Focus on long-COVID: Perimenopause and post-COVID chronic fatigue

Potential pathophysiology

Inflammation is likely to be critical in the pathogenesis of postacute sequelae of SARS-CoV-2 infection, or PASC. Individuals with long COVID have elevated inflammatory markers for several months.¹⁰ The chronic inflammation associated with long COVID could cause disturbances in the ovary and ovarian hormone production.^2,10,11

During perimenopause, the ovary is more sensitive to illnesses such as COVID-19and to stress. The current theory is that COVID-19 affects the ovary with declines in ovarian reserve and ovarian function⁷ and with potential disruptions to the menstrual cycle, gonadal function, and ovarian sufficiency that lead to issues with menopause or fertility, as well as symptom exacerbation around menstruation.¹² Another theory is that SARS-CoV-2 infection affects ovary hormone production, as there is an abundance of angiotensin-converting enzyme-2 receptors on ovarian and endometrial tissue.¹¹ Thus, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely or lengthen the duration of perimenopausal symptoms.

Sex differentiation has been seen with regard to symptomatic COVID-19, with women generally faring better.^13,14 Estradiol has been shown to have beneficial effects during acute COVID-19.¹⁵ With acute COVID-19 infection, women had lower mortality, lower levels of inflammation, higher lymphocyte counts, and faster antibody responses than men.^13,14 In addition, estradiol has been shown to help perimenopausal and menopausal hot flashes, night sweats, and sleep and to improve mood during perimenopause.¹⁶ So it is likely that perimenopausal or menopausal symptomatic women with long COVID treated with estrogen would see improvements in their symptoms both due to the action of estradiol on the ovary as seen during COVID-19 and in perimenopause.

Perimenopause is the transitional period prior to menopause, when the ovaries gradually produce fewer hormones and is associated with erratic hormonal fluctuations. The length of this transitional period varies from 4 to 10 years. Ethnic variations in the duration of hot flashes have been found, noting that Black and Hispanic women have them for an average of 8 to 10 years (longer), White women for an average of 7 years, and Asian, Japanese, and Chinese women for an average of 5 to 6 years (shorter).¹⁷

What should health care providers ask?

Distinguishing perimenopause from long COVID. It is important to try to differentiate between perimenopause and long COVID, and it is possible to have both, with long COVID exacerbating the menopausal symptoms.^7,8 Health care providers should be alert to consider perimenopause if women present with shorter or longer cycles (21-40 days), missed periods (particularly 60 days or 2 months), or worsening perimenopausal mood, migraines, insomnia, or hot flashes. Clinicians should actively enquire about all of these symptoms.

Moreover, if a perimenopausal woman reports acutely worsening symptoms after COVID-19, health care providers should address the perimenopausal symptoms and determine whether hormone therapy is appropriate and could improve their symptoms. Women do not need to wait until they go 1 year without a period to be treated with hormone therapy to improve perimenopausal and menopausal symptoms. If women with long COVID have perimenopause or menopause symptoms, they should have access to evidence-based information and discuss menopausal hormone therapy if appropriate. Hormone therapy could improve both perimenopausal symptoms and the long COVID symptoms if some of the symptoms are due to changes in ovary function. Health care providers could consider progesterone or antidepressants during the second half of the cycle (luteal phase) or estrogen combined with progesterone for the entire cycle.¹⁸

For health care providers working in long COVID clinics, in addition to asking when symptoms started, what makes symptoms worse, the frequency of symptoms, and which activities are affected, ask about perimenopausal and menopausal symptoms. If a woman has irregular periods, sleep disturbances, fatigue, or mood changes, consider that these could be related to long COVID, perimenopause, or both.^8,18 Be able to offer treatment or refer patients to a women’s health specialist who can assess and offer treatment.

A role for vitamin D? A recent retrospective case-matched study found that 6 months after hospital discharge, patients with long COVID had lower levels of 25(OH) vitamin D with the most notable symptom being brain fog.¹⁹ Thus, there may be a role for vitamin D supplementation as a preventive strategy in those being discharged after hospitalization. Vitamin D levels and supplementation have not been otherwise evaluated to date.

