Role of Short-Term Estradiol Supplementation in Symptomatic Postmenopausal COVID-19 Females

Abstract

Background: Protective role of estrogen in COVID-19 was speculated once the epidemiological studies reported increased susceptibility of estrogen-deficient population – males and postmenopausal females to severe disease category and involvement of angiotensin-converting enzyme 2 receptors and renin–angiotensin– aldosterone system in pathophysiology. Materials & Methods: An open-label randomized controlled trial was planned to assess the efficacy of short-course oral estradiol in preventing the clinical progression to severe disease and reduce case-fatality rate and the hospital stay duration in estrogen-deficient postmenopausal women. The intervention group (n = 40) received 2 mg per day of estradiol valerate per orally for 7 days along with the standard care, while the control group (n = 40) received only the standard care. Results: A significant difference was observed in the rate of reverse transcriptase–polymerase chain reaction negativization in the intervention versus control group at day 5 and day 7 of admission (42.5% vs. 15%, P = 0.007; 72.5% versus 50%, P = −0.026). No significant difference was noted in the duration of hospitalization (P = 0.213). A significant decrease was noted in the mean values of inflammatory biomarkers – D-dimer, lactate dehydrogenase, and C-reactive protein on day 5 in the intervention group. Interleukin-6 also showed a declining trend on day 5 in the intervention group, while a rising trend was noted in the control arm. Only one case (2.5%) in the intervention group while seven in the control group (17.5%) progressed to the moderate category; however, the difference was not statistically significant (P = 0.057). Conclusion Oral estradiol in postmenopausal females can be a novel and efficient option for managing nonsevere COVID-19 infection.

Estradiol reduces ACE2 and TMPRSS2 mRNA levels in A549 human lung epithelial cells

“…The same study reported a similar Covid‐19 fatality risk for younger (premenopausal) women, irrespective of ERT; this probably reflects their higher endogenous estradiol (Seeland et al, 2020 ). Additionally, a small randomized trial ( n = 40) in hospitalized Covid‐19 postmenopausal females treated with oral estradiol supplementation (2 mg per day for 7 days) found faster recovery, while its small size ( n = 40) did not allow to identify a reduction in Covid‐19 fatalities (Seth et al, 2021 ). Larger cohorts are definitely required to assess the potential of prescribing estradiol to Covid‐19 patients.…”

Effect of Norelgestromin and Ethinylestradiol in Transdermal Patches on the Clinical Outcomes and Biochemical Parameters of COVID-19 Patients: A Clinical Trial Pilot Study

“…In an open-label randomized controlled trial, it was shown that the use of estradiol valerate (2 mg per day for 7 days) with the standard care in estrogen-deficient postmenopausal women infected with mild and moderate COVID-19 caused a significant decrease in the D-dimer, lactate dehydrogenase (LDH), interleukin (IL)-6, and CRP on day 5 of the intervention [29]. In addition to this study, it has been shown that the use of oral contraceptive pills in 18-45-year-old women infected with COVID-19 significantly reduced the hospital attendance and had a significantly lower predicted COVID-19 [30].…”

Effect of 17β-estradiol on the daily pattern of ACE2, ADAM17, TMPRSS2 and estradiol receptor transcription in the lungs and colon of male rats

“…As E2 administration is being considered as a supportive therapy in Covid-19 treatment [ 25 , 26 ] it may be of interest that E2 also influences the circadian system, which in turn regulates the expression of hundreds of clock-controlled genes. The finding that ACE2 and TMPRSS2 mRNA exerted a low-amplitude rhythm in animals exposed to E2 brings up the idea that the daily pattern in their expression can be modified under conditions of rhythmic E2 administration.…”

“…It was shown that in women above 50 years of age, EHT reduced the risk of fatality from Covid-19 by more than 50% [ 25 ]. Similarly, short-term oral administration of E2 decreased the time to viral clearance in Covid-19 patients [ 26 ]. Although ACE2 levels were not monitored in these studies, it has been demonstrated previously that E2 treatment increased ACE2 activity in the plasma [ 27 ].…”