Hysterectomized Women Research Articles

Benefits and Risks of Menopausal Hormone Therapy

Menopausal Hormone Therapy (MHT) (estrogen/progestogen) is used to treat menopausal complaints and to prevent osteoporosis. Additional preventive benefits are reduction of cardiovascular disease, reduction of colon cancer, and perhaps also Alzheimer’s disease, if started within a “window of opportunity”, i.e. in perimenopause or within 6-10 years after menopause. Primary indication for progestogen addition is to avoid the development of estrogen-dependent endometrial cancer, i.e. addition not recommended in hysterectomized women. Two main schedules, sequential- or continuous-combined estrogen/progestogen regimens, are used. For optimizing menstrual regulation detailed recommendations are given

Adaptation to Hysterectomy: Design and Psychometric Properties Assessment of Hysterectomy Adaptation Scale.

Adaptation to complications of hysterectomy is one of the topics of concern for women and health care providers. There is no instrument for evaluating adaptation to hysterectomy. This study aimed to design the Hysterectomy Adaptation Scale (HAS) and assess its psychometric properties. This methodological study was conducted from 2018 to 2020 in Mashhad, Iran. To develop the item pool, qualitative data from directed content analysis and data from the review of adaptation and coping instruments were used. The face, content, construct validity, internal consistency, and stability were used to evaluate the psychometric properties of HAS. The final version of the HAS consisted of 24 items with a reported content validity index of 0.9. Six factors were extracted from the principal component analysis, which explained 60.3 of the observed variance. Model fit indices in confirmatory factor analysis showed that the model was well fitted. The values of the alpha coefficient and intra-class coefficient were 0.86 and 0.95, respectively. The HAS is a valid and reliable scale for evaluating the adaptation level of hysterectomized Iranian women. HAS can distinguish between hysterectomized women who have adapted to hysterectomy and those who have not. It can be used to assess the adaptation of hysterectomized women in research and clinical practice.

Menopausal symptoms among women with and without hysterectomy

BackgroundRecent studies have associated hysterectomies with an increased risk of several health adversities. However, the effect of hysterectomy on menopausal symptoms and menopause-related quality of life has not been explored much in Indian context. The present study aims to estimate the prevalence and severity of menopausal symptoms and their socio-demographic determinants among North Indian menopausal women with and without hysterectomy. MethodsThis cross-sectional study was conducted among 359 menopausal women aged 40–78 years, of which 266 were without hysterectomy, 66 had undergone hysterectomy before menopause, and 27 after menopause. The prevalence and severity of menopausal symptoms were captured using the MENQOL questionnaire. Appropriate statistical tests (including the chi-square test, t-test, and correlation analysis) were performed to understand the differences in the prevalence and severity of menopausal symptoms among the three groups. ResultsMenopausal symptoms, depending on the hysterectomy status, affected the quality of life of 66.2–78.79% of women. Notably, menopausal symptoms among those who underwent hysterectomy before menopause were significantly higher than those without hysterectomy in terms of both prevalence and severity [mean severity score (SD) = 3.49 (1.5) vs 2.85 (1.4), respectively; p-value= 0.001]. Higher age and longer duration since menopause were inversely correlated with the severity of symptoms among women without hysterectomy, but not among hysterectomized women. ConclusionHysterectomy before menopause may be associated with an increased prevalence of menopausal symptoms and poor quality of life. There is an urgent need to discourage unnecessary hysterectomies and facilitate women undergoing a hysterectomy with adequate post-surgery care.

