A comparison of letrozole regimens for ovulation induction in women with polycystic ovary syndrome.

Objective: To determine the optimal letrozole regimen for ovulation induction (OI) in women with polycystic ovary syndrome (PCOS). Design: Retrospective cohort study. Setting: Single academic fertility clinic from 2015-2022. Patients: A total of 189 OI cycles in 52 patients with PCOS. Interventions: Patients were prescribed 1 of 4 letrozole regimens (group 1: 2.5 mg for 5 days, group 2: 2.5 mg for 10 days, group 3: 5 mg for 5 days, and group 4: 5 mg for 10 days). Main outcome measures: The primary outcome was ovulation, and secondary outcomes included multifollicular development, and clinical pregnancy rate, which were analyzed with binary logistic regression. Kaplan-Meier cumulative response curves and a Cox proportional hazard regression model were used for time-dependent analyses. Results: Mean age was 30.9 years (standard deviation [SD], 3.6) and body mass index was 32.1 kg/m2 (SD, 4.0). Group 2 (odds ratio [OR], 9.12; 95% confidence interval [CI], 1.92-43.25), group 3 (OR, 3.40; 95% CI, 1.57-7.37), and group 4 (OR, 5.94; 95% CI, 2.48-14.23) had improved ovulation rates after the starting regimen as compared with group 1. Cumulative ovulation rates exceeded 84% in all groups, yet those who received 5 mg and/or 10 days achieved ovulation significantly sooner. Multifollicular development was not increased in groups 2-4 as compared with group 1. Groups 2-4 also demonstrated improved time to pregnancy. Conclusions: Ovulation rates are improved when starting with letrozole at 5 mg and/or a 10-day extended course as compared with the frequently-used 2.5 mg for 5 days. This may shorten time to ovulation and pregnancy.

The progestin revolution 2: progestins are now a dominant player in the tight interlink between contraceptive protection and bleeding control-plus more.

The interlink between bleeding control and contraceptive development has always been an important factor. But after many years of advances in contraceptive technology, this interplay has resulted in development of safer and better contraceptive methods that often offer significantly less bleeding for women with both normal bleeding patterns as well as in those suffering from heavy menstrual bleeding (HMB). Recognition of the success of progestin-only methods, such as the hormonal IUDs, progestin dominant oral contraceptives, and the high dose progestin-only pill in substantially decreasing and controlling menstrual bleeding has led the way. This recognition also led to the development of many [non-contraceptive] protocols to stop acute heavy bleeding as well as manage long-term bleeding [using contraceptive methods as well; as non-contraceptive methods].But even better, there is a new PLUS. The distinct benefit and risk profiles of the many different progestins now available are intentionally being used either in combination contraceptive pills [COCPs] or alone, to add additional benefits, to decrease side effects and risks, and increase effectiveness and bleeding control.

The association of hysterectomy with or without ovarian conservation with subclinical atherosclerosis progression in healthy postmenopausal women.

OBJECTIVE: While the deleterious associations of surgical menopause after bilateral oophorectomy with cardiovascular disease are documented, less is specifically known concerning subclinical atherosclerosis progression. METHODS: We used data from 590 healthy postmenopausal women randomized to hormone therapy or placebo in the Early versus Late Intervention Trial with Estradiol (ELITE), which was conducted from July 2005 to February 2013. Subclinical atherosclerosis progression was measured as annual rate of change in carotid artery intima-media thickness (CIMT) over a median 4.8 years. Mixed-effects linear models assessed the association of hysterectomy and bilateral oophorectomy compared with natural menopause with CIMT progression adjusted for age and treatment assignment. We also tested modifying associations by age at or years since oophorectomy or hysterectomy. RESULTS: Among 590 postmenopausal women, 79 (13.4%) underwent hysterectomy with bilateral oophorectomy and 35 (5.9%) underwent hysterectomy with ovarian conservation, a median of 14.3 years before trial randomization. Compared with natural menopause, women who underwent hysterectomy with and without bilateral oophorectomy had higher fasting plasma triglycerides while women who underwent bilateral oophorectomy had lower plasma testosterone. The CIMT progression rate in bilaterally oophorectomized women was 2.2 µm/y greater than natural menopause ( P = 0.08); specifically, compared with natural menopause, the associations were significantly greater in postmenopausal women who were older than 50 years at the time of bilateral oophorectomy ( P = 0.014) and in postmenopausal women who underwent bilateral oophorectomy more than 15 years before randomization ( P = 0.015). Moreover, the CIMT progression rate in hysterectomized women with ovarian conservation was 4.6 µm/y greater than natural menopause ( P = 0.015); in particular, compared with natural menopause, the association was significantly greater in postmenopausal women who underwent hysterectomy with ovarian conservation more than 15 years before randomization ( P = 0.018). CONCLUSIONS: Hysterectomy with bilateral oophorectomy and ovarian conservation were associated with greater subclinical atherosclerosis progression relative to natural menopause. The associations were stronger for later age and longer time since oophorectomy/hysterectomy. Further research should continue to examine long-term atherosclerosis outcomes related to oophorectomy/hysterectomy.

