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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Early Postmenopausal Transdermal 17ß-Estradiol Therapy and Amyloid-ß Deposition.

BACKGROUND: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD). OBJECTIVE: To investigate the effects of hormone therapy on amyloid-ß deposition in recently postmenopausal women. METHODS: Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50µg/day transdermal 17ß-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated. RESULTS: Women (age = 52-65) randomized to transdermal 17ß-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17ß-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers. CONCLUSION: In this pilot study, transdermal 17ß-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-ß deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.

Effect of menstrual cycle phase on background parenchymal uptake at molecular breast imaging.

RATIONALE AND OBJECTIVES: The level of Tc-99m sestamibi uptake within normal fibroglandular tissue on molecular breast imaging (MBI), termed background parenchymal uptake (BPU), has been anecdotally observed to fluctuate with menstrual cycle. Our objective was to assess the impact of menstrual cycle phase on BPU appearance. MATERIALS AND METHODS: Premenopausal volunteers who reported regular menstrual cycles and no exogenous hormone use were recruited to undergo serial MBI examinations during the follicular and luteal phase. A study radiologist, blinded to cycle phase, categorized BPU as photopenic, minimal mild, moderate, or marked. Change in BPU with cycle phase was determined, as well as correlations of BPU with mammographic density and hormone levels. RESULTS: In 42 analyzable participants, high BPU (moderate or marked) was observed more often in luteal phase compared to follicular (P = .016). BPU did not change with phase in 30 of 42 participants (71%) and increased in the luteal phase compared to follicular in 12 (29%). High BPU was more frequent in dense breasts compared to nondense breasts at both the luteal (58% [15 of 26] vs. 13% [2 of 16], P = .004) and follicular phases (35% [9 of 26] vs. 6% [1 of 16], P = .061). Spearman correlation coefficients did not show any correlation of BPU with hormone levels measured at either cycle phase and suggested a weak correlation between change in BPU and changes in estrone and estradiol between phases. CONCLUSIONS: We observed variable effects of menstrual cycle on BPU among our cohort of premenopausal women; however, when high BPU was observed, it was most frequently seen during the luteal phase compared to follicular phase and in women with dense breasts compared to nondense breasts.

Caffeine and menopausal symptoms: what is the association?

OBJECTIVE: We assessed the association between caffeine intake and menopausal symptom bother, particularly vasomotor symptoms. METHODS: A cross-sectional survey was conducted using the Menopause Health Questionnaire, which is a comprehensive survey of menopause-related health information. Questionnaires were completed by 2,507 consecutive women who presented with menopausal concerns at the Women's Health Clinic at Mayo Clinic (Rochester, MN) between July 25, 2005 and July 25, 2011. Data from 1,806 women who met all inclusion criteria were analyzed. Menopausal symptom ratings were compared between women who used caffeine and women who did not use caffeine using two-sample t test and analysis of covariance, with smoking and menopause status included as covariates. In all cases, two-tailed P < 0.05 was considered statistically significant. RESULTS: Caffeine use was positively associated with mean (SD) vasomotor symptom scores (2.30 [0.91] vs 2.15 [0.94], P = 0.011). This finding remained significant after adjustment for menopause status and cigarette smoking (P = 0.027). CONCLUSIONS: Caffeine use is associated with greater vasomotor symptom bother in postmenopausal women.

Oophorectomy, estrogen, and dementia: a 2014 update.

Current evidence suggests that estrogen may have beneficial, neutral, or detrimental effects on the brain depending on age, type of menopause (natural versus induced), or stage of menopause (early versus late), consistent with the timing hypothesis. Three studies have now compared women who underwent bilateral oophorectomy before menopause with referent women and consistently showed an increased risk of cognitive decline and dementia. These studies suggest a sizeable neuroprotective effect of estrogen naturally produced by the ovaries before age 50 years. In this article, we focus on neuroprotection as related to cognitive decline and dementia. Several case-control studies and cohort studies also showed neuroprotective effects in women who received estrogen treatment (ET) in the early postmenopausal stage (most commonly at ages 50-60 years). The majority of women in those observational studies had undergone natural menopause and were treated for the relief of menopausal symptoms. However, the clinical trials by the Women's Health Initiative showed that women who initiated ET alone or in combination with a progestin in the late postmenopausal stage (ages 65-79 years) experienced an increased risk of dementia and cognitive decline regardless of the type of menopause. Three observational studies have now formally tested the timing hypothesis, and showed that the neuroprotective or harmful effects of estrogen depend on age at the time of initiation of treatment and on stage of menopause. Therefore, women who undergo bilateral oophorectomy before the onset of menopause or women who experience premature or early natural menopause should be considered for hormonal treatment until the average age of natural menopause (around age 50 years). Recommendations for the use of ET by women who experience natural menopause at typical ages remain less certain, and more research is needed.

