The COVID-19 pandemic is a disease caused by the SARS-CoV-2 virus and is affecting the entire world population. Available epidemiological data indicate that men suffer more from the disease and with more severe clinical manifestations than women . This different pattern of severity and infection rate between both sexes was also described for another coronavirus, MERS-CoV, which affected several countries 15 years ago .
The data disaggregated by sex of patients affected by COVID-19 provided by China, the first country to be affected by the pandemic, show that the mortality rate among men suffering from the disease is 2.8% while in women it is 1.7% . In addition to sex and gender, age also plays a determining role in the severity of the disease, so that people who present more severe symptoms and die are older than those with moderate or mild conditions, who do not die . COVID-19 have been related to an increased risk of venous thromboembolism (VET) and some scientific societies have recommended discontinuing or limiting the use of CHC during the pandemic while others suggest that it continue to be used.
In this review, we intend to analyse the evidence and recommendations made on the use and/or discontinuation of combined hormonal contraception during the pandemic. This is a narrative review on the impact of oestrogens on COVID-19.
Why do women have less severe COVID-19 symptoms than men?
Different factors have been identified that can explain the differences in the severity of infection between men and women. One of them is related to the potential protective role that the X chromosome can play. The X chromosome gives women, compared to men, a significant advantage in the immune response, with greater production of antibodies and greater activation of cellular immunity .
Another mechanism that has been associated with the lower severity of the disease among women is the role of oestrogens. Oestrogens activate the immune response and regulate the production of cytokines and the renin-angiotensin complex . The role of oestrogens would explain that older women, with lower oestrogens levels, get sicker and more severely than younger women  or, for example, 88% of pregnant women infected by SARS-CoV −2 were asymptomatic . Studies carried out in an animal model have shown that, in rats infected by another type of coronavirus, such as SARS-CoV, which are ovariectomized, the mortality rate from COVID-19 is 85%, while among non-ovariectomized infected rats this rate is 10–20% . Other experimental studies have confirmed that high levels of systemic oestrogens promote an anti-inflammatory response, decreasing the activation of endothelial cells that leads to the stimulation of leukocyte adhesion and their migration to infected tissues .
It is also known that oestrogens play a protective role in endothelial function by activating nitric oxide synthesis, which has a vasodilatory effect and could counteract the vasoconstrictor effect induced by the inflammatory response . Oestrogens have been shown to induce a greater immune response, both humoral and cellular . A study conducted in China among 331 patients hospitalised for COVID-19 observed significant differences in IgG antibody levels in favour of women .
[In addition to the biological factors that differentiate women and men, there are behavioural and lifestyle factors that can influence the development of COVID-19 disease. These differences are shown in Figure 1 .
21 January 2021
Possible explanation for the differences by sex and gender in the severity of COVID-19. (Modified from 13).
Risk of venous thromboembolic disease (VTE) in COVID-19 patients and hormonal contraception
Venous thromboembolic disease is a rare entity in young women, but it has been associated with the use of CHCs, especially in women with other risk factors for this event . Properly evaluating the risk of VTE in CHC users is especially important during the pandemic since it is known that SARS-CoV-2 infection predisposes to thrombosis, both arterial and venous. Autopsies performed on patients who died from COVID-19 have demonstrated the existence of fibrin thrombi in the small pulmonary arterioles and swelling of the endothelium. These findings could be related to an activation of the coagulation cascade in these patients . For this reason, the care protocols for patients with severe COVID-19 disease contemplate the use of anticoagulants .
The mechanisms by which coagulopathy occurs in patients with COVID-19 are not fully understood, but the hypothesis that gains more weight is that of the induction of a prothrombotic state as a consequence of the disproportionate inflammatory response . Currently available evidence places cytokine storm as the determining factor of pulmonary thromboembolism and increased mortality in patients with COVID-19 . The cause for which patients with severe COVID-19 die is not related to the damage caused by the replication of the SARS-CoV-2 virus but rather it seems to be linked to the so-called cytokine storm . In an attempt to protect the body against viral infection, immune cells infiltrate the lungs causing an over activation of monocytes and macrophages and an increase in the production of pro-inflammatory cytokines and tumour necrosis factor alpha .
