Female hormones and COVID-19 Factsheet

Summary Points

• Estrogen is known to improve the way cells that fight infections work and can increase the
  number of these cells
• The risk of death from COVID-19 for women >50 years taking HRT has been shown to
  reduce by more than 50%4
• Low estrogen and low testosterone in women are likely to be associated with Long Covid
• Anecdotally many women with Long Covid have improved with estrogen and testosterone
  replacement
• The majority of women have more benefits than risks from taking HRT

Relevance of estrogen to COVID-19 infections
There are marked differences in morbidity and mortality from COVD-19 between the sexes, with men at a higher risk of severe COVID-19 disease and death than women.
An early study from Wuhan has shown that women with low estrogen levels had more severe infection with COVID-192.

An analysis of electronic health records of nearly 70,000 patients who tested positive for COVID-19 from 17 countries has shown that women taking HRT were more than 50% less likely to die from COVID-19 compared to women not taking HRT(4).

Estrogen and immunity
It is well established that there are differences between female and male sexes in responses to infections, with females having better immune response (ability to fight infections) than males.
There is evidence that estrogen can work as an anti-viral for other infections including hepatitis C, Ebola and HIV infections.

There are numerous ways that estrogen can influence the response to COVID-19 infection especially with the way it improves women’s immune function as well as working in a protective way on the blood vessels and cardiovascular system.
There are estrogen receptors on all cells that fight infections. Estrogen works to improve the number, genetic programming and lifespan of all immune cells including neutrophils, macrophages, dendritic cells and natural killer cells(5).

Estrogen also regulates the production of numerous cytokines (chemicals that are produced by these immune cells) including interleukin-6, interferon and tumour necrosis factor. Estrogen can block the production of interleukin-6 which is important in the cytokine storm which occurs in some people with severe COVID-19 infections. A cytokine storm is when large quantities of cytokines are produced in the body which have a detrimental effect. This is because these cytokines then lead to organ and tissue damage (especially in the lungs)(6).

More specifically to COVID-19 infections, estrogen can inhibit angiotensin-converting enzyme (ACE) which then has a protective effects on the heart, lung, kidneys, central nervous system and gut(7).

Hormones, menopause and HRT
The menopause is a long-term hormone deficiency leading to health risks if not appropriately managed with hormone replacement therapy (HRT). These include increased risk of cardiovascular disease, type 2 diabetes, obesity, osteoporosis, depressive symptoms and dementia.

We now have clear, evidence-based guidelines including from NICE available to ensure women have individualised care and treatment for their perimenopause and menopause(8,9). These guidelines clearly state that the benefits of HRT outweigh the risks in the majority of women. There is a lower risk of death from all causes for women who take HRT in the long term – more than 18 years (10,11).
Research, including Cochrane data, has shown that women taking HRT have a lower risk of heart disease, type 2 diabetes and obesity(12,13).

Despite overwhelming evidence to support the safety and effectiveness of HRT, only the minority of menopausal women take HRT and women from low socio-economic backgrounds are 29% less likely to be given HRT – despite these women often having a higher risk of heart disease so are more likely to benefit from taking HRT(14).

However, many women and healthcare professionals are still worried about the perceived risks of HRT. Much of the negativity regarding HRT stems from the misinterpretation of the Women’s Health Initiative (WHI) study in 2002, which led to a worldwide reduction in HRT use(15). The subsequent sub-analysis of this study revealed reassuring and positive results to support the use of HRT including evidence that women taking estrogen only HRT have a lower future risk of breast cancer and also a lower risk of dying from breast cancer.(16)

There is now robust evidence which shows that transdermal estrogen (given as a patch, gel or spray) in association with natural micronised progesterone represents the optimal HRT regimen(17).

Transdermal estrogen is the preferred route of administration because, in contrast with oral estrogen, it is not associated with an increased risk of clot.

Long Covid and hormones
Long Covid (sometimes called Post-Covid-19 syndrome) occurs in some people who have had an infection with Long Covid in the past and have symptoms which last for more than 12 weeks and are not explained by an alternative diagnosis.
In women who develop COVID-19, being post-menopausal has been independently associated with more severe infection(18,19).

