. We sought to determine the association between route of administration and formulation of estrogen HT and hypertension risk in postmenopausal women. Population-based cohort study with women aged ≥45 years who filled ≥2 consecutive prescriptions for estrogen-only HT, identified from linked provincial health administrative data from Alberta, Canada, between 2008 and 2019. The primary outcome, incident hypertension, was identified using standardized International Classification of Diseases, Ninth and Tenth Revision. Cox proportional hazard models were used to calculate hazard ratios (HRs) for hypertension in women using oral HT compared with nonoral HT (transdermal, vaginal, or intramuscular). In total, 112 240 women used an estrogen-only form of HT. Oral estrogen was associated with a higher risk of hypertension compared with both transdermal (HR, 1.14 [95% CI, 1.08-1.20]) and vaginal (HR, 1.19 [95% CI, 1.13-1.25]) estrogens. Conjugated equine estrogen was associated with an increased risk of hypertension compared with estradiol (HR, 1.08 [95% CI, 1.04-1.14]) but not estrone (HR, 1.00 [95% CI, 0.93-1.10]). Duration of estrogen exposure and cumulative dose of estrogen was positively associated with risk of hypertension. Oral estrogen-only HT use was associated with an increased risk of hypertension in women. In women using estrogen-only HT, nonoral estradiol at the lowest dose and for the shortest time-period is associated with the lowest risk of hypertension.

The route of administration, timing, duration and dose of postmenopausal hormone therapy and cardiovascular outcomes in women: a systematic review.

The effect of postmenopausal hormone therapy (HT) on cardiovascular disease (CVD) risk remains controversial. We aimed to systematically review the evidence regarding the role of dose, route of hormone administration, timing of initiation and duration of HT on cardiovascular risk among postmenopausal women. The electronic databases Medline Ovid, Web of Science and Cochrane Central were systematically searched to identify studies published before 30 January 2018. Reference lists, using Elsevier's Scopus, of the included studies were searched for further identification of relevant studies. Clinical trials and observational studies that assessed clinical and subclinical cardiovascular outcomes in relation to dose, route of administration, duration of use, or timing of HT initiation among postmenopausal women were included. Data were extracted by independent reviewers using a pre-designed data collection form. The Cochrane Collaboration's tool and the Newcastle-Ottawa Scale were used by two independent investigators to assess the risk of bias in RCTs and in prospective observational studies, respectively. In total, 33 unique studies (6 trials and 27 prospective observational studies) were identified, including a total of 2 588 327 women. The synthesis of the existing knowledge on this topic was challenging due to inconsistent findings between some studies, caused by substantial diversity in scientific rigor and quality across the available literature. Overall, the evidence did not support the concerns that oral or transdermal HT increases heart disease risk. Contrary, observational data showed that a beneficial cardioprotective effect can be observed even with use of low doses of oral HT (effect of 0.3 mg/day of oral conjugated equine estrogen was similar to that seen with the standard dose of 0.625 mg/day), but clinical trials to support a cardioprotective benefit of HT in primary prevention have not been identified. Furthermore, the current data suggested that oral and transdermal HT, in dose-dependent manner and irrespective of HT formulation, may increase thromboembolic risk, as well as risk of stroke. However, transdermal estrogen with <50 μg/day of estrogen combined with micronized progesterone appears to be the safer choice with respect to thrombotic and stroke risk. Also, vaginal HT administration may play a role in myocardial infarction and stroke risk prevention, but this is based on limited evidence and requires further investigation. The timing of HT initiation and duration may be important factors to consider when prescribing HT especially in women with adverse cardiometabolic profile and pre-existing conditions such as coronary/carotid atherosclerosis, which are at risk of developing, and thus progressing to CVD. The quality of evidence was generally low or moderate and the findings were based mostly on observational data. Use of low-dose oral and transdermal HT appears to be safe with regard to CVD risk in women in menopausal transition and within the first years (e.g. 10 years) after menopause onset. In women with increased baseline thromboembolic risk, alternative non-hormonal medications are suggested as first-line treatment and transdermal estradiol alone or with micronized progesterone only should be considered when these options are not effective. When HT is initiated >10 years since the menopause onset (>60 years old), due to greater absolute risks of coronary heart disease, stroke and venous thromboembolism, HT should be used for the shortest time possible and in lowest possible dose and preferably transdermal administration should be recommended. However, an individualized treatment approach including baseline CVD risk assessment should be applied when prescribing HT. The majority of studies included in the current review are from North American and European populations, which might limit the generalizability of the findings of this review to the other populations. Finally, the quality of evidence included in this review was generally low or moderate, highlighting a need for more rigorous research to help us better understand HT and cardiovascular health.

