Use Of Postmenopausal Hormone Replacement Therapy Research Articles

Abstract 18381: Long-Term Coronary Artery Disease Risk in Female Adults With Surgically-Induced Menopause : A Systematic Review

Introduction: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in female adults. Prior studies have suggested an association between surgically-induced menopause (SIM) and long-term CAD risk. Yet, the pathophysiology and clinical significance of this relationship remains unclear. As SIM causes a premature cessation of potentially cardioprotective hormones, this review aimed to further investigate if SIM is a risk factor for CAD. Methods: SCOPUS, Web of Science, Cochrane Library, OVID/Embase, SciELO, and LILACS were searched from inception to April 2023 for observational studies reporting the effects of hysterectomy, oophorectomy, and/or salpingectomy prior to age fifty on long-term CAD risk. Results: Among 3056 identified records, nineteen studies were included with a combination of benign and malignant surgical indications. The studies reported on coronary heart disease (n=6), CAD (n=4), ischemic heart disease (n=3), and myocardial infarction (n=7). Sixteen articles with an average of 106,433 participants per study demonstrated a significantly increased risk of CAD following SIM (Table 1). In particular, hysterectomy with or without bilateral oophorectomy, and bilateral oophorectomy alone were found to have the most profound influence. Unilateral oophorectomy or hysterectomy with salpingo-oophorectomy did not appear to increase CAD risk. Average follow-up duration after SIM ranged from six to twenty-four years. Five studies adjusted for post-menopausal hormone replacement therapy use. Conclusions: SIM may elevate long-term CAD risk following hysterectomy and/or bilateral oophorectomy. Given that the majority of SIM are performed pre- or peri-menopausal for benign indications, understanding the associated cardiovascular risks is vital for informed decision-making, early detection, and prevention.

The Effect of Cumulative Lifetime Estrogen Exposure on Cognition in Depressed Versus Non-Depressed Older Women.

Two-thirds of individuals living with Alzheimer's disease are women. Declining estrogen levels influence mood and cognition. Cumulative lifetime estrogen exposure (CLEE) correlates with cognition later in life. We examined the relationship of CLEE to depression and cognition in older women with major depression compared to non-depressed women. Older women (age ≥60years) with depression were compared to non-depressed women using a lifetime estrogen exposure questionnaire. CLEE was defined as combined durations of reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Higher vs lower CLEE groups were based on a median of 474 months of estrogen exposure. University hospital outpatient research program. 135 women ≥60 years; 64 depressed and 71 non-depressed. Participants completed a comprehensive cognitive test battery. General linear models were used to examine the association between cognitive domain scores and CLEE in depressed and non-depressed women, controlling for age, education, and ethnicity. Depressed and non-depressed groups had significantly different levels of CLEE, measured in months: mean 495.7 (SD 108.6) vs 456.4 (SD 66.0) months, F(1,130) = 5.01, p = .03. Within the non-depressed participants, higher CLEE was associated with improved delayed recall (F(1,59) = 5.94, p = .02, effect size = .61), while no such relationship was observed in the depressed group. Higher CLEE was associated with improvement in delayed recall among non-depressed, but not among depressed participants. This suggests a protective role of estrogen on memory in non-depressed older postmenopausal women. Further research should examine the role of the CLEE in antidepressant response and cognitive decline.

The Effect of Cumulative Lifetime Estrogen Exposure on Cognition in Depressed versus Non-Depressed Older Women