Utilizations and characteristics of ovarian conservation at hysterectomy for cervical carcinoma in situ.

OBJECTIVE: To examine the trends and characteristics of ovarian conservation at time of hysterectomy in cervical carcinoma in situ. METHODS: This is a retrospective cohort study examining the Healthcare Cost and Utilization Project's National Inpatient Sample, January 2016 to December 2019. The study population included 6605 patients aged less than 65 years with cervical carcinoma in situ who underwent hysterectomy. Exposure allocation was the adnexal procedure status (ovarian conservation vs. oophorectomy). Main outcome measures were temporal trends of ovarian conservation over time and per patient age. A classification-tree was constructed to examine utilization patterns of ovarian conservation. RESULTS: Ovarian conservation was performed in 57.2% of patients. Ovarian conservation rates were unchanged over time (P-trend = 0.219). Ovarian conservation rates remained stable until age 40 years, ranging from 88.0% to 78.6% (P-trend = 0.236), after which time the rate sharply decreased from 78.6% to 19.1% (P-trend <0.001). In a multivariable analysis, younger age, fewer comorbidities, higher household income, vaginal hysterectomy, and surgery at small bed capacity non-rural hospitals were associated with ovarian conservation (all, P < 0.05). There were 17 utilization patterns of ovarian conservation for which the rate ranged from 17.2% to 94.4% (absolute rate difference 77.2%, P < 0.001). CONCLUSION: Decrease in the utilization of ovarian conservation at hysterectomy for cervical carcinoma in situ occurred at age 40 years, which is earlier than expected.

Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment: protocol for a systematic review and individual participant data meta-analysis.

INTRODUCTION: Dietary and/or physical activity interventions are often recommended for women with overweight or obesity as the first step prior to fertility treatment. However, randomised controlled trials (RCTs) so far have shown inconsistent results. Therefore, we propose this individual participant data meta-analysis (IPDMA) to evaluate the effectiveness and safety of dietary and/or physical activity interventions in women with infertility and overweight or obesity on reproductive, maternal and perinatal outcomes and to explore if there are subgroup(s) of women who benefit from each specific intervention or their combination (treatment-covariate interactions). METHODS AND ANALYSIS: We will include RCTs with dietary and/or physical activity interventions as core interventions prior to fertility treatment in women with infertility and overweight or obesity. The primary outcome will be live birth. We will search MEDLINE, Embase, Cochrane Central Register of Controlled Trials and trial registries to identify eligible studies. We will approach authors of eligible trials to contribute individual participant data (IPD). We will perform risk of bias assessments according to the Risk of Bias 2 tool and a random-effects IPDMA. We will then explore treatment-covariate interactions for important participant-level characteristics. ETHICS AND DISSEMINATION: Formal ethical approval for the project (Venus-IPD) was exempted by the medical ethics committee of the University Medical Center Groningen (METc code: 2021/563, date: 17 November 2021). Data transfer agreement will be obtained from each participating institute/hospital. Outcomes will be disseminated internationally through the collaborative group, conference presentations and peer-reviewed publication. PROSPERO REGISTRATION NUMBER: CRD42021266201.

