The aim of this trial is to determine whether oestrogen treatment mitigates disease progression and severity in confirmed COVID19.

It is known that (i) women are relatively protected from the impacts of other respiratory viruses, and that oestrogen may partly mediate this effect (ii) Oestrogen protects rodents from SARS-CoV-1 related mortality (iii) Women are relatively protected from developing or dying from severe COVID-19 and (iv) Postmenopausal women taking oestrogen replacement appear less likely to suffer Covid19-related critical illness. These effects may be mediated through oestrogen-related immunomodulation. In addition, however, 17β estradiol reduces expression of ACE2 (the receptor protein through which SARS-CoV-2 gains cellular entry) in tissues such as the kidney. As such, supplemental oestrogen may represent an effective therapy for Covid19.

We will randomise adult men and postmenopausal women with confirmed Covid19 disease to receive 10 days of transdermal oestrogen (3mg/day). The primary endpoint will be evidence of disease progression, indicated by hospitalisation (mild cases) or need for mechanical ventilation or death within 28 days of randomisation for those hospiatlsied. Secondary outcomes will include hospital mortality, duration of hospital admission, admission to ICU/ HDU facility, ICU/ HDU length of stay, need for renal replacement therapy, receipt and duration of invasive mechanical ventilation, cause-specific mortality and time to being fit for hospital discharge

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Inclusion Criteria:

• Acute Covid-19 disease (PCR-confirmed or clinically diagnosed with high certainty)
• Adult males > 18 years of age OR
• Post-menopausal women (spontaneous amenorrhoea for >12 months in the absence of any other cause)

Exclusion Criteria:

Women:

• taking oestrogen supplements or oestrogen receptor antagonists
• with abnormal genital bleeding
• with a history of breast cancer
• with a history of endometrial or ovarian cancer
• with untreated endometrial hyperplasia

Men:

• taking hormone therapies (e.g. for prostate cancer)

Any subject:

• failure to obtain consent
• taking lamotrigine
• with a thromboembolic disorder (e.g. Protein C or Protein S deficiency, antithrombin III deficiency)
• with pre-existing liver or renal disease
• with known allergy to exogenous oestrogens
• with a history of porphyria
• with a history of thromboembolic event including deep vein thrombosis, thromboembolic stroke or pulmonary emboli
• taking part in another interventional clinical trial