<h3>Introduction</h3> There are sex differences in the prevalence and age-matched incidence of Alzheimer's Disease (AD), with women constituting up to two-thirds of individuals living with AD in the United States. Symptoms of depression and anxiety are also higher in women and can increase dementia risk. Additionally, the decline in estrogen level impacts cognitive function, often leading to difficulties with memory, attention, and concentration. Estrogen withdrawal during menopause also precipitates an increase in depressive symptoms and cognitive decline. Cumulative lifetime estrogen exposure (CLEE), estimated by variables known to influence estrogen levels across the life span, has been correlated with cognitive function later in life. In particular, higher levels of CLEE are associated with improvement in memory performance in older women. Our report is the first to examine how CLEE relates to depression and cognitive function in older women with depression compared to non-depressed controls. <h3>Methods</h3> A total of 135 participants aged 60 years and older were included in the analysis. Sixty-four clinically depressed women (mean age 69.1 (SD 6.4) years) were compared to 71 non-depressed age-matched controls (mean age 66.1 (SD 8.3) years) using a lifetime estrogen exposure questionnaire. Depressed participants were included with the 24-item Hamilton Rating Scale for Depression (HAMD) score of > 14 at baseline. CLEE was defined by combining the reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Participants were divided into higher versus lower CLEE groups based on a median of 480 months of estrogen exposure. Participants completed a comprehensive neuropsychological test battery that evaluated learning (California Verbal Learning Test-II [Trial 1 through 5 Total] or Hopkins Verbal Learning Test [Total Recall], Rey–Osterrieth Complex Figure Test [3-minute recall]); delayed recall (California Verbal Learning Test-II [long delayed free recall] or Hopkins Verbal Learning Test [Delayed Recall], Rey–Osterrieth Complex Figure Test [30-minute delayed recall]); and executive functioning (Trail Making Test B, Controlled Oral Word Association test [FAS]).We transformed raw scores to <i>z</i>-scores for each test score for each participant. <i>Z-</i>scores were reversed when necessary so that high <i>z</i>-scores represented good performance for all measures. These <i>z</i>-scores were averaged within each neuropsychological domain to produce composite scores.General linear models were used to examine whether cognitive domain scores were associated with CLEE in depressed and non-depressed women, controlling for age, educational level and ethnicity. <h3>Results</h3> Depressed and non-depressed women had significantly different levels of CLEE: 448.6 (SD 66.0) vs. 487.3 (SD 108.6), t(133) = 2.52, p = .01. CLEE was not associated with cognitive performance in the combined sample of depressed and non-depressed participants, controlling for depression status. However, amongst non-depressed participants, higher CLEE group was significantly associated with better performance on delayed recall (F(1,60) = 5.45, p=0.02; effect size = .64). <h3>Conclusions</h3> Consistent with previous findings, higher CLEE was associated with better performance on delayed recall, though we found this effect only among non-depressed participants. This suggests an enduring protective role of estrogen on memory in non-depressed older postmenopausal women. CLEE was not associated with cognitive function in older women with depression. Further research should examine the role of the CLEE in older women in depression, treatment response and in cognitive decline. <h3>Funding</h3> K24 AT009198 R01 AT008383 (NCCIH) R01 AT008383-04S (NCCIH)

Postmenopausal hormone replacement therapy and colorectal cancer risk by molecular subtypes and pathways.

Postmenopausal hormone replacement therapy (HRT) was found to be associated with lower risk of colorectal cancer (CRC). However, little is known regarding associations with molecular subtypes of CRC. The current study includes female participants of a large German population-based case-control study (922 CRC cases and 1,183 controls). Tumor tissue samples were analyzed for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), BRAF and KRAS mutation status. Multivariable logistic regression models were used to assess the association of HRT use with molecular subtypes and pathways. Postmenopausal HRT use was overall associated with reduced risk of CRC (adjusted odds ratio (aOR) 0.62, 95% confidence interval (CI) 0.50-0.76) and no major differences were observed for molecular subtypes or for tumor marker combinations representing molecular pathways. When stratified by median age (≤/>71 years) potentially stronger risk reductions were observed in the older group for subtypes showing MSI (OR = 0.36, 95% CI 0.17-0.76), BRAF mutation (OR = 0.40, 95% CI 0.30-0.83) and CIMP-high (OR = 0.40, 95% CI 0.21-0.73) and for CRC suggestive of the sessile serrated pathway (OR = 0.45, 95% CI 0.20-1.01). In conclusion, postmenopausal use of HRT was similarly associated with risk reduction of major molecular tumor subtypes and pathways of CRC. Potentially stronger risk reductions with CRC subtypes diagnosed at higher ages require confirmation and clarification from other studies. The current study extends the limited understanding of the mechanisms of HRT in CRC prevention.

