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Concept: Oophorectomy

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The reproductive-cell cycle theory of aging posits that reproductive hormone changes associated with menopause and andropause drive senescence via altered cell cycle signaling. Using data from the Wisconsin Longitudinal Study (n = 5,034), we analyzed the relationship between longevity and menopause, including other factors that impact “ovarian lifespan” such as births, oophorectomy, and hormone replacement therapy. We found that later onset of menopause was associated with lower mortality, with and without adjusting for additional factors (years of education, smoking status, body mass index, and marital status). Each year of delayed menopause resulted in a 2.9% reduction in mortality; after including a number of additional controls, the effect was attenuated modestly but remained statistically significant (2.6% reduction in mortality). We also found that no other reproductive parameters assessed added to the prediction of longevity, suggesting that reproductive factors shown to affect longevity elsewhere may be mediated by age of menopause. Thus, surgical and natural menopause at age 40, for example, resulted in identical survival probabilities. These results support the maintenance of the hypothalamic-pituitary-gonadal axis in homeostasis in prolonging human longevity, which provides a coherent framework for understanding the relationship between reproduction and longevity.

Concepts: Oophorectomy, Life expectancy, Gerontology, Organism, Hormone, Senescence, Ageing, Menopause

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OBJECTIVE:: Prophylactic bilateral salpingo-oophorectomy is advised for women with BRCA mutations, but there are adverse consequences of premature menopause. The majority of BRCA-associated ovarian cancers appear to arise in the fallopian tube; therefore, salpingectomy may be an alternative to bilateral salpingo-oophorectomy. We compared the costs and benefits of salpingectomy with bilateral salpingo-oophorectomy among BRCA mutation carriers. METHODS:: We developed a Markov Monte Carlo simulation model to compare three strategies for risk reduction in women with BRCA mutations: 1) bilateral salpingo-oophorectomy; 2) bilateral salpingectomy; and 3) bilateral salpingectomy with delayed oophorectomy. Net health benefits were measured in years-of-life expectancy and quality-adjusted life-year expectancy, and the primary outcome was the incremental cost-effectiveness ratio. The model estimated the number of future breast and ovarian cancers and cardiovascular deaths attributed to premature menopause with each strategy. RESULTS:: Bilateral salpingo-oophorectomy was associated with the lowest cost and highest life expectancy compared with the other two strategies. When quality-of-life measures were included, salpingectomy followed by delayed oophorectomy yielded the highest quality-adjusted life expectancy with incremental cost-effectiveness ratios of $37,805 and $89,680 per quality-adjusted life-year for BRCA1 and BRCA2, respectively, relative to salpingectomy alone. Bilateral salpingo-oophorectomy yielded the lowest number of future breast and ovarian cancers compared with the other two strategies. CONCLUSION:: Bilateral salpingo-oophorectomy offers the greatest risk reduction for breast and ovarian cancer among BRCA mutation carriers. However, when considering quality-adjusted life expectancy, bilateral salpingectomy with delayed oophorectomy is a cost-effective strategy and may be an acceptable alternative for those unwilling to undergo bilateral salpingo-oophorectomy.

Concepts: Cancer, Oophorectomy, Ovarian cancer, Costs, BRCA1, Health economics, BRCA2, Menopause

16

Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the “epigenetic clock”), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women’s Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson’s disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further.

Concepts: Oophorectomy, Estrogen, Genetics, DNA methylation, Gene, Menopause, DNA, Hormone replacement therapy

8

Cognitive neuroscience of aging studies traditionally target participants age 65 and older. However, epidemiological surveys show that many women report increased forgetfulness earlier in the aging process, as they transition to menopause. In this population-based fMRI study, we stepped back by over a decade to characterize the changes in memory circuitry that occur in early midlife, as a function of sex and women’s reproductive stage. Participants (N = 200; age range, 45-55) performed a verbal encoding task during fMRI scanning. Reproductive histories and serologic evaluations were used to determine menopausal status. Results revealed a pronounced impact of reproductive stage on task-evoked hippocampal responses, despite minimal difference in chronological age. Next, we examined the impact of sex and reproductive stage on functional connectivity across task-related brain regions. Postmenopausal women showed enhanced bilateral hippocampal connectivity relative to premenopausal and perimenopausal women. Across women, lower 17β-estradiol concentrations were related to more pronounced alterations in hippocampal connectivity and poorer performance on a subsequent memory retrieval task, strongly implicating sex steroids in the regulation of this circuitry. Finally, subgroup analyses revealed that high-performing postmenopausal women (relative to low and middle performers) exhibited a pattern of brain activity akin to premenopausal women. Together, these findings underscore the importance of considering reproductive stage, not simply chronological age, to identify neuronal and cognitive changes that unfold in the middle decades of life. In keeping with preclinical studies, these human findings suggest that the decline in ovarian estradiol production during menopause plays a significant role in shaping memory circuitry.