Effect of menopausal hormone therapy on arterial wall echomorphology: Results from the Early versus Late Intervention Trial with Estradiol (ELITE).

OBJECTIVE: To evaluate the effect of hormone therapy (HT) on arterial wall composition by ultrasound. BACKGROUND: The effect of HT on the progression of subclinical atherosclerosis has been well-described using measurements of common carotid artery (CCA) wall thickness. However, it is unknown whether the change in arterial wall anatomic structure is accompanied by an effect of HT on arterial wall composition. METHODS: A total of 643 healthy postmenopausal women divided into two strata according to the time since menopause (<6 years, the early-postmenopause group; or >10 years, the late-postmenopause group) were randomized to receive either active treatment or placebo. For hysterectomized women, the active treatment was oral micronized 17ß-estradiol 1 mg/day; for women with a uterus, 4% vaginal micronized progesterone gel 45 mg/day for 10 days each month was added to the estradiol regimen. Gray-scale median of the CCA intima-media complex (IM-GSM), a (unitless) measurement of arterial wall composition based on echogenicity, was determined by high-resolution B-mode ultrasonography. Lower IM-GSM, or less echogenicity, indicates more atherosclerosis. IM-GSM and serum estradiol (E2) concentration were assessed every 6 months over a median 4.8-year trial period. Linear mixed effects regression models were used for all analyses. RESULTS: Overall, IM-GSM progression/year had a negative trajectory, reflecting reduction in echogenicity over time (worsening atherosclerosis). HT effects on IM-GSM progression/year differed by postmenopause strata (interaction p-value = 0.02). IM-GSM progression/year (95% CI) in the early postmenopause group randomized to HT was -0.50 (-0.82, -0.18)/year compared with -1.47 (-1.81, -1.13)/year among those randomized to placebo (p-value <0.0001). In the late postmenopause group, the annual IM-GSM progression rate did not significantly differ between HT and placebo (p = 0.28). Higher mean on-trial E2 (pg/ml) levels were associated with higher IM-GSM progression, indicating less atherosclerosis progression in all women (ß (95% CI) = 0.006 (0.0003, 0.01), p = 0.04). For each pg/dl E2, IM-GSM progression/year was 0.007 ((-0.0002, 0.01), p = 0.056) in the early and 0.003 ((-0.006, 0.01), p = 0.50) in the late postmenopause group (interaction p-value = 0.51). CIMT progression rate (µm/year) was significantly inversely associated with the IM-GSM progression (ß (95% CI) = -4.63 (-5.6, -3.7), p < 0.001). CONCLUSIONS: HT, primarily with oral estradiol, reduced atherogenic progression of arterial wall composition in healthy postmenopausal women who were within 6 years from menopause. TRIAL REGISTRATION NUMBER: NCT01553084.

Substantial variability in ovarian conservation at hysterectomy for endometrial hyperplasia.

BACKGROUND: Although ovarian conservation at hysterectomy for benign gynecologic disease has demonstrated mortality benefit in young patients and this benefit may be sustained up to age 65 years, there is a scarcity of data regarding ovarian conservation in those with a diagnosis of endometrial hyperplasia, a premalignant uterine condition. OBJECTIVE: This study aimed to examine patient, hospital, treatment, and histology characteristics related to ovarian conservation at the time of inpatient hysterectomy for endometrial hyperplasia. STUDY DESIGN: The Healthcare Cost and Utilization Project's National Inpatient Sample was retrospectively queried to examine patients aged ≤65 years with endometrial hyperplasia who had inpatient hysterectomy from January 2016 to December 2019. The exclusion criteria included concurrent gynecologic malignancy, adnexal pathology, and lymphadenectomy. Cases were grouped by adnexal surgery status (ovarian conservation or oophorectomy). A multivariable binary logistic regression model was used to identify independent characteristics for ovarian conservation. A classification tree was constructed with recursive partitioning analysis to examine utilization patterns of ovarian conservation. RESULTS: Overall, 3105 patients (31.1%) underwent ovarian conservation at hysterectomy among 9975 patients. The utilization of ovarian conservation decreased gradually until age 45 years and then markedly decreased by age 52 years (63.3%-15.3%; P<.001). In a multivariable analysis, younger age, non-White, urban nonteaching centers, and vaginal hysterectomy were associated with increased utilization of ovarian conservation, whereas endometrial hyperplasia with atypia, obesity, comorbidity, large bed capacity centers, and Midwest and South regions were associated with decreased utilization of ovarian conservation (all, P<.05). A classification tree identified 17 utilization patterns for ovarian conservation, ranging from 7.8% to 100.0% (absolute rate difference, 92.2%). CONCLUSION: The utilization of ovarian conservation at the time of inpatient hysterectomy in patients undergoing surgical management for endometrial hyperplasia started decreasing in their mid-40s and seemed to occur earlier than in benign hysterectomy. There was substantial variability in ovarian conservation at the time of hysterectomy for endometrial hyperplasia based on patient, hospital, surgical, and histology factors, suggesting the possible benefit of clinical practice guidelines for ovarian conservation in this population.

Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women.

OBJECTIVES: To compare the effect of oral estradiol (E2) plus vaginal progesterone (P4) against placebo on endometrial thickness, endometrial biopsy pathology, cervical cytology and total cancer incidence among healthy postmenopausal women. STUDY DESIGN: This study is a sub-analysis of the Early versus Late Intervention Trial with Estradiol (ELITE), a randomized, double-blinded, placebo-controlled trial that previously demonstrated that hormone therapy (HT) was associated with less progression of subclinical atherosclerosis than placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. This sub-analysis included only ELITE participants with an intact uterus, who were randomized to either daily oral micronized 17-beta-E2 1 mg/day with 4% vaginal micronized P4 gel 45 mg/day for 10 days each month or placebo. MAIN OUTCOME MEASURES: Participants were evaluated at baseline and annually during a median follow-up of 4.8 years for endometrial thickness as determined by pelvic transvaginal ultrasound followed by an endometrial biopsy when indicated, and cervical cytology and cancer incidence. RESULTS: Over up to 80 months of follow-up, participants randomized to oral E2 plus vaginal P4 had progressive and statistically significant increases in endometrial thickness (p<0.001), underwent more endometrial biopsies and had a higher rate of endometrial hyperplasia on endometrial biopsy compared with the placebo group. Due to the close follow-up of participants in the trial protocol, these abnormal findings were effectively treated. CONCLUSION: Our results suggest that 10 days of vaginal P4 45 mg/day is insufficient to completely oppose the effect of oral E2 1 mg/day on the endometrium. Further studies are needed to test alternative doses or frequencies of administration of vaginal P4 for adequate endometrial protection from E2 therapy among postmenopausal women. ClinicalTrials.gov registration NCT00114517.

The Progestin Revolution: progestins are arising as the dominant players in the tight interlink between contraceptives and bleeding control.

Since the introduction of the first modern contraceptive methods, the interlink between bleeding control and contraceptive development has been a dominant and critical factor. This interplay has led to the development of safer and better contraceptive methods that are often used to control bleeding in both women with normal bleeding patterns as well as in those suffering from heavy menstrual bleeding (HMB). The success of progestin-only methods, such as hormonal IUDs or progestin dominant oral contraceptives in substantially decreasing and controlling menstrual bleeding, has led to development of multiple progestin-only protocols for the sole purpose of bleeding control. These include protocols designed to stop acute heavy bleeding as well as manage long-term bleeding. Recent publications describe a variety of protocols using high dose oral progestin pills with or without a medroxyprogesterone acetate (MPA) injection that demonstrate high effectiveness and good tolerability. Comparted to many other progestins, MPA is not converted in part into ethinyl estradiol and appears to have a progestin-only advantage. Norethindrone acetate (NET acetate) is converted in part to ethinyl estradiol and therefore is an especially good option for bleeding control in patients with low estrogen levels that would benefit from estrogen replacement (such as in premenopausal women with premature menopause or hypothalamic hypogonadism).

Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy.

