Loss of Ovarian Hormones and Accelerated Somatic and Mental Aging.

Bilateral oophorectomy in premenopausal women is a unique condition causing the abrupt and premature loss of ovarian hormones, primarily estrogen. Bilateral oophorectomy causes an alteration of several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival. However, many questions remain unanswered.

Evaluating the efficacy of vaginal dehydroepiandosterone for vaginal symptoms in postmenopausal cancer survivors: NCCTG N10C1 (Alliance).

BACKGROUND: Women with estrogen deficiencies can suffer from vaginal symptoms that negatively impact sexual health. This study evaluated vaginal dehydroepiandrosterone (DHEA) for alleviation of vaginal symptoms. METHODS: This three-arm randomized, controlled trial evaluated DHEA 3.25 mg and DHEA 6.5 mg, each compared to a plain moisturizer (PM) over 12 weeks, to improve the severity of vaginal dryness or dyspareunia, measured with an ordinal scale, and overall sexual health using the Female Sexual Function Index (FSFI). Postmenopausal women with a history of breast or gynecologic cancer who had completed primary treatment, had no evidence of disease, and reported at least moderate vaginal symptoms were eligible. The mean change from baseline to week 12 in the severity of vaginal dryness or dyspareunia for each DHEA dose was compared to PM and analyzed by two independent t tests using a Bonferroni correction. RESULTS: Four hundred sixty-four women were randomized. All arms reported improvement in either dryness or dyspareunia. Neither DHEA dose was statistically significantly different from PM at 12 weeks (6.25 mg, p = .08; 3.25 mg, p = 0.48), although a significant difference at 8 weeks for 6.5 mg DHEA was observed (p = 0.005). Women on the 6.5 mg arm of DHEA reported significantly better sexual health on the FSFI (p < 0.001). There were no significant differences in provider-graded toxicities and few significant differences in self-reported side effects. CONCLUSION: PM and DHEA improved vaginal symptoms at 12 weeks. However, vaginal DHEA, 6.5 mg, significantly improved sexual health. Vaginal DHEA warrants further investigation in women with a history of cancer.

Systemic and local effects of vaginal dehydroepiandrosterone (DHEA): NCCTG N10C1 (Alliance).

BACKGROUND: Dehydroepiandrosterone (DHEA) is helpful for treating vaginal symptoms. This secondary analysis evaluated the impact of vaginal DHEA on hormone concentrations, bone turnover, and vaginal cytology in women with a cancer history. METHODS: Postmenopausal women, diagnosed with breast or gynecologic cancer, were eligible if they reported at least moderate vaginal symptoms. Participants could be on tamoxifen or aromatase inhibitors (AIs). Women were randomized to 3.25 versus 6.5 mg/day of DHEA versus a plain moisturizer (PM) control. Sex steroid hormone levels, biomarkers of bone formation, vaginal pH, and maturation index were collected at baseline and 12 weeks. Analysis included independent t tests and Wilcoxon rank tests, comparing each DHEA arm with the control. RESULTS: Three hundred forty-five women contributed evaluable blood and 46 contributed evaluable cytology and pH values. Circulating DHEA-S and testosterone levels were significantly increased in those on vaginal DHEA in a dose-dependent manner compared to PM. Estradiol was significantly increased in those on 6.5 mg/day DHEA but not in those on 3.25 mg/day DHEA (p < 0.05 and p = 0.05, respectively), and not in those on AIs. Biomarkers of bone formation were unchanged in all arms. Maturation of vaginal cells was 100% (3.25 mg/day), 86% (6.5 mg/day), and 64% (PM); pH decreased more in DHEA arms. CONCLUSION: DHEA resulted in increased hormone concentrations, though still in the lowest half or quartile of the postmenopausal range, and provided more favorable effects on vaginal cytology, compared to PM. Estrogen concentrations in women on AIs were not changed. Further research on the benefit of vaginal DHEA is warranted in hormone-dependent cancers.

Outcomes in women age 40 years and older with cytologically benign endometrial cells.