Lifestyle strategies for women with perimenopause and long COVID

Lifestyle strategies should be encouraged for women during perimenopause and long COVID. This includes good nutrition (avoiding carbs and sweets, particularly before menses), getting at least 7 hours of sleep and using sleep hygiene (regular bedtimes, sleep regimen, no late screens), getting regular exercise 5 days per week, reducing stress, avoiding excess alcohol, and not smoking. All of these factors can help women and their ovarian function during this period of ovarian fluctuations.

The timing of menopause and COVID may coincide with midlife stressors, including relationship issues (separations or divorce), health issues for the individual or their partner, widowhood, parenting challenges (care of young children, struggles with adolescents, grown children returning home), being childless, concerns about aging parents and caregiving responsibilities, as well as midlife career, community, or education issues—all of which make both long COVID and perimenopause more challenging to navigate.

Need for research

There is a need for future research to understand the epidemiologic basis and underlying biological mechanisms of sex differences seen in women with long COVID. Studying the effects of COVID-19 on ovarian function could lead to a better understanding of perimenopause, what causes ovarian failure to speed up, and possibly ways to slow it down⁸ since there are health risks of early menopause.¹⁶

References

1. Fernández-de-Las-Peñas C, Palacios-Ceña D, GómezMayordomo V, et al. Defining post-COVID symptoms (postacute COVID, long COVID, persistent post-COVID): an integrative classification. Int J Environ Res Public Health. 2021;18:2621. doi: 10.3390/ijerph18052621
2. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601-615. doi: 10.1038/s41591 -021-01283-z
3. Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022-00846-2
4. Maglietta G, Diodati F, Puntoni M, et al. Prognostic factors for post-COVID-19 syndrome: a systematic review and meta-analysis. J Clin Med. 2022;11:1541. doi: 10.3390 /jcm11061541
5. Notarte KI, de Oliveira MHS, Peligro PJ, et al. Age, sex and previous comorbidities as risk factors not associated with SARS-CoV-2 infection for long COVID-19: a systematic review and meta-analysis. J Clin Med. 2022;11:7314. doi: 10.3390 /jcm11247314
6. Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021;8:100186. doi: 10.1016/j.lanepe.2021.100186
7. Pollack B, von Saltza E, McCorkell L, et al. Female reproductive health impacts of long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023;4:1122673. doi: 10.3389/fresc.2023.1122673
8. Stewart S, Newson L, Briggs TA, et al. Long COVID risk - a signal to address sex hormones and women’s health. Lancet Reg Health Eur. 2021;11:100242. doi: 10.1016 /j.lanepe.2021.100242
9. Li K, Chen G, Hou H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online. 2021;42:260-267. doi: 10.1016 /j.rbmo.2020.09.020
10. Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-tomoderate SARS-CoV-2 infection. Nat Immunol. 2022;23:210216. doi: 10.1038/s41590-021-01113-x
11. Sharp GC, Fraser A, Sawyer G, et al. The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities. Int J Epidemiol. 2022;51:691-700. doi: 10.1093/ije/dyab239
12. Ding T, Wang T, Zhang J, et al. Analysis of ovarian injury associated with COVID-19 disease in reproductive-aged women in Wuhan, China: an observational study. Front Med (Lausanne). 2021;8:635255. doi: 10.3389/fmed.2021.635255
13. Huang B, Cai Y, Li N, et al. Sex-based clinical and immunological differences in COVID-19. BMC Infect Dis. 2021;21:647. doi: 10.1186/s12879-021-06313-2
14. Connor J, Madhavan S, Mokashi M, et al. Health risks and outcomes that disproportionately affect women during the Covid-19 pandemic: a review. Soc Sci Med. 2020;266:113364. doi: 10.1016/j.socscimed.2020.113364
15. Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161:bqaa127. doi:10.1210/endocr/bqaa127
16. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
17. Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531-539. doi:10.1001 /jamainternmed.2014.8063
18. Newson L, Lewis R, O’Hara M. Long COVID and menopause - the important role of hormones in long COVID must be considered. Maturitas. 2021;152:74. doi: 10.1016 /j.maturitas.2021.08.026
19. di Filippo L, Frara S, Nannipieri F, et al. Low Vitamin D levels are associated with long COVID syndrome in COVID-19 survivors. J Clin Endocrinol Metab. 2023;108:e1106-e1116. doi: 10.1210/clinem/dgad207

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