Prescribing menopausal hormone therapy: an evidence-based approach.

The constantly changing landscape regarding menopausal hormone therapy (MHT) has been challenging for providers caring for menopausal women. After a decade of fear and uncertainty regarding MHT, reanalysis of the Women's Health Initiative data and the results of recent studies have provided some clarity regarding the balance of risks and benefits of systemic MHT. Age and years since menopause are now known to be important variables affecting the benefit-risk profile. For symptomatic menopausal women who are under 60 years of age or within 10 years of menopause, the benefits of MHT generally outweigh the risks. Systemic MHT initiated early in menopause appears to slow the progression of atherosclerotic disease, thereby reducing the risk of cardiovascular disease and mortality. During this window of opportunity, MHT might also provide protection against cognitive decline. In older women and women more than 10 years past menopause, the risk-benefit balance of MHT is less favorable, particularly with regard to cardiovascular risk and cognitive impairment. For women entering menopause prematurely (<40 years), MHT ameliorates the risk of cardiovascular disease, osteoporosis, and cognitive decline. Nonoral administration of estrogen offers advantages due to the lack of first-pass hepatic metabolism, which in turn avoids the increased hepatic synthesis of clotting proteins, C-reactive protein, triglycerides, and sex hormone-binding globulin. The duration of combined MHT use is ideally limited to less than 5 years because of the known increase in breast cancer risk after 3-5 years of use. Limitations to use of estrogen only MHT are less clear, since breast cancer risk does not appear to increase with use of estrogen alone. For women under the age of 60 years, or within 10 years of onset of natural menopause, MHT for the treatment of bothersome menopausal symptoms poses low risk and is an acceptable option, particularly when nonhormonal management approaches fail.

Risk of glaucoma after early bilateral oophorectomy.

OBJECTIVE: Because early estrogen deficiency may increase the susceptibility of the optic nerve to glaucoma, we studied the association of early bilateral oophorectomy with glaucoma. METHODS: In the Mayo Clinic Cohort Study of Oophorectomy and Aging, we studied the risk of glaucoma by comparing women who underwent bilateral oophorectomy from 1950 to 1987 with age-matched referent women who did not undergo unilateral or bilateral oophorectomy. Glaucoma diagnostic codes were identified in the records linkage system of the Rochester Epidemiology Project. Hazard ratios (HRs) were calculated during a median follow-up of 25.5 years. Analyses were stratified by age at the time of bilateral oophorectomy (in tertiles). RESULTS: Of 1,044 women who underwent bilateral oophorectomy before menopause, 147 developed glaucoma. Of 1,070 referent women, 133 developed glaucoma. Women who underwent bilateral oophorectomy showed no increased risk of glaucoma in the overall group (HR, 1.12; 95% CI, 0.89-1.42). However, women who underwent oophorectomy before the age of 43 years (n = 344; first tertile) had a significantly increased risk of glaucoma (HR, 1.60; 95% CI, 1.15-2.23). The results did not change after adjustment for hypertension, obesity, diabetes, or disorders of lipid metabolism at baseline. Approximately 11% of women who had undergone bilateral oophorectomy before the age of 43 years were treated with estrogen up to the age of 50 years; however, treatment did not reduce the association (HR, 1.59; 95% CI, 0.81-3.13). CONCLUSIONS: Bilateral oophorectomy before the age of 43 years may increase the risk of glaucoma, and estrogen treatment does not seem to attenuate the risk.

Challenging and complex decisions in the management of the BRCA mutation carrier.

Women afflicted by the hereditary breast and ovarian cancer syndrome face complex decisions regarding medical interventions aimed at reducing their risk of ovarian and breast cancer, interventions which in turn may interfere with their fertility and cause early menopause. This review addresses selected topics of importance and controversy in the management of the BRCA mutation carrier, such as psychological well-being and quality of life, breast and ovarian cancer screening, risk-reducing interventions for breast cancer and ovarian cancer, the issue of hysterectomy at the time of the risk-reducing salpingo-oophorectomy, health consequences of early surgical menopause, and safety of hormonal therapy after oophorectomy. The information presented is based on an extensive review of the literature on the selected topics and on the expertise of our multidisciplinary team.