OBJECTIVE: We sought to estimate cytologically benign endometrial cell (CBEC)-associated endometrial hyperplasia and cancer rates, and describe clinical and histologic outcomes. STUDY DESIGN: Medical records of women age >40 years with CBEC in 2005 through 2010 were reviewed for clinical characteristics; assessment with endometrial biopsy, ultrasound, or hysteroscopy; and consequent outcomes. RESULTS: Of 658 women, 281 (42.7%) were assessed: 39.4% of 330 premenopausal, and 46.0% of 328 postmenopausal women. Among these, cancer rate was 3.6% and differed between premenopausal (0.8%) and postmenopausal (6.0%) women (P = .019). Hyperplasia rate was similar in premenopausal (3.9%) and postmenopausal (3.3%) women. Of 20 assessed women with endometrial pathology, 4 (1 premenopausal) women with cancer and 4 (2 premenopausal) women with hyperplasia had no abnormal bleeding. CONCLUSION: Cancer was more common in postmenopausal women with assessed CBEC while hyperplasia was comparably distributed between premenopausal and postmenopausal women. Findings support CBEC assessment regardless of menopausal status or abnormal bleeding.

Hormonal contraception and migraine: clinical considerations.

Migraine is highly prevalent in women, particularly in the reproductive years when contraception may be needed. Preventive strategies are known to be underutilized for migraine. Women of reproductive age may not only benefit from the use of hormonal contraceptives for contraception, but also for the purpose of reducing the burden of menstrual-related migraine. Although migraine is associated with an increased risk of stroke, the use of low-dose hormonal contraceptives in otherwise healthy women does not appear to confer additional risk.

Hysterectomy, oophorectomy, estrogen, and the risk of dementia.

BACKGROUND: The long-term cognitive effects of hysterectomy and oophorectomy remain controversial. OBJECTIVE: To explore the association of hysterectomy and oophorectomy with the subsequent risk of cognitive impairment or dementia. METHODS: We combined the results from two cohort studies graphically and conducted additional analyses. RESULTS: Combined results from the Mayo Clinic Cohort Study of Oophorectomy and Aging and from a Danish nationwide cohort study suggest that the extent of gynecologic surgery may correlate with a stepwise increase in the risk of cognitive impairment or dementia. Compared with women with no gynecologic surgeries, the risk of cognitive impairment or dementia was increased in women who had hysterectomy alone, further increased in women who had hysterectomy with unilateral oophorectomy, and further increased in women who had hysterectomy with bilateral oophorectomy. The risk increased with younger age at the time of the surgery. CONCLUSION: We hypothesize that both hysterectomy and oophorectomy may have harmful brain effects via direct endocrinological mechanisms or other more complex mechanisms. Estrogen deficiency appears to play a key role in these associations, and estrogen therapy may partly offset the negative effects of the surgeries.

Reassessing hysterectomy.

Hysterectomy is widely used for treating a variety of gynecologic conditions. Most hysterectomies are elective and are performed to treat benign indications for which there are other effective alternatives. Observational studies are increasingly highlighting the effects of hysterectomy and concomitant oophorectomy on a variety of long-term health outcomes including fracture risk, pelvic floor dysfunction, all-cause mortality, cardiovascular disease, and neurologic function. Individualizing therapy and discussing appropriate alternatives to hysterectomy is an important responsibility for all health care providers.

Hormonal manipulation strategies in the management of menstrual migraine and other hormonally related headaches.

Menstrual migraine and other hormonally related headaches are common in women. Falling estrogen levels or estrogen withdrawal after periods of sustained higher levels can trigger migraine. It makes sense to target this trigger for management of hormonally related headaches, particularly when nonhormonal strategies have been unsuccessful. Decision making regarding the use of hormonal contraception and menopausal hormone therapy is complex and commonly driven by other factors, but hormonal manipulation can potentially improve the course of migraine. Providers caring for migraineurs are appropriately concerned about stroke risk. Estrogen-containing hormonal contraceptives are relatively contraindicated for women who have migraine with aura. Postmenopausal hormone therapy is acceptable for women with a history of migraine. For these women, transdermal estradiol is recommended. Estrogen replacement is important for women who undergo an early menopause, whether natural or induced. Practical strategies for hormonal manipulation in the management of migraine and other hormonally related headaches are presented.