The effect and safety of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney outcomes in women: a protocol for systematic review and meta-analysis

BackgroundThe prevalence of menopause in women with or at risk of chronic kidney disease is increasing globally. Although international guidelines on menopause recommend the use of postmenopausal hormone therapy with or without selective estrogen receptor modulators for control of vasomotor symptoms, the effects of these treatments on kidney function and albuminuria are unclear. Furthermore, women with chronic kidney disease are at significantly increased risk of venous thromboembolism and malignancy, well-documented adverse effects of postmenopausal hormone therapy. Our study aims to establish the effect of these treatments on kidney function and albuminuria in women, as well as determine the safety of these treatments in the chronic kidney disease population.MethodsWe will conduct a systematic review and meta-analysis addressing the effect and safety of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney outcomes in women. We plan to search for published (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), tables of contents of relevant journals) and unpublished (ongoing studies, conference proceedings) studies in all languages examining the effect of postmenopausal hormone therapy, including selective estrogen receptor modulators, on kidney function and albuminuria, as well as the risk of adverse outcomes of these treatments in women with chronic kidney disease. Two independent investigators will screen identified abstracts and select studies that examine the effect of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney outcomes in the general population or adverse outcomes in the chronic kidney disease population. Data on study population, intervention, outcomes, as well as study quality and risk of bias will be independently extracted from each eligible study. Along with descriptive presentation of data, outcome measures will be presented as meta-analyses using a random effects model. Planned subgroup analyses will be completed, and meta-regression will be performed if significant heterogeneity is noted.DiscussionBy examining the effects of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney function and albuminuria, the results of this systematic review and meta-analysis will inform management of postmenopausal women in the general population. Furthermore, it will evaluate the safety, including the risks of known adverse outcomes of postmenopausal hormone therapy and selective estrogen receptor modulators, in the already vulnerable chronic kidney disease population.Systematic review registrationPROSPERO CRD42016050651

Menopause and Chronic Kidney Disease

Premature menopause defined as secondary amenorrhea is common in women with kidney disease. Moreover, the aging population has resulted in increasing numbers of postmenopausal women with kidney disease. Though the pathophysiology is poorly understood, kidney transplantation and more frequent hemodialysis can restore menses and fertility, highlighting the challenges of diagnosing and managing the menopausal transition in the female population with kidney disease. Postmenopausal sex hormone levels affect renovascular physiology, but the clinical impact of menopause on kidney function is unclear. There are no guidelines on the use of postmenopausal hormone therapy specific to the population with kidney disease, and studies on the effects of postmenopausal hormone therapy in patients with kidney disease are limited to surrogate measures of cardiovascular and fracture risk. Studies examining the effects of postmenopausal hormone therapy on kidney function and albuminuria report conflicting results, which is likely reflective of differences in formulation, route of administration, accompanying progestin, and timing of initiation of treatment. Large, prospective studies examining the relationship between kidney function and menopause as well as the effects of postmenopausal hormone therapy on important clinical outcomes in women with kidney disease are warranted.

Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

BackgroundData suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.MethodsA total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima–media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.ResultsAfter a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.ConclusionsOral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.)

Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women.