Klotho and Postmenopausal Hormone Replacement Therapy in Women with Chronic Kidney Disease.

Kidney function is highly susceptible to age-related changes, with chronic kidney disease (CKD) serving as an important cause of morbidity and mortality in older patients. The prevalence of CKD in Korea is higher among the elderly, relative to the general population, with the most significant increases seen following the onset of menopause. Under normal conditions, estrogen attenuates renal superoxide production and protects the kidney from oxidative damage. As estrogen levels are known to decrease by as much as 80% during menopause, this represents a significant risk for older women. Postmenopausal hormone replacement therapy (HRT) modulates the renin-angiotensin system, thereby reducing the progressive deterioration of renal function. Use of estrogen-based HRT has been shown to ameliorate renal function in postmenopausal women, and delay CKD progression. Renal expression of klotho, an important suppressor of aging, is markedly decreased in CKD patients, making it a promising candidate for use as a prognostic biomarker in CKD. Here, we review the key links between renal function, sex, age, and estrogen levels during menopause, and discuss the use of postmenopausal HRT in CKD attenuation.

Bioidentical hormones, menopausal women, and the lure of the “natural” in U.S. anti-aging medicine

In 2002, the Women's Health Initiative, a large-scale study of the safety of hormone replacement therapy (HRT) for women conducted in the United States, released results suggesting that use of postmenopausal HRT increased women's risks of stroke and breast cancer. In the years that followed, as rates of HRT prescription fell, another hormonal therapy rose in its wake: bioidentical hormone replacement therapy (BHRT). Anti-aging clinicians, the primary prescribers of BHRT, tout it as a safe and effective alternative to treat menopausal symptoms and, moreover, as a preventative therapy for age-related diseases and ailments. Through in-depth interviews with 31 U.S.-based anti-aging clinicians and 25 female anti-aging patients, we analyze attitudes towards BHRT. We illustrate how these attitudes reveal broader contemporary values, discourses, and discomforts with menopause, aging, and biomedicine. The attraction to and promise of BHRT is rooted in the idea that it is a “natural” therapy. BHRT is given both biomedical and embodied legitimacy by clinicians and patients because of its purported ability to become part of the body's “natural” processes. The normative assumption that “natural” is inherently “good” not only places BHRT beyond reproach, but transforms its use into a health benefit. The clinical approach of anti-aging providers also plays a role by validating patients' embodied experiences and offering a “holistic” solution to their symptoms, which anti-aging patients see as a striking contrast to their experiences with conventional biomedical health care. The perceived virtues of BHRT shed light on the rhetoric of anti-aging medicine and a deeply complicated relationship between conventional biomedicine, hormonal technologies, and women's bodies.

Changes in Postmenopausal Hormone Replacement Therapy Use Among Women With High Cardiovascular Risk

After randomized trials failed to support the use of hormone replacement therapy (HRT) for preventing cardiovascular disease (CVD), HRT use for postmenopausal women declined. Our analysis of 1999-2000 and 2003-2004 National Health and Nutrition Surveys (NHANES) shows that HRT use decreased 19% (from 27.6 to 8.4%; P<.001) among women with CVD versus 3% (from 19.8 to 16.8%; P=.68) among low-risk women, suggesting that most of the drop in HRT use may be among women prescribed HRT as an unproven treatment to prevent CVD.