OBJECTIVE: To identify factors associated with serum estradiol (E2) levels among healthy postmenopausal women using hormone therapy (HT). METHODS: This is an unplanned post hoc analysis of data from ELITE (Early versus Late Intervention Trial with Estradiol), a randomized controlled trial of 1 mg oral E2 with or without vaginal progesterone in healthy early compared with late (<6 years compared with 10 or more years since menopause) postmenopausal women. We included results from visits when women reported at least 80% compliance with HT. Mixed-effects linear models identified factors associated with serum E2 levels while participants were taking HT, assessed every 6 months over a median follow-up of 4.8 years and adjusted for baseline E2 level, visit, and reduced E2 dose. Possible correlates evaluated included demographics, clinical characteristics, medication use, and biomarkers of liver and kidney metabolic function. RESULTS: The analysis included 2,160 E2 measurements in 275 postmenopausal women. Mean±SD age was 55.4±3.9 vs 64.4±5.5 years, and mean±SD time since menopause was 3.6±1.8 vs 16.0±5.6 years for early vs late postmenopausal women. Adjusted for pretreatment E2 level, visit, and reduced dose indicator, higher serum E2 levels were associated with higher body mass index (BMI), higher weight, surgical menopause, alcohol use, and antihypertensive medication use. Current and past smoking and antifungal medication use were associated with lower serum E2 levels. In the multivariable model, higher BMI and alcohol use were associated with higher serum E2 levels, whereas current and past smoking were associated with lower serum E2 levels. These factors were similar between early and late postmenopausal women. CONCLUSION: Factors associated with serum E2 levels among postmenopausal women taking HT include BMI, alcohol use, and smoking. As serum E2 levels relate to HT effect, achievement of desirable E2 levels may be maximized through personalized intervention. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00114517.

Patterns of utilization and outcome of ovarian conservation for young women with minimal-risk endometrial cancer.

OBJECTIVE: To profile patient characteristics associated with and outcomes of ovarian conservation at the time of hysterectomy in young women with minimal-risk endometrial cancer. METHODS: A population-based retrospective analysis of the Nationwide Inpatient Sample between 2007 and 2015 was performed. Women aged <50 with minimal-risk endometrial cancer who had ovarian conservation (n = 2314) were compared to those who had oophorectomy (n = 8191). A classification-tree model with recursive partitioning analysis was constructed to examine patterns of ovarian conservation. Propensity score matching was performed and length of stay and perioperative complications were compared. Two validation cohorts were also analyzed in a similar fashion (benign gynecologic disease and cervical cancer). RESULTS: There were nine distinct patterns of patient characteristics identified, and ovarian conservation rates ranged from 11.7% (women aged 40-49 who underwent abdominal hysterectomy at an urban teaching hospital) to 60.5% (non-obese women aged <40 with median household income ≥$63,000) (absolute difference, 48.8%, 95% confidence interval 39.9-57.7; P < 0.001). After propensity score matching, ovarian conservation was significantly associated with a decreased likelihood of hospitalization >2 days (relative risk reduction, 16.7%, P < 0.001). Rates of surgical complications were not different between the two groups (8.2% versus 8.3%, P = 0.91). In the benign gynecologic disease and cervical cancer cohorts, ovarian conservation was also associated with decreased length of hospitalization (all, P < 0.05). CONCLUSION: There is substantial variability in the utilization of ovarian conservation in young women with minimal-risk endometrial cancer based on patient, surgical, and hospital factors. Our study suggests that guidelines for ovarian conservation in this population would be helpful for improving patient selection and rates of ovarian conservation.

Differential Effect of Plasma Estradiol on Subclinical Atherosclerosis Progression in Early vs Late Postmenopause.