Predictors of patient comfort and adherence with less frequent cervical cancer screening.

BACKGROUND: The Papanicolaou (Pap) test is an effective, well-accepted screening tool that has led to a decrease in cervical cancer incidence and mortality. Updated evidence-based cervical cancer screening guidelines support less frequent testing in low-risk patients but have met resistance from providers and patients. AIMS: To assess patient knowledge about cervical cancer screening and attitudes toward recommendations for less frequent testing. METHODS: A hard copy of an eight-question survey was distributed to 389 women aged 30-64 years at two primary care clinics in Rochester, Minnesota, over a six-week period. RESULTS: The survey response rate was 86.8%. Of the 280 women who responded to a survey question about the cause of cervical cancer, 212 (75.7%) identified human papillomavirus (HPV) as the cause. Multivariable logistic regression analysis showed that this knowledge was not associated with feeling comfortable with a recommendation for less frequent testing or with support for less frequent testing. The only significant predictor of patient comfort and adherence with a two- to three-year Pap testing interval was the patient's belief about whether a Pap test was needed annually or every two or three years. CONCLUSIONS: Patient belief about Pap testing frequency was the strongest predictor of attitude toward less frequent Pap testing and was not based on knowledge of HPV. Future studies should explore why some patients continue to expect annual testing and identify interventions to help providers elicit and change patients' expectations about cervical cancer screening.

Oophorectomy, menopause, estrogen, and cognitive aging: the timing hypothesis.

BACKGROUND: The concept of neuroprotective effects of estrogen in women remains controversial. OBJECTIVE: To explore the timing hypothesis in relation to cognitive aging and dementia. METHODS: We reviewed existing literature, conducted some reanalyses, and combined results graphically. RESULTS: Current evidence suggests that estrogen may have either protective effects or harmful effects on the brain depending on age, type of menopause (natural versus surgical), or stage of menopause. The comparison of women with ovarian conservation versus women who underwent bilateral oophorectomy provided evidence for a sizeable neuroprotective effect of estrogen in women in the premenopausal years (most commonly before age 50 years). Several case-control studies and cohort studies also showed a neuroprotective effect in women who received estrogen treatment in the early postmenopausal phase (most commonly at ages 50-60 years). However, recent clinical trials showed that women who initiated estrogen treatment in the late postmenopausal phase (ages 65-79 years) experienced an increased risk of dementia and cognitive decline. CONCLUSION: The neuroprotective effects of estrogen depend on age, type of menopause, and stage of menopause (timing hypothesis).

Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: A population-based case-control study.

OBJECTIVES: We investigated the association of personal, reproductive, and familial characteristics with bilateral oophorectomy performed for nonmalignant indications in a US population. STUDY DESIGN: In an established cohort study, we used the records-linkage system of the Rochester Epidemiology Project (REP http://www.rochesterproject.org) to identify 1653 premenopausal women who underwent bilateral oophorectomy in Olmsted County, Minnesota between 1988 and 2007 for a nonmalignant indication. Each woman was matched by age (±1 year) to a population-based referent woman who had not undergone bilateral oophorectomy as of the index date. We used case-control analyses to investigate several characteristics associated with bilateral oophorectomy. Odds ratios and their 95% confidence intervals were adjusted for race, education, and income. RESULTS: In the overall analyses, infertility was more common in women who underwent bilateral oophorectomy than in the controls, whereas use of oral contraceptives, a history of breast feeding, and fibrocystic breast disease were less common. The women who underwent bilateral oophorectomy weighed more than controls, had a higher body mass index and were younger at menarche. The associations were more pronounced for women who underwent the bilateral oophorectomy before age 46 years, and some associations were different for women with or without a benign ovarian indication. Reported family histories of uterine and other cancers were more common in women without a benign ovarian indication. CONCLUSIONS: We identified a number of personal, reproductive, and familial characteristics that were associated with bilateral oophorectomy over a 20-year period. Our historical findings may help inform decision-making about oophorectomy in the future.

Data Registry on Experiences of Aging, Menopause, and Sexuality (DREAMS): A cohort profile.