OBJECTIVEIn older women, higher levels of estrogen may exacerbate the increased risk for cognitive impairment conveyed by diabetes. We examined whether the effect of postmenopausal hormone therapy (HT) on cognitive impairment incidence differs depending on type 2 diabetes.RESEARCH DESIGN AND METHODSThe Women’s Health Initiative (WHI) randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without [i.e., unopposed] 2.5 mg/day medroxyprogesterone acetate) or matching placebo for an average of 4.7–5.9 years. A total of 7,233 women, aged 65–80 years, were classified according to type 2 diabetes status and followed for probable dementia and cognitive impairment (mild cognitive impairment or dementia).RESULTSThrough a maximum of 18 years of follow-up, women with diabetes had increased risk of probable dementia (hazard ratio [HR] 1.54 [95% CI 1.16–2.06]) and cognitive impairment (HR 1.83 [1.50–2.23]). The combination of diabetes and random assignment to HT increased their risk of dementia (HR 2.12 [1.47–3.06]) and cognitive impairment (HR 2.20 [1.70–2.87]) compared with women without these conditions, interaction P = 0.09 and P = 0.08. These interactions appeared to be limited to women assigned to unopposed conjugated equine estrogens.CONCLUSIONSThese analyses provide additional support to a prior report that higher levels of estrogen may exacerbate risks that type 2 diabetes poses for cognitive function in older women. The role estrogen plays in suppressing non–glucose-based energy sources in the brain may explain this interaction.

Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes.

To examine whether the effect of postmenopausal hormone therapy (HT) on brain volumes in women aged 65-79 years differs depending on type 2 diabetes status during postintervention follow-up of a randomized controlled clinical trial. The Women's Health Initiative randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without 2.5 mg/day medroxyprogesterone acetate) or placebo for an average of 5.6 years. A total of 1,402 trial participants underwent brain MRI 2.4 years after the trials; these were repeated in 699 women 4.7 years later. General linear models were used to assess the interaction between diabetes status and HT assignment on brain volumes. Women with diabetes at baseline or during follow-up who had been assigned to HT compared to placebo had mean decrement in total brain volume of -18.6 mL (95% confidence interval [CI] -29.6, -7.6). For women without diabetes, this mean decrement was -0.4 (95% CI -3.8, 3.0) (interaction p=0.002). This interaction was evident for total gray matter (p<0.001) and hippocampal (p=0.006) volumes. It was not evident for changes in brain volumes over follow-up or for ischemic lesion volumes and was not influenced by diabetes duration or oral medications. For women aged 65 years or older who are at increased risk for brain atrophy due to type 2 diabetes, prescription of postmenopausal HT is associated with lower gray matter (total and hippocampal) volumes. Interactions with diabetes and insulin resistance may explain divergent findings on how estrogen influences brain volume among older women.

THU0434 The Association between Postmenopausal Hormone Therapy and the Risk of Rheumatoid Arthritis: Results from the Swedish EIRA Study

BackgroundThe role of hormonal/reproductive factors has been hypothesized to contribute to the risk of Rheumatoid arthritis (RA), but the literature is somewhat contradictory. Postmenopausal hormone (PMH) use has previously been...