Context: The Early vs Late Intervention Trial with Estradiol showed that hormone therapy (HT) reduced progression of atherosclerosis when initiated in early but not in late postmenopause. Objective: This posttrial analysis examined the association between plasma estradiol (E2) levels and atherosclerosis determined by rate of change in carotid artery intima-media thickness (CIMT) and tested whether this association is equally evident in early (<6 years) vs late (≥10 years) postmenopause. Design: Randomized controlled trial stratified by time since menopause (ClinicalTrials.gov no. NCT00114517). Mixed-effects linear models tested the association of E2 levels with CIMT rate of change. Setting: Los Angeles, California. Participants: Healthy women in postmenopause. Intervention: Oral E2 with/without cyclic vaginal progesterone. Main Outcome Measures: Plasma E2 levels and CIMT assessed every 6 months over an average of 4.8 years. Results: Among 596 women in postmenopause, higher E2 level was inversely associated with CIMT progression in those in early postmenopause (P = 0.041) and positively associated with CIMT progression in those in late postmenopause (P = 0.006) (P for interaction <0.001). CIMT progression rates for the lowest vs highest quartile of E2 levels among women in early postmenopause were 8.5 and 7.2 µm/y, respectively , whereas among women in late postmenopause they were 9.8 and 11.7 µm/y, respectively. Conclusion: E2 levels were differentially associated with atherosclerosis progression according to timing of HT initiation. With higher E2 levels, CIMT progression rate was decreased among women in early postmenopause but increased among women in late postmenopause. These results support the timing hypothesis of HT initiation on cardiovascular benefit, with reduced atherosclerosis progression for initiation during early postmenopause.

Ovarian Conservation and Overall Survival in Young Women With Early-Stage Cervical Cancer.

OBJECTIVE: To identify predictors of ovarian conservation at hysterectomy and to examine the association of ovarian conservation and survival of young women with early-stage cervical cancer. METHODS: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results Program to identify hysterectomy-based surgically treated patients with stage I cervical cancer diagnosed between 1983 and 2012 (N=16,511). Multivariable models were used to identify independent factors associated with ovarian conservation. Among the subgroup of 9,419 women younger than 50 years of age with stage I disease, survival outcomes and causes of death were examined for 3,908 (41.5%) women who underwent ovarian conservation at hysterectomy without radiotherapy. RESULTS: On multivariable analysis, age younger than 50 years, stage IA disease, and squamous histology were independent factors associated with ovarian conservation (all, P<.001). Among 5,526 women younger than 50 years of age with stage IA disease who underwent hysterectomy without radiotherapy, overall survival was significantly higher in patients undergoing ovarian conservation than in those undergoing oophorectomy (20-year rate, 93.5% compared with 86.8%, P<.001); cervical cancer-specific survival was similar between the patients who underwent ovarian conservation and those who underwent oophorectomy (98.8% compared with 97.8%, P=.12). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.63, 95% confidence interval [CI] 0.49-0.82, P=.001) and was independently associated with lower cumulative risks of death resulting from cardiovascular disease (20-year cumulative rate, 1.2% compared with 3.3%, adjusted hazard ratio 0.47, 95% CI 0.26-0.86, P=.014) and other chronic disease (0.5% compared with 1.4%, adjusted hazard ratio 0.24, 95% CI 0.09-0.65, P=.005) compared with oophorectomy. Both cervical cancer-specific survival (20-year rate, 93.1% compared with 92.0%, P=.37) and overall survival (86.7% compared with 84.6%, P=.12) were similar between ovarian conservation and oophorectomy among 3,893 women younger than 50 years of age with stage IB disease who underwent hysterectomy without radiotherapy. CONCLUSION: Among young women with stage IA cervical cancer, ovarian conservation at hysterectomy is associated with decreased all-cause mortality including death resulting from cardiovascular disease and other chronic diseases.

Ovarian Conservation and Overall Survival in Young Women With Early-Stage Low-Grade Endometrial Cancer.