A retrospective study of a cohort of 552 patients with COVID-19 who were evaluated during their hospital stay and after discharge to determine the number of recorded thrombotic events, concluded that the increased risk of VTE occurs during the acute phase of the disease, which coincides with the cytokine storm, but the risk decreases rapidly after this phase . In this study, the authors confirmed the low rate of thrombotic events in COVID-19 patients after being discharged from hospital, even in the case of not being anticoagulated. To some extent, this observational study calls into question the need to anticoagulate COVID-19 patients after discharge from hospital.
Steroid hormones are strong immunomodulators capable of influencing the immune and inflammatory response produced by COVID-19 disease. In addition, 17 beta oestradiol suppresses the production of pro-inflammatory cytokines (interleukin 6, interleukin 1 beta, and tumour necrosis factor alpha) while stimulating the production of anti-inflammatory cytokines (interleukin 4 and interleukin 10) by T lymphocytes and stimulates the production of antibodies by B lymphocytes . Oestrogens could counteract this increased thrombotic risk due to their antiplatelet activity and activation of nitric oxide .
Based on the foregoing, some authors even recommend the use of oestrogens in the treatment of COVID-19, either in the form of conjugated equine oestrogens , either in the form of 17 beta oestradiol , or in the form of selective modulators of the receptor. oestrogen (SERM) . This last group of researchers has already demonstrated the usefulness of SERMs in experimental studies in other coronavirus infections such as MERS-CoV and SARS-Cov, especially toremifene citrate, one of the classic SERMs .
A randomised clinical trial is currently underway to assess whether oestradiol administered transdermal, in the form of a patch, to patients with COVID-19, can reduce the severity of the disease compared to usual care. The trial began recruiting patients in April 2020 and is scheduled to end in November 2020. This trial is expected to recruit 110 patients .
Can we continue to prescribe CHC during the COVID-19 pandemic?
To answer this question, I believe it is convenient to distinguish between three types of patients: (1) patients with moderate or severe COVID-19 who require hospital admission for their control and treatment; (2) asymptomatic or paucisymptomatic patients with COVID-19 without hospital admission and (3) patients without COVID-19 but exposed, like the general population, to a possible SARS-CoV-2 infection.
Moderate or severe COIVD-19 patients admitted to hospital
These patients generally meet the three Virchow conditions for VTE: vascular damage, prothrombotic state, and venous stasis due to prolonged immobilisation . Of the three components of Virchow’s triad, in patients with COVID-19 the most relevant is the vascular damage, which causes an alteration of the endothelium, considering that the alteration of the coagulation factors has a residual role in thrombus formation in these patients . However, it is known that the patients who evolve worse and require hospital admission are the oldest , so it is unlikely that a young woman, CHC user, will be admitted to the hospital for COVID-19 and may raise the question. to withdraw or continue the use of the contraceptive.
Patients with mild or asymptomatic COVID-19
The Spanish study group of thromboembolic risk in women with COVID-19 under hormonal treatment recommended, in general, for this type of patients to change the CHC to a progestin-only method if there are additional risk factors for VTE . In a letter to the Editor sent after the publication of the article, the authors of these recommendations specify that they do not advise against the use of oestrogens, but against the use of oral oestrogens, opening the door to the possibility of using oestrogens transdermally in the case of postmenopausal women in hormonal replacement therapy (HRT) . Similar recommendations have been made by other authors from other countries where COVID-19 has had very high incidence rates, such as Brazil . On the contrary, the Italian Society of Contraception recommends not suspending contraceptive treatment with oestrogens in these types of patients, considering that the suspension of the oestrogen supply could accelerate the progression of COVID-19 . In the same way, other authors consider that there is no reason not to use CHCs during the pandemic due to the protection they offer against unwanted pregnancy and the beneficial effects on the immune system during SARS infection -CoV-2 .