Steroid hormone levels in postmenopausal hysterectomised women with and without ovarian conservation: the continuous endocrine function of the ovaries

This study aims to clarify the effect of postmenopausal bilateral oophorectomy on plasma steroid hormone levels. Women who were submitted in the postmenopausal period to hysterectomy for uterine benign conditions were divided into two groups: 18 women had isolated hysterectomy and 11 had hysterectomy with bilateral salpingo-oophorectomy. In both groups serum hormone levels were quantified by solid phase extraction and gas chromatography and tandem mass spectrometry. Differences in dehydroepiandrosterone (DHEA), testosterone, androstenedione and oestradiol were determined in both groups. The analysis revealed lower steroid levels in the bilateral salpingo-oophorectomy group when compared to the isolated hysterectomy group with statistically significant differences found for DHEA (5.8 ± 3.2 vs. 9.4 ± 4.4 ng/mL; p = 0.019) and oestradiol (0.69 ± 0.4 vs. 1.48 ± 4.3 ng/mL; p = 0.007). The results are consistent with a significant endocrine activity of the postmenopausal ovary. The clinical consequences of these findings need to be clarified and postmenopausal prophylactic bilateral salpingo-oophorectomy re-evaluated. IMPACT STATEMENT What is already known on this subject? Although it is consensual that premenopausal prophylactic bilateral oophorectomy should not be performed because it has harmful effects on women's health, the evidence regarding the effects of postmenopausal prophylactic bilateral oophorectomy is scarce and this procedure continues to be a regular practice. Few studies have demonstrated that postmenopausal ovaries still have endocrine activity that may impact older women's health. What do the results of this study add? This is the first study to compare hormone levels of postmenopausal women based on their hysterectomy and oophorectomy status using GC-MS/MS, a highly sensitive bioanalytical assay for the measurement of steroid hormones. Previous studies relied on immunoassays and did not compare DHEA levels, which according to the intracrinology theory is a precursor for androgens and oestrogens. In this study, statistically significant lower levels of DHEA and oestradiol were found after postmenopausal bilateral salpingo-oophorectomy. What are the implications of these findings for clinical practice and/or further research? This is a pilot study that may lead to further investigation in this area to clarify the impact of the prophylactic removal of postmenopausal ovaries on older women′s health and lead to changes in surgical procedures.

Trends in Hysterectomy Incidence Rates During 2000-2015 in Denmark: Shifting from Abdominal to Minimally Invasive Surgical Procedures.

BackgroundHysterectomy (removal of the uterus) is a common surgical procedure in gynecology. Although minimally invasive surgical procedures have been introduced, hysterectomy is still associated with risk of short- and long-term complications. Given that hysterectomized women are no longer at risk of either hysterectomy or being diagnosed with endometrial or cervical cancer, it is important to describe trends in hysterectomy rates.ObjectiveTo describe trends in hysterectomy incidence rates overall and stratified by age, indication, and procedure.MethodsNationwide population-based cohort study using Danish national registries, 2000–2015, was conducted. We calculated the overall hysterectomy-corrected and age-standardized incidence rates of hysterectomy among women ≥20 years old. Incidence rates were stratified by age group, indication, and surgical procedure. We performed trend analyses using Joinpoint regression, thereby estimating the average annual percentage change (AAPC).ResultsA total of 98,484 women had a hysterectomy during the study period, corresponding to an overall age-standardized, hysterectomy-corrected hysterectomy incidence rate (SIR) of 351.1 per 100,000 person-years (95% CI 348.9;353.3). SIR of hysterectomy declined over time (AAPC −1.4; 95% CI −1.9;-1.0), which was driven by a decline in rates of benign hysterectomy (AAPC −2.1; 95% CI −2.7;-1.6). Irrespective of indication, rates of abdominal hysterectomy declined substantially during the study period and were surpassed by rates of minimally invasive procedures (ie, laparoscopy and robot-assisted laparoscopy) in 2013.ConclusionHysterectomy-corrected incidence rates of benign hysterectomy declined over time. Irrespective of indication, we observed a shift in surgical procedure over time, from abdominal hysterectomy to minimally invasive surgical procedures.