OBJECTIVE: To characterize contributing factors for ovarian conservation during surgical treatment for endometrial cancer and to examine the association of ovarian conservation on survival of young women with early-stage, low-grade tumors. METHODS: This was a population-based study using the Surveillance, Epidemiology, and End Results program to identify surgically treated stage I type I (grade 1-2 endometrioid histology) endometrial cancer cases diagnosed between 1983 and 2012 (N=86,005). Multivariable models were used to identify independent factors for ovarian conservation. Survival outcomes and cause of death were examined for women aged younger than 50 with stage I type I endometrial cancer who underwent ovarian conservation (1,242 among 12,860 women [9.7%]). RESULTS: On multivariable analysis, age younger than 50 years, grade 1 endometrioid histology, and tumor size 2.0 cm or less were noted to be independent factors for ovarian conservation (all, P<.001). For 9,110 women aged younger than 50 years with stage I grade 1 tumors, cause-specific survival was similar between ovarian conservation and oophorectomy cases (20-year rates 98.9% compared with 97.7%, P=.31), whereas overall survival was significantly higher in ovarian conservation cases than oophorectomy cases (88.8% compared with 82.0%, P=.011). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.73, 95% confidence interval [CI] 0.54-0.98, P=.036) and was independently associated with a lower cumulative risk of death resulting from cardiovascular disease compared with oophorectomy (20-year rates, 2.3% compared with 3.7%, adjusted hazard ratio 0.40, 95% CI 0.17-0.91, P=.029). Contrary, cause-specific survival (20-year rates 94.6% compared with 96.1%, P=.68) and overall survival (81.0% compared with 80.6%, P=.91) were similar between ovarian conservation and oophorectomy among 3,750 women aged younger than 50 years with stage I grade 2 tumors. CONCLUSION: Ovarian conservation is performed in less than 10% of young women with stage I type I endometrial cancer. Ovarian conservation is associated with decreased mortality in young women with stage I grade 1 tumors.

Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis.

OBJECTIVE: To test the hypothesis that effects of estrogen-containing hormone therapy on cognitive abilities differ between postmenopausal women near to, and further from, menopause. METHODS: In this randomized, double-blind, placebo-controlled trial, healthy women within 6 years of menopause or 10+ years after menopause were randomly assigned to oral 17ß-estradiol 1 mg/d or placebo. Women with a uterus received cyclic micronized progesterone vaginal gel or placebo. The primary outcome assessed at 2.5 and 5 years, compared between treatment groups, was change in a standardized composite of neuropsychological test scores assessing verbal episodic memory. Secondary outcomes assessed executive functions and global cognition. RESULTS: A total of 567 women were included in modified intention-to-treat analyses after a mean treatment duration of 57 months. For verbal memory, the mean estradiol minus placebo standardized difference in composite scores (-0.06, 95% confidence interval -0.22 to 0.09) was not significant (2-tailed p = 0.33). Differences were similar in early and late postmenopause groups (2-tailed interaction p = 0.88). Interactions between postmenopause groups and differences between treatment groups were not significant for executive functions or global cognition. CONCLUSIONS: Estradiol initiated within 6 years of menopause does not affect verbal memory, executive functions, or global cognition differently than therapy begun 10+ years after menopause. Estradiol neither benefits nor harms these cognitive abilities regardless of time since menopause. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that estradiol initiated within 6 years of menopause does not affect cognition at 2.5 years differently than estradiol initiated 10+ years after menopause.

Rationale for Developing a Specimen Bank to Study the Pathogenesis of High-Grade Serous Carcinoma: A Review of the Evidence.

Women with clinically detected high-grade serous carcinomas (HGSC) generally present with advanced-stage disease, which portends a poor prognosis, despite extensive surgery and intensive chemotherapy. Historically, HGSCs were presumed to arise from the ovarian surface epithelium (OSE), but the inability to identify early-stage HGSCs and their putative precursors in the ovary dimmed prospects for advancing our knowledge of the pathogenesis of these tumors and translating these findings into effective prevention strategies. Over the last decade, increased BRCA1/2 mutation testing coupled with performance of risk-reducing surgeries has enabled studies that have provided strong evidence that many, but probably not all, HGSCs among BRCA1/2 mutation carriers appear to arise from the fallopian tubes, rather than from the ovaries. This shift in our understanding of the pathogenesis of HGSCs provides an important opportunity to achieve practice changing advances; however, the scarcity of clinically annotated tissues containing early lesions, particularly among women at average risk, poses challenges to progress. Accordingly, we review studies that have kindled our evolving understanding of the pathogenesis of HGSC and present the rationale for developing an epidemiologically annotated national specimen resource to support this research. Cancer Prev Res; 9(9); 713-20. ©2016 AACR.

Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol.

BACKGROUND: Data 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. METHODS: A 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 17ß-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. RESULTS: After 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. CONCLUSIONS: Oral 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.).