The largest group of patients with Long Covid appears to be women in their early 50s. The average age of the menopause is 51 and the majority of women are perimenopausal in their 40s. Many of the symptoms due to Long Covid are similar to perimenopausal and menopausal symptoms.
Similar to other post-viral syndromes, Long Covid is more common in women, with those coming to the end of their reproductive lives seem to be particularly affected. It is likely that the coronavirus directly affects the way the ovaries work and produce hormones.

The virus responsible for COVID-19 enters cells via a specific receptor, ACE 2, which is present on the ovary. The hormones estrogen and testosterone are both produced by the ovaries and their levels reduce during the perimenopause and menopause.

An online survey of 1,294 women with Long Covid found that 73% of women reported that their periods have changed since having symptoms of COVID-19. Furthermore, 72% of women reported hat their symptoms of Long Covid changed in relation to their menstrual cycle with 77% of women reporting their symptoms being worse prior to or during their periods (when hormone levels are at their lowest).
These symptoms are likely to be related to low estrogen and testosterone levels so consideration should be given as a priority to replacing these low hormone levels with the right dose and type of HRT.

All women who attend a Long Covid clinic need to be asked about the possibility of being perimenopausal or menopausal. Before the attend the clinic, they should be encouraged to download the free balance app and create a health report which includes a menopause symptom questionnaire – www.balance-app.com

References

1. Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. J Immunol 2017;198(10):4046-4053
2. Ding T, Zhang J, Wang T, Cui P, Chen Z, Jiang J, et al. A Multi-hospital Study in Wuhan, China: Protective Effects of Non-menopause and Female Hormones on SARS-CoV-2 infection. medRxiv 2020; https://www.medrxiv.org/content/10.1101/2020.03.26.20043943v1
3. Fukuma N, Takimoto E, Ueda K, et al. Estrogen Receptor-alpha Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy. JACC Basic Transl Sci. 2020;5(3):282-295
4. Seeland U, Coluzzi F, Simmaco M, Mura C, Bourne PE et al. Evidence for treatment with estradiol for women with SARS-CoV-2 infection. medRxiv 2020; https://www.medrxiv.org/content/10.1101/2020.08.21.20179671v1
5. Ghosh S, Klein RS. Sex drives dimorphic immune responses to viral infections. J Immunol 2017; 198(5): 1782–1790
6. Trenti A, Tedesco S, Boscaro C, Trevisi L, Bolego C, Cignarella A. Estrogen, Angiogenesis, Immunity and Cell Metabolism: Solving the Puzzle Int J Mol Sci 2018; 19(3): 85
7. La Vignera S, Cannarella R, Condorelli RA, Torre F, Aversa A, Calogero AE. Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D. Int J Mol Sci 2020;21(8):2948
8. National Institute for Health and Care Excellence. NICE guideline NG23 – Menopause: diagnosis and management 2015 [May 2017]. Available from: https://www.nice.org.uk/guidance/ng23
9. Baber RJ, Panay N, Fenton A, Group IMSW. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016;19:109-50
10. Manson JE, Aragaki AK, Rossouw JE et al. Menopausal Hormone Therapy and Long-term AllCause and Cause-Specific mortality: The Women’s Health Initiative Randomized Trials. JAMA. 2017; 318(10):927-938
11. Chlebowski RT, Anderson GL, Aragaki AK, er al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA. 2020 Jul 28;324(4):369-380
12. Boardman HM, Hartley L, Eisinga A et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015 Mar 10; 3: CD002229
13. M. Gambacciani, A. Cagnacci & S. Lello Hormone replacement therapy and prevention of chronic conditions. Climacteric 2019;22:303-306
14. Hillman S, Shantikumar S, Ridha A, Todkill D, Dale J. Socioeconomic status and HRT prescribing: a study of practice-level data in England. BJGP 2020;70(700):e772-e777.
15. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33
16. Chlebowski RT, Anderson GL, Aragaki AK, Manson JE, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA. 2020 Jul 28;324(4):369-380
17. Davey DA. Menopausal hormone therapy: a better and safer future. Climacteric 2018; 21:5;454-
    461
18. Nabavi N. Long covid: How to define it and how to manage it. BMJ 2020;370:m3489.
19. Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, et al. Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App. medRxiv 2020; https://doi.org/10.1101/2020.10.19.20214494