Genitourinary syndrome of menopause in Chinese perimenopausal and postmenopausal women

Objective The aim of this study was to investigate genitourinary syndrome of menopause (GSM) in a large cohort, analyzing the dependency on age and menopausal status and possible differences between non-hysterectomized and hysterectomized women. Methods Data were assessed by validated questionnaires, collected over 2 years for all eligible women attending our ‘Menopause Clinic’ from 31 Chinese provinces. Simple and unconditional logistic regression analysis was used with adjustments by all analyzed factors. Results A total of 4063 women (mean age 50.53 ± 6.57 years), 2107 perimenopausal and 1956 postmenopausal, were included. Almost all GSM symptoms were more frequent and severe in postmenopausal women. GSM was more frequent in hysterectomized women compared to non-hysterectomized women. Independent of menopausal status, low sexual interest (92.78%), urinary incontinence (91.65%) and vaginal dryness (91.60%) were the top three GSM symptoms. Most severe were low sexual interest (21.01%), vaginal pain (20.10%) and decreased sexual pleasure (17.13%). Prevalence and severity of GSM were not related to age, but were related to menopausal status and increased with time since menopause. Conclusions Within 2 years, more than 4000 women with GSM traveled from all over China to our specialized clinic, indicating the great importance of GSM. Hysterectomy can increase the risk of GSM, and GSM symptoms increase from perimenopause to postmenopause and with an increase of time since menopause, pointing to the dependency on the loss of ovarian function.

Hysterectomies are associated with an increased risk of osteoporosis and bone fracture: A population-based cohort study.

This study investigated the risk of osteoporosis or bone fractures (vertebrae, hip and others) in hysterectomized women in Taiwan. This is a retrospective population-based cohort study from 2000 to 2013. Women aged ≥30 years who underwent hysterectomy between 2000 and 2012 were included in this study. The comparison group was randomly selected from the database with a 1:4 matching with age and index year. Incidence rate and hazard ratios of osteoporosis and bone fracture between hysterectomized women and the comparison group were calculated. Cox proportional hazard regressions were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). We identified 9,189 hysterectomized women and 33,942 age-matched women without a hysterectomy. All women were followed for a median time of about 7 years. The adjusted hazard ratio (aHR) of subsequent osteoporosis or bone fracture was higher in the hysterectomy women (2.26, 95% confidence interval [CI] = 2.09-2.44) than in the comparison group. In the subgroup analysis, oophorectomy and estrogen therapy increase the risk of osteoporosis or fracture in both groups. Regarding the fracture site, the aHR of vertebral fracture (4.92, 95% CI = 3.78-6.40) was higher in the hysterectomized women than in the comparison group. As follow-up time increasing, the aHR of vertebral fracture in hysterectomized women were 4.33 (95% CI = 2.99-6.28), 3.89 (95% CI = 2.60-5.82) and 5.42 (95% CI = 2.66-11.01) for <5, 5-9 and ≥9 years of follow-up, respectively. In conclusion, we found that hysterectomized women might be associated with increased risks of developing osteoporosis or bone fracture.

Postmenopausal hormone therapy in BRCA gene mutation carriers: to whom and which?

ABSTRACT Introduction Risk-reducing-salpingo-oophorectomy (RRSO) inevitably leads BRCA mutation carriers to premature menopause. Areas covered To evaluate the existing evidence for use of postmenopausal hormone therapy (HT) in BRCAmc, after RRSO or menopause occurring naturally, for both breast cancer (BC) survivors and those without BC. Expert opinion All BC survivors are excluded from any HT treatment: in other BRCAmc, before 51 years of age the benefits of HT overcome the risks after RRSO and/or premature ovarian insufficiency (POF). After 51 years of age, it is important to treat only women with important vasomotor symptoms, after the failure of alternative therapies. Estrogens-only therapy plays a key role in hysterectomized women (HW). In the case of an intact uterus (UW), associations with the lowest dose of progestins/natural progesterone derivatives have to be preferred, as progestins has been shown to play an important role in BC transformation, especially in BRCA1mc. No studies have been performed in BRCAmc with regard to ‘progestin-free’ HT, in particular the old tibolone (both in HW and UW) and the new tissue-selective estrogen complex (in UW). However, preliminary data obtained from the general population are reassuring about the use of these ‘progestin-free’ preparations and BC safety.