The Women’s Health Initiative—A Victory for Women and Their Health

The history of medicine abounds with dogmas assumed and later overcome. Nowhere is that dynamic more evident than in women’s health. Several decades ago, menopausal hormone therapywaswidelyassumedtobebeneficial forwomen, not only to relieve vasomotor symptoms, but also to reduce a woman’s risk for chronicdiseasesof aging, includingheartdisease. Observational studies suggested a slight net benefit of hormonetherapy,andbythemid-1990s,at least40%ofwomen in the United States were prescribed hormone therapy.1 The Women’s Health Initiative (WHI), funded by the National Institutes of Heath (NIH) with taxpayer dollars, has now set the record straight. Evidence first from the original primary end point studies published in 20022 and2004,3 andnow fromthe 13-year follow-up study published byManson et al4 in this issue of JAMA clearly demonstrates that the hormone therapy story is farmore complicated than suggestedby the initial observational studies. In addition, there are many lessons to be learnedabout thevalueof publicly funded, objective, prevention-oriented clinical studies. TheWHI was launched in 1991 by then NIH Director Bernadine Healy, MD, in response to public outcry regarding the paucityofmedical research findings involvingwomenandminorities.Cardiovascular careguidelines, forexample,hadbeen basedonphase3clinical trials conducted predominantly in whitemenwithout attention to possible sex or ethnic differences in treatment outcomes. The NIH Revitalization Act of 1993establishedguidelines5 for the inclusionofwomenand minorities in clinical research. The guidelines ensure that all NIH-fundedclinical research isconducted inamanner thatelicits information about individuals of both sexes anddiverse racial andethnicgroupsand,particularly inphase3clinical trials, that examines differential effects on these groups. This is important because scientific evidence often leads to a change in health policy or standard of care. Nowhere is this more evident than in theWHI. TheWHI consists of a set of clinical trials and an observational study, which together were conducted with the consent of 161 808generally healthypostmenopausalwomenbetween the ages of 50 and 79 years. The clinical trials were designed to test the effects of postmenopausal hormone therapy,dietmodification, andcalciumandvitaminDsupplementationonheart disease, bone fractures, andbreast andcolorectal cancer. These clinical trials consisted of (1) hormone therapy trials, (2) a dietary modification trial, and (3) a calciumand vitaminD trial. The hormone therapy trial included a studyof theeffectsof estrogenplusprogestin inwomenwith auterus and a studyof the effects of estrogen alone inwomen without a uterus. (Womenwith a uteruswere givenprogestin incombinationwithestrogen,which isapracticeknowntoprevent endometrial cancer.) In both hormone therapy studies, womenwere randomly assigned to either thehormonemedication being studied or placebo; women were enrolled from 1993 to 1998. In 2002, the National Heart, Lung, and Blood Institute, which bears responsibility for funding and oversight of the WHI, announced that it had stopped the estrogen plus progestin trial when investigators found that the health risks of the combination hormone therapy outweighed the benefits after participants were followed up for an average of 5.6 years.2 The estrogen alone study was stopped in 2004 for safety concerns as well; risks of hormone therapy were greater than overall benefits in women followed up for an average of 7 years.3 The women in both of these hormone studies participated in a follow-up phase, which was completed in 2010, and these findings are reported in this issue of JAMA.4 The observational study enlisted 93 676 women whose health was tracked during an average of 8 years through the completion of periodic health forms and clinic visits. These women were not required to take any medication or change their health habits. What were the lessons from the primary end point studies, and what happens to the risks and benefits of hormone therapy following intervention and over time? Results reported in2002and2004demonstrated thatbothestrogenplus progestinandestrogenalone increased the riskof stroke,problems with memory and dementia, thrombosis in the legs or lungs, urinary incontinence, and gallbladder disease; however, both treatments reduced the risk of fractures andof diabetes. Estrogen plus progestin increased the risk of heart disease and breast cancer, whereas estrogen alone did not; however, both treatments had no effect on colorectal cancer. Subsequently, the trials studyingdietarymodificationandcalciumandvitaminD, respectively, found thatwomenwhoconsumed a low-fat diet had a tendency toward a reduced risk of breast cancer andminimal change in risk of heart disease and stroke,6,7 whereas calcium and vitamin D provided a modest benefit in preserving bone mass and preventing hip fractures, but increased the risk of kidney stones.8 The current 13-year follow-up study confirms the initial findings from the estrogen plus progestin and estrogen alone trials; postintervention, most risks and benefits were reduced but persisted in the estrogen plus progestin group, Related article page 1353 Opinion

Hormone therapy (HT) in menopausal women with rheumatoid arthritis: a systematic review of ht effects on disease activity

A systematic review of the existing published literature was conducted to evaluate the effect of post-menopausal hormone therapy (HT) on disease activity in menopausal patients with rheumatoid arthritis (RA).

Effects of Postmenopausal Hormone Therapy on Incident Atrial Fibrillation

Background— Atrial fibrillation (AF) is less prevalent in women versus men, but associated with higher risks of stroke and death in women. The role hormone therapy plays in AF is not well understood. Methods and Results— The Women’s Health Initiative randomized postmenopausal women to placebo or conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) if they had a uterus (N=16 608) or to conjugated equine estrogens only if they had prior hysterectomy (N=10 739). Incident AF was identified by ECG and diagnosis codes from Medicare claims or hospitalization records. Hazard ratios for incident AF were estimated using Cox proportional hazards regression. After excluding participants with baseline AF, there were 611 incident AF cases over a mean of 5.6 years among 16 128 estrogen plus progestin participants, and 683 cases over a mean of 7.1 years among 10 251 conjugated equine estrogens alone participants. Incident AF was more frequent in the active groups of both trials, reaching statistical significance in the trial of conjugated equine estrogens alone in women with prior hysterectomy (hazard ratio, 1.17; CI, 1.00–1.36; P =0.045) and in the pooled analysis (hazard ratio, 1.12; CI, 1.00–1.24; P =0.05), but not in the estrogen plus progestin trial (hazard ratio, 1.07; CI, 0.91–1.25; P =0.44). These results were only minimally affected by adjustment for incident stroke, coronary heart disease, and heart failure. Conclusions— Incident AF was modestly elevated in hysterectomized women randomized to postmenopausal E-alone, and in the pooled group randomized to E-alone or estrogen plus progestin. The trend in women with intact uterus receiving estrogen plus progestin, considered separately, was not statistically significant.