The Women's Health Clinic (WHC) at Mayo Clinic in Rochester, Minnesota, has provided consultative care to women with menopausal and sexual health concerns since 2005. Clinical information on the 8688 women seen in the WHC through May 2017 who gave consent for the use of their medical records in research is contained in the Data Registry on Experiences of Aging, Menopause, and Sexuality (DREAMS). Initially, DREAMS was created to improve the clinical care of women, but it has become a valuable research tool. About 25% of the DREAMS women have been seen in the WHC 2 or more times, allowing for passive longitudinal follow-up. Additionally, about 25% of the DREAMS women live in the 27-county region included in the expanded Rochester Epidemiology Project medical records linkage system, providing additional information on those women. The cohort has been used to investigate associations between: caffeine intake and vasomotor symptom bother; recent abuse (physical, sexual, verbal, and emotional) and menopausal symptoms; specific menopausal symptoms and self-reported view of menopause; and obstructive sleep apnea risk and vasomotor symptom severity and the experience of vasomotor symptoms in women older than 60 years. A study nearing completion describes a clinical series of over 3500 women presenting for sexual health consultation by sexual function domain and by decade of life. Other studies under way are determining correlates with sexual health and dysfunction. Planned studies will investigate associations between the experience with menopause and the risk of disease.

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

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

Adverse childhood or adult experiences and risk of bilateral oophorectomy: a population-based case-control study.

OBJECTIVES: Bilateral oophorectomy has commonly been performed in conjunction with hysterectomy even in women without a clear ovarian indication; however, oophorectomy may have long-term deleterious consequences. To better understand this surgical practice from the woman's perspective, we studied the possible association of adverse childhood or adult experiences with the subsequent occurrence of bilateral oophorectomy. DESIGN: Population-based case-control study. SETTING: Olmsted County, Minnesota (USA). PARTICIPANTS: From an established population-based cohort study, we sampled 128 women who underwent bilateral oophorectomy before age 46 years for a non-cancerous condition in 1988-2007 (cases) and 128 age-matched controls (±1 year). METHODS: Information about adverse experiences was abstracted from the medical records dating back to age 15 years or earlier archived in the Rochester Epidemiology Project (REP) records-linkage system. Adverse childhood experiences were summarised using the Adverse Childhood Experience (ACE) score. RESULTS: We observed an association of bilateral oophorectomy performed before age 46 years with verbal or emotional abuse, physical abuse, any abuse, substance abuse in the household, and with an ACE score ≥1 experienced before age 19 years (OR=3.23; 95% CI 1.73 to 6.02; p<0.001). In women who underwent the oophorectomy before age 40 years, we also observed a strong association with physical abuse experienced during adulthood (OR=4.33; 95% CI 1.23 to 15.21; p=0.02). Several of the associations were higher in women who underwent oophorectomy at a younger age (<40 years) and in women without an ovarian indication for the surgery. None of the psychosocial or medical variables explored as potential confounders or intervening variables changed the results noticeably. CONCLUSIONS: Women who suffered adverse childhood experiences or adult abuse are at increased risk of undergoing bilateral oophorectomy before menopause. We suggest that the association may be explained by a series of biological, emotional, and psychodynamic mechanisms.

Bilateral Oophorectomy and Accelerated Aging: Cause or Effect?

BACKGROUND: The cause-effect relationship between bilateral oophorectomy and accelerated aging remains controversial. We conducted new analyses to further address this controversy. METHODS: The Rochester Epidemiology Project records-linkage system was used to identify all premenopausal women who underwent bilateral oophorectomy for a noncancerous condition before age 50 years between 1988 and 2007 in Olmsted County, MN. Each woman was randomly matched to a referent woman born in the same year (±1 year) who had not undergone bilateral oophorectomy. We studied the rate of accumulation of 18 common chronic conditions over a median of approximately 14 years of follow-up (historical cohort study). Analyses were restricted to women free of any of the 18 chronic conditions at the time of oophorectomy (or index date). RESULTS: After adjustments for race/ethnicity, education, body mass index, smoking, and age and calendar year at the index date, women who underwent oophorectomy before age 46 years experienced an accelerated rate of accumulation of the 18 chronic conditions considered together (hazard ratio = 1.24; 95% confidence interval: 1.12, 1.37; p < .001). The single-year incidence rate of new conditions was most different in the first 6 years after oophorectomy but the difference attenuated thereafter. Findings did not vary by surgical indication for the oophorectomy. CONCLUSIONS: Bilateral oophorectomy is associated with a higher risk of multimorbidity among women who did not have any of the 18 selected conditions at baseline. The association did not vary by surgical indication for oophorectomy. Our findings suggest that bilateral oophorectomy is causally linked to accelerated aging.