Risk of vaginal cancer among hysterectomised women with cervical intraepithelial neoplasia: a population-based national cohort study.

To study the risk of vaginal cancer among hysterectomised women with and without cervical intraepithelial neoplasia (CIN). Population-based national cohort study. All Swedish women, 5 million in total, aged 20 and up, 1987-2011 using national registries. The study cohort was subdivided into four exposure groups: hysterectomised with no previous history of CIN3 and without prevalent CIN at hysterectomy; hysterectomised with a history of CIN3/adenocarcinoma in situ (AIS); hysterectomised with prevalent CIN at hysterectomy; non-hysterectomised. Vaginal cancer. We identified 898 incident cases of vaginal cancer.Women with prevalent CIN at hysterectomy and those with a history of CIN3/AIS had incidence rates (IR) of vaginal cancer of 51.3 (95% CI 34.4-76.5) and 17.1 (95% CI 12.5-23.4) per 100000, respectively. Age-adjusted IR-ratios (IRRs) compared with hysterectomised women with benign cervical history were 21.0 (95% CI 13.4-32.9) and 5.81 (95% CI 4.00-8.43), respectively. IR for non-hysterectomised women was 0.87 (95% CI 0.81-0.93) and IRR was 0.37 (95% CI 0.30-0.46). In hysterectomised women with prevalent CIN, the IR remained high after 15years of follow up: 65.7 (95% CI 21.2-203.6). Our findings suggest that hysterectomised women with prevalent CIN at surgery should be offered surveillance. Hysterectomised women without the studied risk factors have a more than doubled risk of contracting vaginal cancer compared with non-hysterectomised women in the general population. Still, the incidence rate does not justify screening. High risk of contracting vaginal cancer among hysterectomised women having prevalent CIN at surgery.

Insomnia and sexual dysfunction associated with severe worsening of the quality of life in sexually active hysterectomized women.

Introduction Hysterectomy is a common gynecologic surgery carried out to remove the pathologic uterus. Objective: To establish if sleep disorders and sexual function are associated with deterioration of the quality of life (QoL) in hysterectomized and sexually active women. Methods: A cross-sectional study was carried out with inhabitants from two cities of the Colombian Caribbean. The pollsters invited women aged between 40-59 years to participate; in their communities they applied surveys with demographic characteristics: Female Sexual Function Index, Atenas Insomnia Scale and Menopause Rating Scale. Sexually active women were selected; then the association was established with logistic regression. Results: 522 women were studied with an average age of 50 years: 30% oophorectomized, 59.8% Hispanic, 40.2% afro-descendants and 22.2% hormonal therapy users. 80% of them had somato/vegetative, psychological or urogenital deterioration; 29.1% with severe deterioration of QoL and 47.5% with insomnia. Out of 390 (74.7%) with sexual activity, 59.7% suffered from sexual dysfunction. Insomnia: OR:3.05 [95%CI:1.86-4.99], sexual dysfunction OR:3.52 [95%CI:2.01-6.17], dissatisfaction about sexuality OR:4.77 [95%CI:2.08-10.93], low or non-existent sexual desire OR:2.94 [95%CI:1.65-5.25], daytime drowsiness OR:3.15 [95%CI:1.59-6.24] and decrease in daytime well-being OR:3.18 [95%CI:1.79-5.64]. These were factors associated with severe worsening of QoL, while the presence of genital lubrication was protective, OR: 0.44 [95%CI:0.21-0.93], p=0.0332. Conclusion: It was observed that insomnia and sexual dysfunction behaved as factors associated with three times more severe deterioration of the QoL in climacteric and sexually active women previously hysterectomized.