Estrogen-biosynthesis gene CYP17 and its interactions with reproductive, hormonal and lifestyle factors in breast cancer risk: results from the Long Island Breast Cancer Study Project

The genes that are involved in estrogen biosynthesis, cellular binding and metabolism may contribute to breast cancer susceptibility. We examined the effect of the CYP17 promoter T --> C polymorphism and its interactions with the reproductive history, exogenous hormone use and selected lifestyle risk factors on breast cancer risk among 1037 population-based incident cases and 1096 population-based controls in the Long Island Breast Cancer Study Project. Overall, there were no associations between the CYP17 genotype and breast cancer risk. Among postmenopausal women, the joint exposure to higher body mass index (BMI) and the variant C allele was associated with an increased risk of breast cancer [odds ratio (OR), 1.60; 95% confidence interval (CI), 1.15-2.22]. The joint exposure to the variant C allele and long-term use of hormone replacement therapy (HRT) (>51 months) was related to an increased risk of breast cancer (OR, 1.51; 95% CI, 0.99-2.31) especially estrogen receptor-positive, progesterone receptor-positive breast cancer (OR, 1.87; 95% CI, 1.08-3.25). Among the control population, the CYP17 variant C allele was inversely associated with long-term use of postmenopausal HRT and a higher BMI in postmenopausal women. In conclusion, the findings suggest that the CYP17 variant C allele may increase breast cancer risk in conjunction with long-term HRT use and high BMI in postmenopausal women.

Hormonal Replacement Therapy After Menopause Is Protective of Disease Activity in Women With Inflammatory Bowel Disease

The nature of inflammatory bowel disease (IBD) following menopause has not been previously studied. The aim of this study was to characterize the effect of menopause on disease activity and identify possible modifiers of disease activity. This was a retrospective study of women followed at the University of Chicago IBD Clinic. Disease activity was assessed using clinical scoring systems during the pre- and postmenstrual periods of subjects. Variables of interest included: history of smoking, use of oral contraceptives (OCP) prior to onset of menopause, and use of hormone replacement therapy (HRT). Sixty-five women were included, 20 with ulcerative colitis and 45 with Crohn's disease. The median age of menopause was similar to historical controls. Twenty-three patients (35%) experienced active symptoms in the premenopausal time period and 25 patients (38%) had disease indices consistent with a flare within the first 2 yr after menopause (P > 0.05). There was no relation between those who had a pre- versus postmenstrual flare as a group (P > 0.05). However, there was a significant protective effect on disease activity with postmenopausal HRT use (hazard ratio [HR] 0.18, 95% confidence interval [CI] 0.04-0.72). There was also a dose-response effect noted with an HR with longer duration of use (0.20, 0.07-0.65). The likelihood of having a flare postmenopause is not different from having it premenopause. HRT, however, may provide a protective effect for disease activity in the postmenopausal period. The anti-inflammatory effects of estrogen may be the mechanism for this observation.

Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study.

BackgroundPostmenopausal hormone-replacement therapy (HRT) increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood.MethodsWe obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women.ResultsHRT use in patients with estrogen receptor (ER) protein positive tumors (n = 72) was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen.ConclusionOur findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells.

Myocardial infarction risk and hormone replacement: Differences between products

Objectives To establish the risk of myocardial infarction (MI) in users of hormone replacement therapy (HRT) compared with non-users and to compare the risk between different HRT regimens. Methods A population-based cohort and case-control study, and a case-control study nested within a cohort of HRT users, using the UK General Practice Research Database. Differences between HRT regimen, mode of administration and duration and recency of use were examined whilst adjusting for confounding. Results In the cohort and case-control study, 4537 cases of MI were identified in 2.62 million observed women years, cases were age-matched to 27,220 controls. In both studies, current and past HRT use were associated with reduced risk estimates for MI compared with no prior use. MIs were less likely to be fatal amongst women who had used HRT than amongst never users (OR adj 0.58; 95% CI 0.45–0.75). No difference in risk was seen between current and past use, oral and transdermal HRT or between different regimens ( p > 0.44). In the nested study, no difference was found in the association with MI risk between different oestrogen–progestogen combinations or between different combinations and tibolone. Unopposed oestrogen use was not associated with a decrease in risk compared with combined HRT. Conclusions These results are consistent with previous observational studies in supporting the hypothesis that use of postmenopausal HRT is associated with a decrease in risk of acute myocardial infarction (AMI). Case fatality differed between HRT users and non-users, suggesting a protective effect of HRT. This study does not demonstrate a difference between regimens.