Longer Duration of Hormonal Contraceptive Use Predicts Better Cognitive Outcomes Later in Life

The cognitive effects of postmenopausal hormone therapy (HT) have been studied extensively, but little is known about the relationship between premenopausal hormone use and cognition. Hormonal contraceptive use vs. nonuse may be a potential factor influencing cognitive processes in midlife. The aim of this study is to explore the effect of modification of hormone milieu through use of hormonal contraception in premenopausal women and midlife cognitive function. Subjects were 261 cognitively normal women, aged 40-65 (mean μ=52), enrolled in the Wisconsin Registry for Alzheimer's Prevention. All women completed the Women's Health History Questionnaire and a self-report health history questionnaire and were administered a battery of neuropsychologic tests. Cognitive results were analyzed using summary scores for the domains of Verbal Ability, Visuo-spatial Ability, Working Memory, Verbal Learning & Memory, and Speed & Flexibility derived using a confirmatory factor analysis. Hormonal contraceptive ever users performed significantly better than never users in the domains of Visuo-spatial Ability (μ=0.75, 95% confidence interval [CI] 0.23-1.28, p=0.005) and Speed & Flexibility (μ=0.52, 95% CI -0.16-1.04, p=0.007), with duration-dependent increases in performance, especially in ever users with ≥ 15 years of use. These data provide preliminary evidence that hormonal contraceptive use may influence cognitive outcomes, even years after use is discontinued. Hormonal contraceptive users scored better in domains of Visuo-spatial Ability and Speed & Flexibility than never users, with a duration-dependent trend. Further research is needed to explore the use of hormonal contraceptives to prevent or delay cognitive decline and to clarify the physiologic basis of this phenomenon.

Interaction between oral estrogen plus progestogen therapy and ABO blood groups on coagulation activation in postmenopausal women

The aim of this study was to investigate the effect of postmenopausal hormone therapy on coagulation and whether this effect differs according to ABO blood groups. This was a prospective observational study to evaluate factor VIII (FVIII) activity, factor von Willebrand (vWF), and D-dimer (D-Di) levels and ABO blood groups in 61 postmenopausal women using oral estrogen plus progestogen therapy (EPT; 2 mg estradiol + 1 mg norethisterone acetate) for 3 months and in 101 women not using EPT. After 3 months, all eligible women who had completed the treatment scheme proposed for the EPT group or those who opted to participate but had not undergone EPT had a blood sample collected for analysis. Significant differences were observed in FVIII activity and vWF levels in the control group between those carrying group O and non-group O blood. For EPT users, significant differences were observed for FVIII activity, vWF, and D-Di levels. After a multivariate regression analysis, FVIII activity and ABO blood groups were independently associated with vWF levels, whereas interaction between ABO blood groups and EPT were independently associated with FVIII activity. Besides diabetes, the ABO × EPT interaction was also noted to be independently associated with D-Di levels. These findings suggest an interactive effect between oral EPT and non-O blood groups, contributing to the mechanism by which estrogen triggers the hypercoagulability state and increased risk for venous thrombosis in women undergoing oral EPT.

Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Ischemic Stroke due to Postmenopausal Hormone Therapy

To test whether changes in plasma tissue factor pathway inhibitor (TFPI) levels or activated protein C resistance (normalized activated protein C resistance ratio [nAPCsr]) modify the increased risk of ischemic stroke due to postmenopausal hormone therapy. Nested case-control study of 455 cases of ischemic stroke and 565 matched control subjects in the Women's Health Initiative trials of postmenopausal hormone therapy. Baseline free TFPI was associated with ischemic stroke risk (OR per SD increase, 1.17; 95% CI, 1.01-1.37; P=0.039), but baseline nAPCsr was not (OR per SD increase, 0.89; 95% CI, 0.75-1.05; P=0.15). Baseline TFPI levels and nAPCsr did not modify the effect of postmenopausal hormone therapy on ischemic stroke. Treatment-induced mean changes of -28% in free TFPI and +65% in nAPCsr did not change the risk of ischemic stroke (interaction P=0.452 and 0.971, respectively). In subgroup analyses, baseline nAPCsr was inversely associated with lacunar strokes (OR per SD increase, 0.74; 95% CI, 0.57-0.96; P=0.025) and baseline free TFPI interacted with treatment to increase large vessel atherosclerotic strokes (P=0.008). Procoagulant changes in TFPI or nAPCsr do not modify the increased ischemic stroke risk due to postmenopausal hormone therapy. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT 00000611.

Use of estradiol–progestin therapy associates with increased risk for uterine sarcomas

Objective Insufficient data exist on the effect of postmenopausal hormone therapy as the risk factor for uterine sarcomas. We therefore evaluated the association of estradiol–progestin therapy (EPT) with the risk of uterine sarcoma in nation-wide cohort study. Methods All Finnish women (> 50 years of age) who had used EPT during the years 1994–2008 for at least 6 months (n = 243,857) were identified from the national Medical Reimbursement Registry. Their incidence of uterine stromal and leiomyosarcoma among the EPT users was compared to that in the background population with the aid of the Finnish Cancer Registry. Results A total of 76 uterine sarcomas were encountered in the EPT cohort; 45 (59%) were leiomyosarcomas, 24 (32%) stromal sarcomas and 7 (9%) other sarcomas. The exposure to EPT for less than 5 years did not associate with significant rises in the sarcoma risk but longer exposure was accompanied with significant risk elevations for all uterine sarcomas: the standardized incidence ratio (SIR) for 5–10 years of use was 2.0, 95% confidence interval (CI) 1.4–2.9 and for ≥ 10 years of use 3.0 (1.3–5.9): the SIRs were highest for leiomyosarcoma. The sequential and continuous uses of progestin were associated with similar increased SIRs for uterine sarcoma. Conclusions The use of EPT for 5 years or more is associated with an increased risk for uterine sarcomas. This turns to an absolute excess risk of 2–3 extra uterine sarcoma cases per 10,000 long-time EPT users followed for 10 years.

Effects of hormone therapy on ambulatory blood pressure in postmenopausal Korean women

Background Previous studies of the effects of postmenopausal hormone therapy (HT) on blood pressure have yielded inconsistent results.Objectives To examine the impact of HT on 24-h ambulatory blood pressure.Methods A total of 67 postmenopausal Korean women (age 57.1 ± 5.7 years) received 2 months of HT consisting of conjugated equine estrogen (CEE, 0.625 mg/day) with or without micronized progesterone (100 mg/day). Ambulatory blood pressure monitoring was performed at baseline and after HT. Subjects were divided into those with normal blood pressure (n == 25) and those with high blood pressure (n == 42), based on their baseline daytime blood pressure.Results Parity and body mass index were higher in the group with high blood pressure than in the group with normal blood pressure. For both systolic and diastolic blood pressures throughout the day, significant negative correlations were observed between basal blood pressure and blood pressure difference after HT. During the daytime period, HT increased systolic and diastolic blood pressures in the subjects with normal blood pressure and decreased systolic and diastolic blood pressures in those with high blood pressure. When micronized progesterone was added to the CEE treatment, the increase in daytime blood pressure in the group with normal blood pressure was abolished, and the decrease in systolic blood pressure throughout the day in the group with high blood pressure was potentiated.Conclusions HT had either blood pressure-elevating or blood pressure-lowering effects in postmenopausal Korean women, depending on basal blood pressure. CEE increased the daytime blood pressure in women with normal blood pressure, but reduced it in women with high blood pressure. Micronized progesterone may provide beneficial effects on blood pressure when combined with CEE.