The influence of total hysterectomy in a cervical cancer screening population: a register-based cross-sectional study

BackgroundHigh coverage of a screening program is essential to program success. Many European screening programs cover only 10–80% of their target population. A possible explanation for the low coverage may be that some women in the screening population have had a total hysterectomy, thus they are not at risk of cervical cancer. The aim of this study was to identify the prevalence of hysterectomy in the target population of the Danish National Cervical Cancer Screening Program (NCCSP) and to recalculate coverage after excluding women with total hysterectomy. Furthermore, to analyze the association between hysterectomy and sociodemographic factors within the screening population.MethodsA population-based cross-sectional study using register data on all women in the target population of the NCCSP on January 12, 2012 (women born January 12, 1947, to January 12, 1986).The total coverage included women with hysterectomy in the target population whereas the recalculated coverage was calculated excluding women with total hysterectomy. To test the differences between the total coverage and the recalculated coverage, a two-sample z-test between the proportion of covered hysterectomized women and the proportion of covered non-hysterectomised women were used. A logistic regression model adjusted for age and sociodemographic characteristics was used to analyze the association between sociodemographic factors and total hysterectomy.ResultsThe coverage among women aged 26–49 years and 55–64 years were 77.4% and 72.7%, respectively. The recalculated coverage was 78.2% (26–49 years) and 79.4% (55–64 years). Recalculating the coverage did not result in coverage higher than 82.7% at any age. The effect of excluding women with total hysterectomy increased with age, reaching its maximum of 8 % points for the oldest women. Women with higher socioeconomic status (higher education and higher disposable income) had lower odds of being hysterectomized compared to other women. Also, immigrants and descendants had lower odds of being hysterectomized compared to ethnic Danes.ConclusionsExcluding women with total hysterectomy only partly explained the low coverage of the NCCSP. Thus, initiatives must be made to improve acceptability of and accessibility to the NCCSP, especially in the youngest and the oldest women.

Home HPV Self-Collection in HIV-Infected Women: Assessing Acceptability and Prevalence [13M

INTRODUCTION: Up to 55% of women living with HIV (WLHIV) are under-screened for cervical cancer, despite higher risk. Our objective was to examine HPV prevalence, compare home self-collected (SC) to clinician-collected (CC) HPV positivity, and measure acceptability of SC. METHODS: A prospective cohort study of WLHIV was conducted from February–September 2016 in Baltimore. IRB approval was obtained. Pregnant and hysterectomized women were excluded. HPV E6/E7 mRNA was detected from SC cervicovaginal and CC cervical cytobrushes using transcription mediated amplification. HPV DNA was detected from a 2nd CC cervical cytobrush using DNA nucleic acid hybridization. Descriptive and Cohen's kappa statistics were performed. RESULTS: There were 68 participants with mean age 48 (SD 9.6). The majority (89%) were Black with median CD4 count of 623 (IQR 379-811). Among the 81% of subjects who returned the home SC kits, HPV E6/E7 mRNA prevalence was 50.9% and 41.8% for SC and CC samples, respectively, while DNA prevalence was 34%. Concordance between SC and CC E6/E7 was 76.4% (ĸ=.53, p &lt; .001), and 95.7% (ĸ=.91, p &lt; .001) between CC E6/E7 and DNA. Pap tests were normal among 81.5% of negative home SC tests. The majority (83.3%) would use the swab again and recommend the swab to family/friends (88.2%). CONCLUSION: There was moderate agreement between home SC and CC HPV positivity. Home SC was acceptable. Most participants would use the swab again and recommend it to family/friends. Home SC could be used as an alternative method to screen WLHIV who do not regularly visit women's health clinics.

Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial

miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes. In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18-65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-α based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using the SAS procedure Proc Plan. The first cohort received one subcutaneous injection of 2 mg/kg RG-101 or placebo; the second cohort received one subcutaneous injection of 4 mg/kg or placebo. Patients were followed up for 8 weeks (all patients) and up to 76 weeks (patients with no viral rebound and excluding those who were randomised to the placebo group) after randomisation. The primary objective was safety and tolerability of RG-101. This trial was registered with EudraCT, number 2013-002978-49. Between June 4, 2014, and Oct 27, 2014, we enrolled 32 patients with chronic HCV genotype 1 (n=16), 3 (n=10), or 4 (n=6) infections. In the first cohort, 14 patients were randomly assigned to receive 2 mg/kg RG-101 and two patients were randomly assigned to receive placebo, and in the second cohort, 14 patients were randomly assigned to receive 4 mg/kg RG-101 and two patients were randomly assigned to receive placebo. Overall, 26 of the 28 patients dosed with RG-101 reported at least one treatment-related adverse event. At week 4, the median viral load reduction from baseline was 4·42 (IQR 3·23-5·00) and 5·07 (4·19-5·35) log10 IU/mL in patients dosed with 2 mg/kg RG-101 or 4 mg/kg RG-101. Three patients had undetectable HCV RNA levels 76 weeks after a single dose of RG-101. Viral rebound at or before week 12 was associated with the appearance of resistance associated substitutions in miR-122 binding regions in the 5' UTR of the HCV genome. This study showed that one administration of 2 mg/kg or 4 mg/kg RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated anti-miR-122 oligonucleotide, was well tolerated and resulted in substantial viral load reduction in all treated patients within 4 weeks, and sustained virological response in three patients for 76 weeks. Regulus Therapeutics, Inc.

The temporal and age-dependent patterns of hysterectomy-corrected cervical cancer incidence rates in Denmark: a population-based cohort study.

Hysterectomy is a common gynecological procedure; however, the incidence of total and subtotal hysterectomy varies across countries, by age, and over time. As only women with an intact cervix are at risk of cervical cancer, failing to remove hysterectomized women from the denominator may underestimate the cervical cancer incidence. We aimed to describe the temporal and age-dependent patterns of cervical cancer incidence in Denmark before and after correction for hysterectomy. Using data from national registries we calculated uncorrected and hysterectomy-corrected cervical cancer incidence rates among women ≥20 years during 2000-11. Hysterectomy-corrected rates were calculated by subtracting post-hysterectomy person-years from the denominator. The overall uncorrected cervical cancer incidence rate was 17.8/100 000 person-years (95% CI 17.3-18.3). After correction for hysterectomy, the rate increased by 8.4% to 19.3/100 000 person-years (95% CI 18.8-19.9). The highest uncorrected incidence was seen in women aged 35-39 years, peaking at 24.4/100 000 person-years, whereas the highest hysterectomy-corrected cervical cancer incidence rate was observed in women aged 75-79 years (29.4/100 000 person-years). Over time, women ≥60 years had the highest hysterectomy-corrected cervical cancer incidence. Correcting for hysterectomy incidence resulted in a higher cervical cancer incidence and a shift in the peak incidence from age 35-39 years to age 75-79 years. Over time, women ≥60 years were at the highest risk of cervical cancer. Given the high incidence in women >60-65 years, when women are eligible to exit screening, a revision of the screening guidelines may be warranted.

Impact of Estrogen Therapy on Lymphocyte Homeostasis and the Response to Seasonal Influenza Vaccine in Post-Menopausal Women

It is widely recognized that changes in levels of ovarian steroids modulate severity of autoimmune disease and immune function in young adult women. These observations suggest that the loss of ovarian steroids associated with menopause could affect the age-related decline in immune function, known as immune senescence. Therefore, in this study, we determined the impact of menopause and estrogen therapy (ET) on lymphocyte subset frequency as well as the immune response to seasonal influenza vaccine in three different groups: 1) young adult women (regular menstrual cycles, not on hormonal contraception); 2) post-menopausal (at least 2 years) women who are not receiving any form of hormone therapy (HT) and 3) post-menopausal hysterectomized women receiving ET. Although the numbers of circulating CD4 and CD20 B cells were reduced in the post-menopausal group receiving ET, we also detected a better preservation of naïve B cells, decreased CD4 T cell inflammatory cytokine production, and slightly lower circulating levels of the pro-inflammatory cytokine IL-6. Following vaccination, young adult women generated more robust antibody and T cell responses than both post-menopausal groups. Despite similar vaccine responses between the two post-menopausal groups, we observed a direct correlation between plasma 17β estradiol (E2) levels and fold increase in IgG titers within the ET group. These findings suggest that ET affects immune homeostasis and that higher plasma E2 levels may enhance humoral responses in post-menopausal women.