Insulin Resistance and Postmenopausal Hormone Replacement Therapy

Insulin resistance causes hyperglycemia by disturbing glucose uptake in the tissues and increasing hepatic glucose production. Hyperinsulinemia has a predictive role in the generation of type 2 diabetes in nondiabetic individuals. Both insulin resistance and the associated disturbances are responsible for increased cardiovascular risk. Women of reproductive age are protected from cardiovascular disease although in the postmenopausal period the risk becomes equal to that in men and exceeds that in men later on. This observation leads us to consider the role of estrogen deficiency in the pathogenesis of cardiovascular disease. Hormone replacement therapy (HRT) is a successful method in the management of certain clinical situations in postmenopausal women. The interactions among estrogen, menopause, and cardiovascular risk bring forth the question of whether the HRT affects insulin resistance or not. The studies so far have yielded controversial results. The overall results of recent reports indicate that postmenopausal HRT improves insulin resistance. However, the available evidence is not strong enough to suggest the use of postmenopausal HRT as a first-line therapeutic measure in the management of insulin resistance.

Postmenopausal hormone replacement therapy use and risk of endometrial cancer in Japanese women

Postmenopausal hormone replacement therapy use and risk of endometrial cancer in Japanese women

Postmenopausal hormone replacement therapy use by older Mexican-American women.

To determine the prevalence of current hormone replacement therapy (HRT) use and describe its correlates among community-dwelling, Mexican-American women aged 67 and older. A population-based survey of older Mexican-Americans conducted in 1995/1996. Five Southwestern states: Texas, New Mexico, California, Arizona, and Colorado. An area probability sample of 1,424 noninstitutionalized Mexican-American women aged 67 and older (mean age = 75.1) completed the survey instrument via a 90-minute in-home interview, which included examination and recording of all medications taken. Current use of HRT. In this sample of older Mexican-American women, 4.7% were current users of HRT. Controlling for sociodemographic characteristics (age, marital status, living arrangements, years of education, income, language of interview), current HRT use is significantly related to years of education (per each year) (odds ratio (OR) = 1.13; 95% confidence interval (CI) = 1.05-1.20), having had a hysterectomy (OR = 4.37; 95% CI 2.50-7.64), a diagnosis of osteoporosis (OR = 3.40, 95% CI = 1.58-7.33), age at menopause (per each year) (OR = 1.07; 95% CI = 1.03-1.12), ever having a mammogram (OR = 3.72; 95% CI = 1.66-8.37), ever having a Pap test/pelvic examination (OR = 2.11; 95% CI = 1.08-4.12), having spoken with a pharmacist within the past year regarding health conditions (OR = 1.96; 95% CI = 1.06-3.65), and having Medicare plus private insurance (OR = 2.13; 95% CI = 1.14-3.97). The prevalence of HRT use is lower than that reported in the older non-Hispanic white female population. In general, these findings indicate that access to and utilization of the traditional U.S. health care system are indicators of HRT use.

Postmenopausal hormone replacement therapy use and risk of endometrial cancer in Japanese women

The relationship between the risk of endometrial cancer and the use of non-contraceptive estrogens by Japanese postmenopausal women was investigated in a hospital-based case–control study of 1025 womenwith endometrial cancer and 1267 with other conditions. The overall odds ratio (OR) for estrogen use with or without progestins, compared with never use of any type of estrogens, was 0.917 (95% confidenceinterval (CI) 0.622–1.353), suggesting that hormone replacement therapy is not a causative agent for endometrial cancer in Japanese women, and that a recent increase in the incidence of endometrialcancer in Japanese women may be related to changes in their life-style. However, although not statistically significant, women who used estrogen without progestin for 12 or more months had an OR of 2.552(CI 0.231–28.192), while those who used estrogen with progestin for 12 or more months had an OR of 0.425 (CI 0.086–2.113). These results indicate that the addition of a progestin should be consideredfor reducing the risk of endometrial cancer in Japanese women.