Cohort profile: the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) in Olmsted County, Minnesota (USA).

PURPOSE: This cohort study was established to investigate the effects of unilateral and bilateral oophorectomy on the ageing processes in women. PARTICIPANTS: We used the records-linkage system of the Rochester Epidemiology Project (REP, http://www.rochesterproject.org) to identify 570 women who underwent unilateral oophorectomy and 1653 women who underwent bilateral oophorectomy in Olmsted County, Minnesota from 1988 through 2007 (20 years). Each woman was matched by age (±1 year) to a population-based referent woman who had not undergone any oophorectomy (570 referent women) or bilateral oophorectomy (1653 referent women). These four cohorts are being followed to assess morbidity and mortality and to study imaging and biological markers related to ageing. FINDINGS TO DATE: An extensive medical record abstraction using the REP has been completed for each woman to obtain demographic, reproductive and adult life characteristics and extensive clinical information about the surgical procedure and subsequent oestrogen replacement therapy (or other sex steroid therapy). The cohorts have been used to date to study the accumulation of multiple chronic conditions following bilateral oophorectomy in women with or without chronic conditions at the time of the oophorectomy (or index date). From the cohorts, we have also derived a sample of 128 pairs of women for a case-control study linking adverse childhood or adult experiences to the risk of bilateral oophorectomy. FUTURE PLANS: We hypothesise that the abrupt hormonal changes caused by bilateral oophorectomy in younger women have a major effect on the ageing processes across the full body. Therefore, we plan to investigate the risk of a wide range of chronic conditions following bilateral oophorectomy. Specific studies are underway for kidney diseases, psychiatric diseases and neurological diseases. In addition, we plan to invite a subsample of women from the bilateral oophorectomy cohort to participate in an in-person study involving brain imaging and the collection of biomarkers.

Aortic hemodynamics and white matter hyperintensities in normotensive postmenopausal women.

Hypertension is associated with development of white matter hyperintensities (WMH) in the brain, which are risk factors for mild cognitive impairment. Hormonal shifts at menopause alter vascular function putting women at risk for both hypertension and WMH. Elevations in aortic hemodynamics precede the appearance of clinically defined hypertension but the relationship of aortic hemodynamics to development of WMH in women is not known. Therefore, this study aimed to characterize aortic hemodynamics in relationship to WMH in postmenopausal women. Aortic systolic and diastolic blood pressure (BP), aortic augmentation index (Alx) and aortic round trip travel time (Aortic T R) by tonometry were examined in 53 postmenopausal women (age 60 ± 2 years). WMH was calculated from fluid-attenuated inversion recovery MRI using a semi-automated segmentation algorithm. WMH as a fraction of total white matter volume positively associated with aortic systolic BP (regression coefficient = 0.018; p = 0.04) after adjusting for age. In addition, WMH fraction was positively associated with AIx (0.025; p = 0.04), and inversely associated with Aortic T R (-0.015; p = 0.04) after adjusting for age. Our results suggest that assessing aortic hemodynamics may identify individuals at risk for accelerated development of WMH and guide early treatment to reduce WMH burden and cognitive impairment in the future.

Accelerated Accumulation of Multimorbidity After Bilateral Oophorectomy: A Population-Based Cohort Study.