Persistency with estrogen replacement therapy among hysterectomized women after the Women’s Health Initiative study

ABSTRACTObjectives Many women are reluctant to undergo estrogen replacement therapy (ERT) and discontinue the treatment within 12 months. The aim of this study was to investigate the persistence rates of ERT in hysterectomized women over the past decade, reflecting changes in the post-Women's Health Initiative (WHI) era.Methods We analyzed 8045 patients receiving ERT from 2004 to 2013 using the Disease Analyzer database.Results After 12 months of follow-up, only 24.6% of patients receiving 1 mg and 24.5% of patients receiving 2 mg of oral ERT were still on treatment (p < 0.0001). The persistency rate of patients receiving <50 μg of transdermal ERT was 28.6% compared to 33.5% for patients receiving >50 μg within the 12 months of follow-up. ERT that began in 2007–2009 was associated with a higher discontinuation rate (hazard ratio 1.06, p = 0.0660) than ERT that began in 2010–2013 (hazard ratio 0.88, p = 0.0001).Conclusions Our results indicate low persistency rates in women on ERT irrespective of the dose as well as the route of administration. However, a decrease in discontinuation rates was found when comparing women in the early vs. late post WHI era.

Mechanistic Progress of Estrogen-induced Apoptosis in Estrogen-deprived Breast Cancer Cells

The laboratory discovery of estrogen-induced apoptosis has been translated to treat antihormone resistant patients and to reduce the incidence of breast cancer in postmenopausal hysterectomized women with estrogen replacement therapy (ERT). The key step is the selection pressure exerted by long-term antiestrogen therapy or over 5 years of menopause to specific breast cancer cell populations that will be vulnerable to estrogen-induced apoptosis. However, the mechanisms underlying estrogen-induced apoptosis are currently unclear. At the cellular level, estrogen-induced apoptosis is dependent upon the estrogen receptor (ER), which can be completely blocked by antiestrogen ICI 182,780 or 4-hydroxytamoxifen (4-OHT). Knockdown of ER alpha, but not ER beta, through specific small interfering RNAs effectively blocks estrogen-induced apoptosis, indicating that the ER alpha subtype participates in apoptosis. Further examinations demonstrate that estrogen-induced apoptosis is due to accumulation of endoplasmic reticulum stress, inflammatory responses, and oxidative stress, which, in turn, activate the intrinsic mitochondrial pathway and the extrinsic death receptor pathway to complete the process. This contrasts with paclitaxel, which causes G2 arrest with immediate apoptosis. These stress responses are modulated by glucocorticoids and the c-Src inhibitor to block estrogen-induced apoptosis, but the mechanism for estrogen action is through a genomic pathway rather than a non-genomic pathway. In the nucleus, estrogen activates classic ERE-regulated endogenous genes, but the ERE transcriptional pathway does not directly participate in the estrogen-induced apoptosis in vitro or in vivo. Simultaneously, estrogen activates a non-classic transcriptional pathway involving the interaction of ER with transcription factors such as activator protein-1 (AP-1), which may regulate proliferation, stress responses, or apoptosis. Investigation of how AP-1 modulates the stress responses to trigger estrogen-induced apoptosis will ultimately uncover the mechanisms underlying estrogen-induced apoptosis.

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.

