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Summary

A recent publication by Rocca and co-workers [1], with accompanying commentary [2], expands this group’s previous work [3] investigating the impact of bilateral oophorectomy (BO) on neurocognitive outcomes in women. The aim of the current study was to investigate the risk of mild cognitive impairment in premenopausal women who underwent BO. This study involved 2,732 women aged 50-89 years randomly sampled from Olmsted County, Minnesota USA. Participants underwent physician examination, assessment of depression and anxiety, and neuropsychological testing covering four cognitive domains including memory, attention and executive function, visuo-spatial ability and language. Z scores were calculated for individual tests and domains. Cognitive function was assessed, according to clinical and cognitive criteria, as unimpaired, mild cognitive impairment (MCI) or dementia. Retrospective linked data was used to identify co-morbidities, age at BO, surgical indication for BO, and use of estrogen therapy. Demographic data was collected, body mass index calculated and apolipoprotein (APO) E4 genotyping performed. Median time between BO before age 50 and cognitive evaluation was 30 years. Median age at evaluation was 74 years where 259/2,732 women underwent premenopausal BO before age 50 and 161 women prior to age 46 years. Women with BO (n=625) had increased prevalence of hypertension, diabetes, heart disease and stroke compared to women without BO. Of 2,732 women, 2,449 were cognitively unimpaired and 283 classified as MCI. Compared to women without BO (adjusted for age, education and APO E genotype), women with BO before age 46 years had higher odds of MCI (OR 2.21; 95% CI 1.41-3.45) with lower scores for global cognition, attention and executive function domains. Increased risk persisted (OR 2.07; 95% CI 1.32-3.26) following adjustment for hypertension, dyslipidemia, diabetes, heart disease and stroke. These findings contrast with women with BO at older age before menopause or postmenopause where MCI risk was similar to women without BO. The use of estrogen therapy in women with BO before age 46 years did not alter this risk (adjusted OR MCI with estrogen use 2.56 versus 2.05 without estrogen use); however, this analysis was based on 19 non-users and 11 users of estrogen therapy in women with MCI and thus underpowered. Lower scores were observed in all four cognitive domains in women with BO before age 40 years (n=51). Although underpowered, there is a suggestion that MCI risk varies with indication for BO. In the discussion the authors speculate regarding potential mechanisms underlying their findings. The authors acknowledge the limitations including the presence of assessment of cognitive function at one time point only, predominately white women residing in one USA county limiting generalisability and inadequate power to further explore estrogen use. The authors conclude by highlighting the need for increased awareness of the potential cognitive impact of premenopausal BO by physicians and inclusion into any discussion of the risks of BO.

Commentary

A 2019 meta-analysis reported a 70% increased risk of dementia (2 studies, 6,256 women) and cognitive decline (1 study, 926 women) in women with surgical menopause ≤ age 45 years [4]. Previous studies from the Mayo cohort have also observed an increased risk of Parkinson’s disease and neurological related mortality [3]. The current study provides new evidence with longer follow-up period, comprehensive assessment of different cognitive domains and details regarding medical history including indications for BO. The increased risk of MCI in women with BO occurring before age 46 years is consistent with previous observational data [4]. However, whether subsequent estrogen therapy modifies this risk in young women, especially in regard to the use of transdermal estrogen, remains unclear, with inconsistent results observed in small studies with short follow-up [4,5].

Multiple mechanisms may underlie the cognitive changes. Estrogen receptors are located throughout the brain and estrogen exerts a neuroprotective effect [6]. Both estrogen deprivation and vascular disease are involved in the aetiology of neurodegeneration [6]. Accelerated aging, indicated by changes in DNA methylation, is observed with estrogen deprivation in women with BO prior to age 50 years [7]. Structural abnormalities in the median temporal lobe are associated with BO [4]. Cardiac risk factors and stroke predict cognitive decline and dementia [6]. An increased prevalence of cardiovascular disease and cardiac risk factors was reported in women with BO and vascular pathology may contribute to the impairment in attention and executive cognitive domains observed in the current study [1,2]. Early menopause, especially surgical menopause, is associated with an increased risk of cardiovascular disease including stroke; an effect which is moderated by hormone therapy use [8]. However, the finding that increased MCI risk persisted following adjustment for cardiovascular factors suggests that MCI may be partly mediated by neurodegeneration independent of vascular pathology. Szoeke and co-workers [6] postulate a 30-year evolution of neurodegenerative disease, hence the importance of the long follow-up observed in this study.