OBJECTIVE: To study the association between bilateral oophorectomy and the rate of accumulation of multimorbidity. PATIENTS AND METHODS: In this historical cohort study, the Rochester Epidemiology Project records-linkage system was used to identify all premenopausal women who underwent bilateral oophorectomy before age 50 years between January 1, 1988, and December 31, 2007, in Olmsted County, Minnesota. Each woman was randomly matched to a referent woman born in the same year (±1 year) who had not undergone bilateral oophorectomy. We studied the rate of accumulation of 18 common chronic conditions over a median of approximately 14 years of follow-up. RESULTS: Although women who underwent bilateral oophorectomy already had a higher multimorbidity burden at the time of oophorectomy, they also experienced an increased risk of subsequent multimorbidity. After adjustments for 18 chronic conditions present at baseline, race/ethnicity, education, body mass index, smoking, age at baseline, and calendar year at baseline, women who underwent oophorectomy before age 46 years experienced an increased risk of depression, hyperlipidemia, cardiac arrhythmias, coronary artery disease, arthritis, asthma, chronic obstructive pulmonary disease, and osteoporosis. In addition, they experienced an accelerated rate of accumulation of the 18 chronic conditions considered together (hazard ratio, 1.22; 95% CI, 1.14-1.31; P<.001). Several of these associations were reduced in women who received estrogen therapy. CONCLUSION: Bilateral oophorectomy is associated with a higher risk of multimorbidity, even after adjustment for conditions present at baseline and for several possible confounders. However, several of these associations were reduced in women who received estrogen therapy.

Self-reported verbal abuse in 1300+ older women within a private, tertiary women's health clinic.

OBJECTIVE: Several studies describe "elder abuse" among residents of nursing homes, but this issue is less well studied among independently functioning, community-based women. The current study was undertaken to report rates of self-reported intimate partner violence - with a focus on verbal abuse - among older women within a private tertiary women's health clinic. METHODS: This study focused on women who completed a questionnaire on domestic abuse. RESULTS: A total of 1389 women with a median age of 55 years (range: 50, 90) are the focus of this report. Most 1102 (79%) were married. Within this group, 100 (7%) women reported verbal abuse within the last year. Rates of physical and sexual abuse were much lower with 9 women (1%) and 2 (<1%), respectively. In univariate analyses, being divorced, being an alcoholic, and having suffered prior abuse were associated with reported verbal abuse. In multivariate analyses, self-reported alcoholism and physical abuse were independently associated with reported verbal abuse. CONCLUSION: This study found a notable rate of patient-reported verbal abuse in older women within a private, tertiary women's health clinic. IMPLICATIONS: This observation should prompt healthcare providers to ask about intimate partner violence - and specifically verbal abuse - regardless of healthcare setting.

Effects of hormone therapy on brain structure: A randomized controlled trial.

OBJECTIVE: To investigate the effects of hormone therapy on brain structure in a randomized, double-blinded, placebo-controlled trial in recently postmenopausal women. METHODS: Participants (aged 42-56 years, within 5-36 months past menopause) in the Kronos Early Estrogen Prevention Study were randomized to (1) 0.45 mg/d oral conjugated equine estrogens (CEE), (2) 50 µg/d transdermal 17ß-estradiol, or (3) placebo pills and patch for 48 months. Oral progesterone (200 mg/d) was given to active treatment groups for 12 days each month. MRI and cognitive testing were performed in a subset of participants at baseline, and at 18, 36, and 48 months of randomization (n = 95). Changes in whole brain, ventricular, and white matter hyperintensity volumes, and in global cognitive function, were measured. RESULTS: Higher rates of ventricular expansion were observed in both the CEE and the 17ß-estradiol groups compared to placebo; however, the difference was significant only in the CEE group (p = 0.01). Rates of ventricular expansion correlated with rates of decrease in brain volume (r = -0.58; p ≤ 0.001) and with rates of increase in white matter hyperintensity volume (r = 0.27; p = 0.01) after adjusting for age. The changes were not different between the CEE and 17ß-estradiol groups for any of the MRI measures. The change in global cognitive function was not different across the groups. CONCLUSIONS: Ventricular volumes increased to a greater extent in recently menopausal women who received CEE compared to placebo but without changes in cognitive performance. Because the sample size was small and the follow-up limited to 4 years, the findings should be interpreted with caution and need confirmation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that brain ventricular volume increased to a greater extent in recently menopausal women who received oral CEE compared to placebo.