Confounding Effects of Hormone Replacement Therapy in Protein Biomarker Studies

We have recently investigated effects of hormone replacement therapy (HRT) on the serum proteome, and found a high proportion of proteins with altered levels associated with oral estrogen and/or estrogen plus progesterone treatment. Given this finding, we have investigated the extent to which exposure to HRT may have a confounding effect in the assessment of circulating proteins as cancer biomarkers. We utilize mass spectrometry data collected from the HRT serum proteome studies to estimate the overall effect of postmenopausal hormone therapy on candidate ovarian cancer biomarkers that have been previously reported. Levels of approximately half of the proteins reported as potential ovarian cancer biomarkers were found to be affected by HRT. The impact of HRT on levels of insulin-like growth factor and inhibin protein families was found to be substantial. We conclude that the potential confounding effect of HRT and other types of exposures should be taken into consideration in cancer biomarker study design. HRT significantly affects the serum proteome and should be taken into account as part of biomarker study design and data analysis.

Estrogen Receptor Polymorphisms and the Vascular Effects of Hormone Therapy

To test whether estrogen receptor polymorphisms modify the effects of postmenopausal hormone therapy on biomarkers and on risk of coronary heart disease events, stroke, or venous thromboembolism. The design was a nested case-control study in the Women's Health Initiative trials of postmenopausal hormone therapy. The study included all cases in the first 4 years: 359 cases of coronary heart disease, 248 of stroke, and 217 of venous thromboembolism. Six estrogen receptor-α polymorphisms and 1 estrogen receptor-β polymorphism were genotyped; 8 biomarkers known to be affected by hormone therapy were measured at baseline and 1 year after randomization. The polymorphisms were not associated with risk of vascular events and did not modify the increased risks of coronary heart disease, stroke, or venous thromboembolism due to hormone therapy. However, a reduced response of plasmin-antiplasmin to hormone therapy was noted for estrogen receptor-1 IVS1 (intron number 1)-354 (interaction P<0.0001, corrected for multiple comparisons P=0.014) and estrogen receptor-1 IVS1-1415 (interaction P<0.0001, corrected P=0.014). Estrogen receptor polymorphisms reduce the effect of postmenopausal hormone therapy on plasmin-antiplasmin, a marker of coagulation and fibrinolysis. However, screening for estrogen receptor polymorphisms to identify women at less risk of adverse cardiovascular outcomes is not likely to be useful in making decisions about hormone therapy treatment.

Ambient Particulate Matter Air Pollution and Venous Thromboembolism in the Women’s Health Initiative Hormone Therapy Trials

BackgroundThe putative effects of postmenopausal hormone therapy on the association between particulate matter (PM) air pollution and venous thromboembolism (VTE) have not been assessed in a randomized trial of hormone therapy, despite its widespread use among postmenopausal women.ObjectiveIn this study, we examined whether hormone therapy modifies the association of PM with VTE risk.MethodsPostmenopausal women 50–79 years of age (n = 26,450) who did not have a history of VTE and who were not taking anticoagulants were enrolled in the Women’s Health Initiative Hormone Therapy trials at 40 geographically diverse U.S. clinical centers. The women were randomized to treatment with estrogen versus placebo (E trial) or to estrogen plus progestin versus placebo (E + P trial). We used age-stratified Cox proportional hazard models to examine the association between time to incident, centrally adjudicated VTE, and daily mean PM concentrations spatially interpolated at geocoded addresses of the participants and averaged over 1, 7, 30, and 365 days.ResultsDuring the follow-up period (mean, 7.7 years), 508 participants (2.0%) had VTEs at a rate of 2.6 events per 1,000 person-years. Unadjusted and covariate-adjusted VTE risk was not associated with concentrations of PM < 2.5 μm (PM2.5) or < 10 μm (PM10)] in aerodynamic diameter and PM × active treatment interactions were not statistically significant (p > 0.05) regardless of PM averaging period, either before or after combining data from both trials [e.g., combined trial-adjusted hazard ratios (95% confidence intervals) per 10 μg/m3 increase in annual mean PM2.5 and PM10, were 0.93 (0.54–1.60) and 1.05 (0.72–1.53), respectively]. Findings were insensitive to alternative exposure metrics, outcome definitions, time scales, analytic methods, and censoring dates.ConclusionsIn contrast to prior research, our findings provide little evidence of an association between short-term or long-term PM exposure and VTE, or clinically important modification by randomized exposure to exogenous estrogens among postmenopausal women.