Summary
Women at high risk of ovarian cancer are commonly advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) prior to natural menopause. During the natural menopausal transition cognitive symptoms are frequently reported; however, very few studies have examined cognitive changes following surgical menopause. To address this gap, Ramachandra et al. [1] analyzed the cognitive experiences of women within 24 months after BSO. Authors performed an observational cross-sectional sub-study, part of a larger project, the Early Menopause and Cognition Study (EM-COG), in order to investigate perceived cognitive experiences in Australian women (n = 16) who underwent risk-reducing BSO using qualitative interviews. Thematic analysis was undertaken to identify key themes. Fifteen out of 16 participants (93.75%) reported changes in cognition within 24 months after BSO. Reported key cognitive symptoms were brain fog, memory and retrieval difficulties, slower processing speed and attention difficulties. Five participants (31.3%) experienced negative mood symptoms post BSO. The authors conclude indicating that their results suggest that women experience subjective cognitive changes within 24 months post BSO; hence, this period could be a vulnerable window women’s cognitive health. Although these findings need to be confirmed by a large prospective study, authors indicate that psychoeducation and awareness will be helpful in managing cognitive symptoms after surgical menopause.
Commentary
This small qualitative study [1] has perhaps raised more questions than it has provided answers, but the finding of relatively early onset of cognitive issues after risk reducing BSO adds to the considerable list of potential adverse sequalae which can occur due to early surgical menopause. If the relationship between risk reducing BSO and cognitive problems is causative and not merely associative, it is of great concern how rapidly the problems appear to have developed, and it raises several questions. Firstly, regarding the possible etiological mechanism, evidence suggests that an early menopausal transition is associated with epigenetic aging, arteriosclerosis in the central nervous system and accumulation of Alzheimer pathology. However, the rapidity of onset indicates that the procedure has a significant psychological impact which is not fully mitigated by the reduction in cancer risk or addition of hormone therapy. We know that in women with premature ovarian insufficiency, there is a significant impact on body image, mood and outlook on life. The loss of reproductive potential also has a profound psychological effect. Although this is a slightly older age cohort, this may be a factor even in individuals whose families are deemed to be complete [2]. I totally agree with the authors that there should be neuropsychological testing pre- and post- risk reducing BSO, provision of adequate information, and that future research should examine the potential benefits of psychoeducation [1].
As more candidate genes are discovered for gynecological malignancies, it is likely that the number of young women undergoing risk reducing sterilizing surgery will only increase. Due to the high risk of ovarian cancer in this group of women with BRCA, the current consensus view is that the pros far outweigh the cons for risk reducing BSO to be performed, but the counselling process should always include the possibility that short- and long-term adverse effects may occur, particularly if there are problems with subsequent hormone replacement. Data of the numbers needed to harm from large prospective studies and registries would facilitate more accurate weighing up of the long-term risks against the benefits of risk reducing BSO in BRCA carriers [3].
Although the benefits of hormone therapy are not evident from the findings in this study, previous research has shown that estrogen therapy can reverse the decline in verbal learning and memory that can occur following removal of the ovaries [4]. There are of course many other reasons why hormone therapy should be offered following surgical early menopause, even in a group of women who are at increased risk of hormone sensitive malignancy, given the potential for numerous health consequences. It is encouraging that the large majority were still using hormone therapy when interviewed in this research population, which is important not only to maintain quality of life, but also to prevent the possible sequalae of long-term estrogen deficiency such as osteoporosis, cardiovascular disease, parkinsonism, dementia, non-ovarian/breast cancers and increased all-cause mortality [5-6]. There is accumulating evidence that the use of hormone therapy after risk reducing BSO does not attenuate the oncological benefits of the procedure [7].
However, there are many unanswered questions. For instance, is the absence of benefit for cognitive symptoms in this study because of an inadequate dose or suboptimal type of hormone therapy the women were administered, or due to a lack of compliance with treatment? It is possible that synthetic progestogens may have had an attenuating effect on the cognitive benefits of estrogen, in which case unopposed estrogen alone might be a better option. Nevertheless, this is only feasible if a hysterectomy is performed at the time of BSO. The dose, type of estrogen, route of administration, type of progestogen, and the possible role of androgens all need to be considered in future research.
I would like to congratulate the authors for conducting this important research [1] in an area of unmet need. Although this was a paper reporting on a small sub-study, the findings are particularly worthy of comment because of the absence of research in this important area. It has been acknowledged that there are limitations to this study. The authors point out that the small number of patients, with absence of a control group, makes it difficult to draw any firm conclusions from these data. The large “loss to follow up group” may have biased the findings; these individuals may have been less affected by surgery and therefore less willing to participate in the study. Variable intervals since surgery may have also introduced bias as to how well the events were recalled at the time of interview. Finally, was the sub-study population truly representative of the larger project population in the Early Menopause and Cognition Study (EM-COG)?
Conclusion
Despite the limitations of this small qualitative sub-study, it demonstrates the potential concerns of early surgical menopause in this group of patients and highlights the need for larger prospective randomized clinical trials with validated questionnaires to fully define the extent of the problems, and how they can be mitigated. In the meantime, it is critical that these young women receive, in addition to genetic counselling, extensive pre-surgical counselling to clarify both the benefits and risks of surgery. Signposting to evidence-based research, and patient advocacy groups is of critical importance to ensure that these young women are empowered to make evidence-based decisions, where they fully understand the implications of the intervention as well as the risks of not having it. Although not aimed specifically at early menopause, the International Menopause Society White Paper, and associated materials, provide a good framework of the type of information healthcare professionals require for clinical counselling and decision-making in women with cognitive problems [8].
Nick Panay
Professor of Practice, Imperial College London, UK
President, International Menopause Society
References
- Ramachandra A, Thomas EHX, Vincent AJ, Hickey M, Warren N, Kulkarni J, et al. Subjective cognitive changes following premenopausal risk-reducing bilateral salpingo-oophorectomy. Climacteric. 2023;26(6):625-631.
https://pubmed.ncbi.nlm.nih.gov/37751773/ - Singer D, Mann E, Hunter MS, Pitkin J, Panay N. The silent grief: psychosocial aspects of premature ovarian failure. Climacteric. 2011;14(4):428-437.
https://pubmed.ncbi.nlm.nih.gov/21762006/ - 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/ - Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology. 1988;13(4):345-357.
https://pubmed.ncbi.nlm.nih.gov/3067252/ - Hamoda H, Sharma A. Premature ovarian insufficiency, early menopause, and induced menopause. Best Pract Res Clin Endocrinol Metab. 2024;38(1):101823.
https://pubmed.ncbi.nlm.nih.gov/37802711/ - 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/ - Vermeulen RFM, Korse CM, Kenter GG, Brood-van Zanten MMA, Beurden MV. Safety of hormone replacement therapy following risk-reducing salpingo-oophorectomy: systematic review of literature and guidelines. Climacteric. 2019;22(4):352-360.
https://pubmed.ncbi.nlm.nih.gov/30905183/ - Maki PM, Jaff NG. Brain fog in menopause: a health-care professional’s guide for decision-making and counseling on cognition. Climacteric. 2022;25(6):570-578.
https://pubmed.ncbi.nlm.nih.gov/36178170/
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