Concepts: Ovary, Osteoporosis, Oophorectomy, Hormone replacement therapy, Menstrual cycle, Memory, Estrogen, Menopause

6

Exosomes participate in intercellular messaging by transporting bioactive lipid-, protein- and RNA-molecules and -complexes. The contents of the exosomes reflect the physiological status of an individual making exosomes promising targets for biomarker analyses. In the present study we extracted exosome microRNAs (exomiRs) from serum samples of premenopausal women (n = 8) and monozygotic postmenopausal twins (n = 10 female pairs), discordant for the use of estrogenic hormone replacement therapy (HRT), in order to see whether the age or/and the use of HRT associates with exomiR content. A total of 241 exomiRs were detected by next generation sequencing, 10 showing age, 14 HRT and 10 age +HRT -related differences. When comparing the groups, differentially expressed miRs were predicted to affect cell proliferation processes showing inactivation with younger age and HRT usage. MiR-106-5p, -148a-3p, -27-3p, -126-5p, -28-3p and -30a-5p were significantly associated with serum 17β-estradiol. MiRs formed two hierarchical clusters being indicative of positive or negative health outcomes involving associations with body composition, serum 17β-estradiol, fat-, glucose- and inflammatory markers. Circulating exomiR clusters, obtained by NGS, could be used as indicators of metabolic and inflammatory status affected by hormonal changes at menopause. Furthermore, the individual effects of HRT-usage could be evaluated based on the serum exomiR signature.

Concepts: Oophorectomy, Protein, Metabolism, Osteoporosis, Hormone replacement therapy, Estrogen, Hormone, Menopause

5

Risk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention to prevent ovarian cancer (OC). It is only available to high-risk women with >10% lifetime OC risk. This threshold has not been formally tested for cost-effectiveness.

Concepts: Hazard prevention, Metastasis, Hereditary nonpolyposis colorectal cancer, BRCA2, Menopause, Oophorectomy, Hysterectomy, Ovary

4

Our understanding of the complex relationship between menopausal hormone therapy (MHT) and cardiovascular disease (CVD) risk has been informed by detailed analyses in the Women’s Health Initiative (WHI), the largest randomized, placebo-controlled trial evaluating MHT in postmenopausal women. Although the WHI demonstrated increased risk of CVD events with MHT in the overall cohort, subsequent secondary analyses demonstrated that these risks were influenced by the woman’s age and time since menopause, with lower absolute risks and hazard ratios for younger than older women. As MHT is the most effective treatment for the vasomotor symptoms of menopause, it is important to understand its risks and how to conduct risk stratification for symptomatic women. In addition to reviewing the WHI findings, studies pre- and post-WHI are reviewed to describe the relationship between MHT and CVD risk in menopausal women. The absolute risks of adverse cardiovascular events for MHT initiated in women close to menopause are low, and all-cause mortality effects are neutral or even favorable for younger menopausal women. The WHI has advanced and refined our understanding of the relationship between MHT and CVD risk. Although MHT should not be used for CVD prevention, absolute risks of CVD are low when MHT is started close to menopause in healthy women and hazard ratios tend to be lower for younger than older women. For women in early menopause and without contraindications to treatment, the benefits of MHT are likely to outweigh the risks when used for menopausal symptom management.

Concepts: Menstrual cycle, Oophorectomy, Hormone, Endocrinology, Osteoporosis, Estrogen, Hormone replacement therapy, Menopause

4

Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.

Concepts: Follicle-stimulating hormone, Endocrinology, Oophorectomy, Hormone, Estrogen, Hormone replacement therapy, Menopause, Osteoporosis

3

Life expectancy statistics predict that in a couple of decades women will enjoy a mean life of 90 years. Assuming a median age for the onset of menopause of 51, women will spend about 40 years in menopause. Harvesting and freezing ovarian cortical tissue at a younger age to permit future transplantation for postponing menopause and its sequelae could become a possible option. However, both medical and ethical issues need to be addressed before this can be offered as a treatment for menopause.

Concepts: Population, Oophorectomy, Virtue, Mean, Menopause, Ovary, Estrogen, Life expectancy

3

OBJECTIVES: To compare the changes in risk factors for cardiovascular disease (CVD) leading up to and following hysterectomy with or without bilateral oophorectomy with the changes observed up to and following natural menopause. BACKGROUND: Evidence suggests that hysterectomy status with or without bilateral oophorectomy may increase risk for CVD but most studies retrospectively assess menopausal status. METHODS: Study of Women’s Health across the Nation enrolled 3,302 premenopausal women not using hormone therapy between the ages of 42-52 years of age and followed them annually for over 11 years for sociodemographic characteristics, menopausal status, surgeries, body mass index (BMI), medication use, lifestyle factors, lipids, blood pressure, insulin resistance, and hemostatic and inflammatory factors. By 2008, 1,769 women had reached natural menopause, 77 women had a hysterectomy with ovarian conservation, and 106 women had a hysterectomy with bilateral oophorectomy. Piece-wise hierarchical growth models compared these groups on annual changes in CVD risk factors prior to and following final menstrual period (FMP) or surgery. RESULTS: Multivariable analyses showed that annual changes in CVD risk factors did not vary by group with few exceptions, and the significant group differences that did emerge were not in the anticipated direction. CONCLUSIONS: Hysterectomy with or without ovarian conservation is not a key determinant of CVD risk factor status either before or after elective surgery in mid-life. These results should provide reassurance to women and their clinicians that hysterectomy in mid-life is unlikely to accelerate women’s CVD risk.

Concepts: Body mass index, Menstruation, Hormone replacement therapy, Oophorectomy, Estrogen, Hysterectomy, Menstrual cycle, Menopause