The successful use of high-dose synthetic estrogens to treat postmenopausal metastatic breast cancer is the first effective 'chemical therapy' proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) in postmenopausal hysterectomized women, which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen-induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long-term estrogen deprivation. However, estrogen-independent growth occurs through trial and error. At the cellular level, estrogen-induced apoptosis is dependent upon the presence of the estrogen receptor (ER), which can be blocked by nonsteroidal or steroidal antiestrogens. The shape of an estrogenic ligand programs the conformation of the ER complex, which, in turn, can modulate estrogen-induced apoptosis: class I planar estrogens (e.g., estradiol) trigger apoptosis after 24 h, whereas class II angular estrogens (e.g., bisphenol triphenylethylene) delay the process until after 72 h. This contrasts with paclitaxel, which causes G2 blockade with immediate apoptosis. The process is complete within 24 h. Estrogen-induced apoptosis is modulated by glucocorticoids and cSrc inhibitors, but the target mechanism for estrogen action is genomic and not through a nongenomic pathway. The process is stepwise through the creation of endoplasmic reticulum stress and inflammatory responses, which then initiate an unfolded protein response. This, in turn, initiates apoptosis through the intrinsic pathway (mitochondrial) with the subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a 5-year gap is necessary after menopause to permit the selection of estrogen-deprived breast cancer cell populations to cause them to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around menopause encourages growth of ER-positive tumor cells, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen-induced apoptosis can be orchestrated in the laboratory in estrogen-deprived breast cancers now supports the clinical findings regarding the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long-term antihormonal adjuvant therapy, and the results of treatment with ERT and ERT plus progestin in the Women's Health Initiative for women over the age of 60. Principles have emerged for understanding and applying physiological estrogen therapy appropriately by targeting the correct patient populations.

The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years

We examined the effect of estrogen avoidance on mortality rates among hysterectomized women aged 50 to 59 years. We derived a formula to relate the excess mortality among hysterectomized women aged 50 to 59 years assigned to placebo in the Women's Health Initiative randomized controlled trial to the entire population of comparable women in the United States, incorporating the decline in estrogen use observed between 2002 and 2011. Over a 10-year span, starting in 2002, a minimum of 18 601 and as many as 91 610 postmenopausal women died prematurely because of the avoidance of estrogen therapy (ET). ET in younger postmenopausal women is associated with a decisive reduction in all-cause mortality, but estrogen use in this population is low and continuing to fall. Our data indicate an associated annual mortality toll in the thousands of women aged 50 to 59 years. Informed discussion between these women and their health care providers about the effects of ET is a matter of considerable urgency.

Hysterectomy in young women associates with higher risk of stroke: A nationwide cohort study

Hysterectomy is a common procedure for treatment of numerous gynecologic diseases. However, reduction of endogenous sex hormone levels has been reported in hysterectomized women, and the association of hysterectomy with the cardiovascular risk remains controversial. We aimed to investigate the influence of hysterectomy on the risk of stroke and coronary heart disease, with adjustment for traditional risk factors. A nationwide population-based study was conducted using the Taiwan National Health Insurance database from 1 million sampling cohort data set. A total of 7605 women who underwent hysterectomy without simultaneous oophorectomy from 1997 to 2009 were identified. The control group consisted of 30,420 women without hysterectomy, selected by matching the age, hypertension, diabetes, dyslipidemia, and the commencement date of follow-up. A total of 558 strokes and 599 coronary heart diseases (CHD) developed during a median 7.24 years follow-up. The difference was not significant between women with and without hysterectomy for stroke (2.34 vs. 2.08 per 1000 person-year, p = 0.26) and CHD (2.39 vs. 2.26, p = 0.53). However, of the women who underwent hysterectomy before 45 years, the hazard ratio of hysterectomy was 2.29 (95% CI, 1.52-3.44) for stroke and 1.14 (95% CI, 0.71-1.83) for CHD. Categorized by the patients' age at operation, the associations between hysterectomy and the risk of stroke were different. The excess risk of stroke was observed in women who had hysterectomy before 45 years and remained significant even after accounting for baseline cardiovascular risk factors.