This study contributes to the evidence highlighting the adverse impact of early menopause on health outcomes in women, including cardiovascular disease, osteoporosis, depression and increased mortality. It emphasises the need to individualise and provide adequate risk/benefit information to premenopausal women contemplating BO. Finally, as recommended by international societies [9,10], hormone therapy should be offered to young women with premature/ early menopause. Further research is needed to examine these associations in general populations, and further quantify risks and clarify the effect, optimal regimen and duration of hormone therapy.

Clinical Associate Prof. Amanda Vincent, MBBS, B Med Sci (Hons), PhD, FRACP
Head, Early Menopause research, Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University; Endocrinologist, Department of Endocrinology, Monash Health, Clayton, Victoria, Australia; Board member of the International Menopause Society

References

  1. Rocca WA, Lohse CM, Smith CY, Fields JA, Machulda MM, Mielke MM. Association of Premenopausal Bilateral Oophorectomy With Cognitive Performance and Risk of Mild Cognitive Impairment. JAMA Netw Open. 2021;4(11):e2131448.
    https://pubmed.ncbi.nlm.nih.gov/34762113/
  2. Georgakis MK, Petridou ET. Long-term Risk of Cognitive Impairment and Dementia Following Bilateral Oophorectomy in Premenopausal Women-Time to Rethink Policies? JAMA Netw Open. 2021;4(11):e2133016.
    https://pubmed.ncbi.nlm.nih.gov/34762116/
  3. Rocca WA, Mielke MM, Gazzuola Rocca L, Stewart EA. Premature or early bilateral oophorectomy: a 2021 update. Climacteric. 2021;24(5):466-473.
    https://pubmed.ncbi.nlm.nih.gov/33719814/
  4. Georgakis MK, Beskou-Kontou T, Theodoridis I, Skalkidou A, Petridou ET. Surgical menopause in association with cognitive function and risk of dementia: A systematic review and meta-analysis. Psychoneuroendocrinology. 2019;106:9-19.
    https://pubmed.ncbi.nlm.nih.gov/30928686/
  5. Chang H, Kamara D, Bresee C, Lester J, Cass I. Short-term impact of surgically induced menopause on cognitive function and wellbeing in women at high risk for ovarian cancer following risk-reducing bilateral salpingo-oophorectomy. Menopause. 2020;28(4):354-359.
    https://pubmed.ncbi.nlm.nih.gov/33350669/
  6. Szoeke C, Downie SJ, Parker AF, Phillips S. Sex hormones, vascular factors and cognition. Front Neuroendocrinol. 2021;62:100927.
    https://pubmed.ncbi.nlm.nih.gov/34119528/
  7. Levine ME, Lu AT, Chen BH, et al. Menopause accelerates biological aging. Proc Natl Acad Sci U S A. 2016;113(33):9327-32.
    https://pubmed.ncbi.nlm.nih.gov/27457926/
  8. Zhu D, Chung HF, Dobson AJ, et al. Type of menopause, age of menopause and variations in the risk of incident cardiovascular disease: pooled analysis of individual data from 10 international studies. Hum Reprod. 2020;35(8):1933-1943.
    https://pubmed.ncbi.nlm.nih.gov/32563191/
  9. European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926-37.
    https://pubmed.ncbi.nlm.nih.gov/27008889/
  10. Lambrinoudaki I, Paschou SA, Lumsden MA, et al. Premature ovarian insufficiency: a toolkit for the primary care physician. Climacteric. 2021;24(5):425-437.
    https://pubmed.ncbi.nlm.nih.gov/33434082/

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