Prevalence and duration of postmenopausal hormone replacement therapy use in a managed care organization, 1990-1995.

To determine the prevalence and duration of postmenopausal hormone replacement therapy (HRT) use and identify correlates of adherence to therapy. Population-based cohort study. Staff-model health maintenance organization. Female members, 40 years and older. Prevalence and duration of use were measured between 1990 and 1995. Duration was assessed by Kaplan-Meier and proportional hazards methods. Hormone replacement therapy use increased from 10.3% in 1990 to 20.7% in 1995. Greatest use (24%) occurred among menopausal women age 50 to 54 years. Less than 5% of women 75 and older used HRT. Among 1,680 first-time recipients of HRT, two thirds of initial prescriptions were written by internists. Thirty-eight percent discontinued HRT within 1 year. For the subset whose indication for therapy was ascertained, prevention of chronic disease was associated with a 33% 1-year discontinuation rate. Factors associated with longer duration of therapy included white race (relative risk [RR], 1.63; 95% confidence interval [95% CI], 1.32 to 2.02), younger age (RR, 1.02 per year; 95% CI 1.01 to 1.03), and changing the preparation or dose of estrogen (RR, 5.62; 95% CI, 4.33 to 7.25). The formulation (esterified estrogens 0.625 mg versus conjugated estrogens 0.625 mg) was also associated with greater duration of use; all other estrogens were, as a group, associated with shorter duration of use. Those who received their initial HRT prescription from an internist were more likely to continue therapy than those who received it from a gynecologist. Despite increased use of HRT, only a minority of women in this population used HRT, and many of those discontinued therapy within 1 year.

Hormone Replacement Therapy and Risk of Breast Cancer With a Favorable Histology: Results of the Iowa Women’s Health Study

ContextLong-term, postmenopausal use of hormone replacement therapy (HRT) appears to increase breast cancer risk. Whether the effect of HRT use on risk of breast cancer varies among histological types of invasive carcinoma is unknown.ObjectiveTo determine associations between HRT use and risk of ductal carcinoma in situ (DCIS), invasive carcinoma with favorable histology, and invasive ductal or lobular carcinoma.DesignProspective cohort study whose participants were followed up continuously for 11 years from January 1986 to December 1996.Setting and ParticipantsIowa Women's Health Study, a population-based random sample of postmenopausal women aged 55 to 69 years in 1986. A total of 1520 incident breast cancer cases occurred in the at-risk cohort of 37,105 women.Main Outcome MeasuresMultivariate-adjusted relative risk (RR) of tumor-specific breast cancers associated with duration of ever, current, or past HRT use.ResultsDuration of ever HRT use was associated with risk of invasive carcinoma with a favorable histology, with an RR of 1.81 (95% confidence interval [CI], 1.07-3.07) for those who used HRT 5 or fewer years vs an RR of 2.65 (95% CI, 1.34-5.23) for those who used HRT for more than 5 years (P for trend=.005) after adjustment for age and other breast cancer risk factors. There was no association between ever HRT use and the incidence of DCIS or invasive ductal or lobular carcinoma. Among current hormone users, after adjusting for age and other breast cancer risk factors, the RRs (95% CIs) of invasive carcinoma with a favorable histology were 4.42 (2.00-9.76) and 2.63 (1.18-5.89) for 5 or fewer years of use and for more than 5 years of use, respectively. Risk of invasive ductal or lobular carcinoma was associated with current use (≤5 years) of HRT with an RR of 1.38 (95% CI, 1.03-1.85).ConclusionsExposure to HRT was associated most strongly with an increased risk of invasive breast cancer with a favorable prognosis. These data add important clinical information for assessing the risks and benefits of HRT use.