Contributing factors for menopausal symptoms after surgical staging for endometrial cancer.

OBJECTIVE: The aim of the study was to examine contributing factors associated with developing menopausal symptoms after surgical staging in women with endometrial cancer. METHODS: This is a retrospective study examining patients with endometrial cancer who were premenopausal at the time of hysterectomy-based surgical staging including bilateral oophorectomy between January 2000 and October 2013. Cox proportional hazard regression model was used to evaluate demographics, medical comorbidity, liver function tests, tumor factors, and medication history for menopausal symptoms. RESULTS: There were 269 premenopausal women who were eligible. Mean age was 44.5 years, and the majority had endometrioid histology (91.1%), grade 1 tumor (60.2%), and stage I disease (65.8%). Postoperatively, 73 (27.1%) women developed menopausal symptoms, with hot flushes (20.1%) being the most common symptom followed by night sweats (4.1%). On multivariate analysis, younger age was independently associated with increased risk of developing menopausal symptoms (hazard ratio per unit 0.91, 95% CI 0.88-0.94, P < 0.01). In addition, lower albumin level remained an independent predictor for decreased risk of developing menopausal symptoms (hazard ratio per unit 2.16, 95% CI 1.19-3.93, P = 0.012). Lower albumin level was associated with medical comorbidity (hypertension and diabetes mellitus), use of antihypertensive/glycemic agents (angiotensin-converting enzyme inhibitors or receptor blocker, hydrochlorothiazide, sulfonylurea, and insulin), aggressive tumor (high cancer antigen 125 level, nonendometrioid histology, and advanced stage), and abnormal liver function (high alkaline phosphatase level and low total protein level; all, P < 0.05). CONCLUSIONS: Assessing albumin level, medical comorbidity, and medication type for the development of postoperative menopausal symptoms is a valuable step in the preoperative management of women with endometrial cancer.

Surgical menopause and increased risk of nonalcoholic fatty liver disease in endometrial cancer.

OBJECTIVE: Our objective was to examine risk factors associated with development of nonalcoholic fatty liver disease (NAFLD) among women with endometrial cancer who underwent surgical staging with or without oophorectomy. METHODS: This is a retrospective study that evaluated endometrial cancer cases that underwent surgical staging (n = 666) and endometrial hyperplasia cases that underwent hysterectomy-based treatment (n = 209). This study included 712 oophorectomy cases and 163 nonoophorectomy cases. Archived records were reviewed for participant demographics, medical comorbidities, operative notes, histology results, and radiology reports for NAFLD. Cumulative risks of NAFLD after surgical operation were correlated to demographics and medical comorbidities. RESULTS: The cumulative prevalence of NAFLD in 875 women with endometrial tumor was 14.1%, 20.5%, and 38.4% at 1, 2, and 5 years after surgical operation, respectively. On multivariate analysis, after controlling for age, ethnicity, body mass index, medical comorbidities, tumor type, hormonal treatment pattern, and oophorectomy status, age younger than 40 years (2-y cumulative prevalence, 26.6% vs 16.8%; hazard ratio [HR], 1.85; 95% CI, 1.27-2.71; P = 0.001) and age 40 to 49 years (2-y cumulative prevalence, 23.1% vs 16.8%; HR, 1.49; 95% CI, 1.08-2.04; P = 0.015) remained significant predictors for developing NAFLD after surgical operation compared with age 50 years or older. Oophorectomy was an independent predictor for increased risk of NAFLD (20.9% vs 15.9%; HR, 1.70; 95% CI, 1.01-2.86; P = 0.047). In addition, NAFLD was significantly associated with postoperative development of diabetes mellitus (39.2% vs 15.3%; HR, 2.26; 95% CI, 1.52-3.35; P < 0.0001) and hypercholesterolemia (34.3% vs 17.5%; HR, 1.71; 95% CI, 1.12-2.63; P = 0.014). CONCLUSIONS: Oophorectomy in young women with endometrial cancer significantly increases the risk of NAFLD. This is associated with development of diabetes mellitus and hypercholesterolemia after oophorectomy.