It is pending to define whether, in the same way as in patients with COVID-19 it is recommended to use oestradiol transdermally, instead of orally, for HRT, the use of ethinyl oestradiol by a non-oral route can be recommended. In contraception we have two combined non-oral hormonal methods: the transdermal patch and the contraceptive vaginal ring. Data from a very large epidemiological study demonstrated that the risk of thrombotic events among users of the contraceptive patch was higher than that of users of the contraceptive vaginal ring . However, it is known that the route of administration of ethinylestradiol does not seem to influence its impact on coagulation parameters .
At the time of this review, no comparative studies have been found between the different contraceptive methods that analyse the occurrence of thrombotic events when used by COVID-19 patients.
Likewise, we do not have evidence on the impact of the use of CHCs with oestradiol valerate or 17 beta oestradiol in patients with COVID-19. What is known is that the impact on the coagulation parameters of contraceptives containing oestradiol is less than that induced by those containing ethinylestradiol . There are no studies that show that this lower impact on the procoagulant activity of oral contraceptives with oestradiol translates into fewer VTE events in patients with COVID-19, although we can consider it to be biologically plausible.
Patients without COVID-19
This group of women corresponds to that of the general population, exposed to a possible infection by SARS-CoV-2 and the development of the COVID-19 disease.
During the period of time between May 7 and June 15, 2020, researchers from Kings College London and the University of Liverpool collected information on hormonal status and COVID-19 disease among 1.6 million women in the UK, through an app designed by them (COVID Symptom Tracker) . With these data, they conducted a case-control study in which the cases were defined as women between 18 and 45 years of age, with a Body Mass Index (BMI) of 20–35 kg/m2 who used CHCs (64,253 women) and controls were defined as women of the same age range and BMI who did not use any form of hormonal contraception (231,436 controls). The risk (Odds ratio [OR]) of suffering from COVID-19 disease was lower for women who used CHC than for those who did not use it (OR = 0.87 95% confidence interval (CI): 0.81–0.93). The study authors concluded that their data demonstrate a protective effect of oestrogens against symptomatic COVID-19.
In the case of considering substituting CHC for another type of oestrogen-free contraceptive to avoid the risk of VTE in patients susceptible to COVID-19, some authors postulate that, given the time necessary for the normalisation of coagulation parameters after the suspension of the CHC (approximately 2 months), it would be better to add anticoagulant treatment to women using CHC sick with COVID-19, than to suspend the CHC and switch to using contraception with only progestins or non-hormonal contraception .
The SARS-CoV-2 virus pandemic has been affecting all of humanity since the beginning of the year and, at the time of writing this review, we are being affected by the second wave of infection and disease. In the last months of 2020, there are thousands of articles published related to COVID-19 but few that analyse the topic that prompted this work: the use of CHCs during the pandemic.
There is evidence, known for a long time, of the role that oestrogens play in the immune response, which, together with other factors associated with lifestyle and behaviour, explains that women have a lower rate of infection by SARS-CoV-2 and, above all, have less severe symptoms and a lower fatality rate from COVID-19.
We have found no evidence of a possible increased risk of VTE in CHC users suffering from COVID-19. The mechanisms by which VTE occurs in CHC users appear to be different from the mechanisms by which VTE occurs in COVID-19 patients. There are no published data on the possible summative effect of the two risk factors.
The recommendations made for continuing the use, abandonment or change of contraceptive method in women with COVID-19 or at risk of being infected by SARS-CoV-2 reflect the opinions of expert groups, but are not based on scientific work designed to such aim. We have identified a retrospective study in which it was observed that women who used CHC orally were less infected with SARS-CoV-2 than those who did not use it.
There is some evidence of the therapeutic role of oestradiol in the most severe stages of the disease, but the possibility of continuing to use CHCs with low doses of non-oral ethinylestradiol or with 17 beta oestradiol orally has not been explored. Clinical studies are needed to analyse the VTE safety of low-dose non-oral ethinyl oestradiol preparations or oestradiol preparations in patients with COVID-19.
In conclusion, according with the Italian Society of Contraception  we can continue to prescribe and use hormonal methods with EE.