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Review 1: "Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study"

This is a reliable study that shows the protective role of estrogens against COVID-19 severe complications among 1.6 million UK women. Novel findings show potential increased risk amongst postmenopausal women and a potentially protective role of COCP in premenopasual women.

Published onAug 21, 2020
Review 1: "Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study"
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key-enterThis Pub is a Review of
Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study

Background: Men and older women have been shown to be at higher risk of adverse COVID-19 outcomes. Animal model studies of SARS-CoV and MERS suggest that the age and sex difference in COVID-19 symptom severity may be due to a protective effect of the female sex hormone estrogen. Females have shown an ability to mount a stronger immune response to a variety of viral infections because of more robust humoral and cellular immune responses. Objectives: We sought to determine whether COVID-19 positivity increases in women entering menopause. We also aimed to identify whether premenopausal women taking exogenous hormones in the form of the combined oral contraceptive pill (COCP) and post-menopausal women taking hormone replacement therapy (HRT) have lower predicted rates of COVID-19, using our published symptom-based model. Design: The COVID Symptom Study developed by Kings College London and Zoe Global Limited was launched in the UK on 24th March 2020. It captured self-reported information related to COVID-19 symptoms. Data used for this study included records collected between 7th May - 15th June 2020. Main outcome measures: We investigated links between COVID-19 rates and 1) menopausal status, 2) COCP use and 3) HRT use, using symptom-based predicted COVID-19, tested COVID-19, and disease severity based on requirement for hospital attendance or respiratory support. Participants: Female users of the COVID Symptom Tracker Application in the UK, including 152,637 women for menopause status, 295,689 for COCP use, and 151,193 for HRT use. Analyses were adjusted for age, smoking and BMI. Results: Post-menopausal women aged 40-60 years had a higher rate of predicted COVID (P=0.003) and a corresponding range of symptoms, with consistent, but not significant trends observed for tested COVID-19 and disease severity. Women aged 18-45 years taking COCP had a significantly lower predicted COVID-19 (P=8.03E-05), with a reduction in hospital attendance (P=0.023). Post-menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P=2.22E-05) for HRT users alone. Conclusions: Our findings support a protective effect of estrogen on COVID-19, based on positive association between predicted COVID-19 and menopausal status, and a negative association with COCP use. HRT use was positively associated with COVID-19 symptoms; however, the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential comorbidities. Trial registration: The App Ethics has been approved by KCL ethics Committee REMAS ID 18210, review reference LRS-19/20-18210

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



I read with interest the study by Costeira R et al. about the role of estrogens in COVID-19 symptoms according to data from the COVID Symptom Study Smartphone Application App. It includes more than 1.6 million women in the UK, with all analyses adjusted for age, BMI and smoking status.

The protective role of estrogens in this study is evident. Women in postmenopause (i.e. with hypoestrogenism due to ovarian physiological failure) presented a higher rate of predicted COVID-19 and associated symptoms. Moreover, women using combined hormonal contraceptives (CHCs) had a lower rate of predicted COVID-19 and a corresponding reduced frequency of symptoms, associated also with a lower rate of hospitalisation.

On the other hand, the protective role of hormone therapy (HT) for menopausal symptoms was controversial: HT use was associated with an increased rate of predicted COVID-19. However, HT results should be considered with caution due to lack of data on HRT type, high mean age of users (> 58 years old), the different route of administration and duration of treatment.

It is well known that estrogens stimulate the humoral response to viral infections by inducing higher levels of antibodies and activating antibody-producing cells. Moreover, ACE2 expression in endothelial cells, a natural protection to COVID-19 infection, is stimulated by estrogens. This has just suggested by previous studies and commentaries recently published, showing that excess death rate by COVID-19 is lower in women than in men (Cagnacci A, Xholli A; AJOG 2020) and that the virus has a clear gendered impact already from the first Chinese reports (Grandi G et al; EJCRHC 2020).

Therefore, this has been confirmed by the guidelines of The Italian Society of Contraception, in which the use of CHCs is recommended during the pandemic (Fruzzetti F et al, EJCRHC 2020). Women on CHCs are generally healthy, non-smokers and with no pre-existing chronic diseases, including cardiovascular and cerebrovascular diseases, respiratory system diseases, cancer, and chronic liver and kidney disease (respecting the Medical Elegibility Criteria).

The topic remains still controversial for HT: Italian Menopause Society recommended that HT should be continued, unless the woman is severely ill (Cagnacci A et al, Maturitas 2020). The Spanish Society had a different position: it is suggested that HT is withdrawn during the period of isolation and reduced mobility (Ramirez I et al, Maturitas 2020). For the Spanish the thromboembolic risk is very important in the balance of risks and benefits: but who has ever highlighted the thrombotic risk of HT in “normal” times? Unfortunately, this controversy will be still without a clear answer, even after this study.

Before the preprint can be published, minor revision is recommended. Adding key references is recommended:

-       Cagnacci A, Xholli A. Age-related difference in the rate of coronavirus disease 2019 mortality in women versus men. Am J Obstet Gynecol. 2020 May 24:S0002-9378(20)30572-X.

-       Grandi G, Facchinetti F, Bitzer J. The gendered impact of coronavirus disease (COVID-19): do estrogens play a role? Eur J Contracept Reprod Health Care. 2020 Jun;25(3):233-234.

-       Fruzzetti F, Cagnacci A, Primiero F, De Leo V, Bastianelli C, Bruni V, Caruso S, Di Carlo C, Farris M, Grandi G, Grasso A, Guida M, Meriggiola M, Paoletti AM, Cianci A, Nappi C, Volpe A. Contraception during Coronavirus-Covid 19 pandemia. Recommendations of the Board of the Italian Society of Contraception. Eur J Contracept Reprod Health Care. 2020 Jun;25(3):231-232.

-       Cagnacci A, Bonaccorsi G, Gambacciani M; board of the Italian Menopause Society. Reflections and recommendations on the COVID-19 pandemic: Should hormone therapy be discontinued? Maturitas. 2020 Aug;138:76-77.

-       Ramírez I, De la Viuda E, Baquedano L, Coronado P, Llaneza P, Mendoza N, Otero B, Sánchez S, Cancelo MJ, Páramo JA, Cano A. Managing thromboembolic risk with menopausal hormone therapy and hormonal contraception in the COVID-19 pandemic: Recommendations from the Spanish Menopause Society, Sociedad Española de Ginecología y Obstetricia and Sociedad Española de Trombosis y Hemostasia. Maturitas. 2020 Jul;137:57-62.

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