Costeira et al.  performed a retrospective case-control study to identify the association between estrogens and rate of COVID-19 positivity and severity. The study analyzed the self-reported data of 1.6 million UK women through the COVID Symptoms Study Smartphone application. The authors compared the risk of predicted COVID-19, frequency of symptoms, hospitalizations and need of respiratory support in three populations: menopausal woman (152,637), premenopausal woman using of combine oral contraceptive pill (COCP) (295,689), and menopausal women using hormone replacement therapy (HRT) (1’511,930). The control populations were adjusted for age, body mass index, and smoking status.
Compared to premenopausal woman, menopausal ones showed an increased risk of predicted COVID-19 (OR=1.22, p=0.003), symptoms, and a no significant increase in need of respiratory support (OR=1.6, p<0.05). Use of COCP was associated to a lower rate of predicted COVID-19 (OR=0.87, p<0.001), a decrease frequency of symptoms and hospitalizations (OR=0.79, p=0.02). For women on HRT the rate of predicted and symptomatic COVID-19 significantly increased (p<0.001). The author conclude that their study supports a protective effect of estrogens against COVID-19 in premenopausal women. The data regarding the HRT population should be considered with caution due to the lack of data on HRT type, route of administration and duration of treatment.
The global data of COVID-19 have shown males to have a higher risk of severe disease and mortality than females. This observation suggests that gender represents a risk factor in COVID-19 morbidity and fatality, independent of age and susceptibility [2,3]. This sex-related different can be partially explained by the presence of an additional X chromosome due to the fact that most of immune-associated genes reside in X chromosome. Mechanisms as skewed inactivation, escaping X inactivation and mosaicism may improve female adaptive immune response efficacy . Observational studies have highlighted that the mortality rate among SARC-CoV-2-positive pregnant women in the USA significantly was lower than in the general female population (0.16% vs. 2.24%) and that the severity of disease tends to increase immediately in the postpartum period, when blood level of sex-hormones, and in particular progesterone, drop .
The present study by Costeira et al.  evidenced that the severity of COVID-19 increases in menopause women and decreases in premenopausal ones using COCP. These data have been confirmed by a subsequent systemic analysis conducted by Li et al. , that highlighted a significantly increase in COVID-19 mortality in females from the age of 55. These evidences show how the gender-related difference can be only partially explained by genetic causes and they suggest a protective role of female sex hormones.
Sex steroids play important roles in the modulation of inflammatory processes. Estradiol and progesterone are anti-inflammatory, promote immunotolerance, reshape competence of immune cells, and stimulate antibody production . After the menopause, the decline of sex hormones reduces the number of B and T cells, while increasing the production of pro-inflammatory cytokines . Estradiol acts as a specific SARS-CoV-2 resistance factor: high estradiol concentrations decrease lung angiotensin-converting enzyme 2 (ACE2), used by SARS-CoV-2 to gain access in the respiratory epithelium [4,5]. Furthermore, elevated estrogen concentration and/or estrogen receptor alpha (ERα) activation have been shown to enhance type I and III interferon (IFN) synthesis, leading to a decrease in virus titer . Li et al  determined in their systematic analysis that estrogens, interacting with ESR1/2 receptors, can specifically inhibit SARS-CoV-2 caused inflammation and immune response signaling in host cells .
The differences in immune response, induced by high level of sex hormones, may explain the increased vulnerability to COVID-19 of man and of postmenopausal woman. Therefore, it is rational to consider sex steroid hormones as potential treatment option in alleviating the course of SARS-Cov-2 infection. Unexpectedly, the present study showed an increase in SARS-Cov-2 positivity and frequency of symptoms in menopausal women using HRT compared to the control group: although the study also showed a non-significant reduction in need of respiratory support in this population . In any case, the authors invite caution in the interpretation of these data due to the presence of potential bias regarding the lack of differences between HRT and potential population selection bias.
Based on the multiple sources of evidence that show how sex hormones can have a protective role against SARS-Cov-2, there are presently two ongoing clinical trials which aim to investigate if the addition of estrogen and progestins therapies can be safe and effective in reducing the severity of COVID-19 symptoms .
Francesca Massimello, MD
Paolo Mannella, MD, PhD
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Costeira R, Karla AL, Murray B, et al. Estrogen and COVID-19 Symptoms: Associations in Women from the COVID Symptom Study. PLoS One. 2021:16(9):e0257051.
- Jin JM, Bai P, He W, et al. Gender Differences in Patients With COVID-19: Focus on Severity and Mortality. Front Public Health. 2020;8:152.
- Okpechi SC, Fong JT, Gill SS, et al. Global Sex Disparity of COVID-19: A Descriptive Review of Sex Hormones and Consideration for the Potential Therapeutic Use of Hormone Replacement Therapy in Older Adults. Aging Dis. 2021;12(2):671-683.
- Pinna G. Sex and COVID-19: A Protective Role for Reproductive Steroids. Trends Endocrinol Metab. 2021;32(1):3-6.
- Li F, Boon ACM, Michelson AP, Foraker RE, Zhan M, Payne PRO. Estrogen Hormone Is an Essential Sex Factor Inhibiting Inflammation and Immune Response in COVID-19. Res Sq. 2021:rs.3.rs-936900.
- Viveiros A, Rasmuson J, Vu J, et al. Sex Differences in COVID-19: Candidate Pathways, Genetics of ACE2, and Sex Hormones. Am J Physiol Heart Circ Physiol. 2021;320(1):H296-H304.
- Lovre D, Bateman K, Sherman M, Fonseca VA, Lefante J, Mauvais-Jarvis F. Acute estradiol and progesterone therapy in hospitalised adults to reduce COVID-19 severity: a randomised control trial. BMJ Open. 2021;11(11):e053684.
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