Reply to Jakovac: Sex differences in COVID-19 course and outcome: progesterone should not be neglected.

to the editor: The Letter to the Editor entitled “Sex differences in COVID-19 course and outcome: progesterone should not be neglected” (4a) in response to our study (2) included a proposition of the benefits of progesterone use for COVID-19 course and outcome. In fact, one recent review also suggested the use of sex hormones, such as estradiol and progesterone, in the fight against COVID-19 (5). Additionally, there is one ongoing study registered at ClinicalTrials.gov (NCT04365127—Progesterone for the Treatment of COVID-19 in Hospitalized Men) in which volunteer men who are hospitalized with COVID-19 and meet the eligibility criteria will receive 100 mg of progesterone administered subcutaneously twice daily for 5 days, in addition to institutional standard of care.

The organism’s first antiviral responses against pathogens are made by the activation inflammatory pathways of the immune system; in this scenario, estradiol can be important, as it has immunostimulatory roles (6) and can help the organism to respond to the viral infection. However, an exaggerated immune response, known as a “cytokine storm,” can lead to increased severity of the disease and progesterone and testosterone might be used in this case, as both are immunosuppressive and counteract the pathways affected by estradiol (6). As widely reported by many studies, scientific reports and by the media, the highest mortality in patients with COVID-19 is observed in older and immunocompromised individuals. Age increases the levels of proinflammatory cytokines and decreases the expression of immune memory/effector cells which could lead to increased susceptibility to infections and worsening of the disease (3). This remodeling of the immune system and decline in immune efficacy with age could drive a decreased response to vaccines (3) and can be a challenge in the control of COVID-19.

Age is accompanied by a decline in sex hormones in both sexes, which could be related to the remodeling of the immune system (3). Therefore, sex hormone replacement could be important in the context of COVID-19 and cytokine release (as we discussed in our study), as sex hormones modulate the immune system and can help with the balance of inflammatory and anti-inflammatory cytokines (6). Nevertheless, sex hormone therapies can also bring risks, as they can change many homeostatic parameters, depending on type of hormone (different synthetic variations or bioidentical), the dose used, the via (oral, transdermal, etc.), and the period of use, since many studies already shown high risk for vascular problems related hormonal replacement therapy.

In this regard, one French study of 271 postmenopausal women who had previously presented venous thrombotic event (VTE) episode showed that oral hormone treatment users had 4-fold-increased odds of a VTE, whereas transdermal hormone users had no increased risk (1).

Therefore, it is important to highlight that synthetic progestins present differing degrees of androgenic and thromboembolic properties that should be considered when prescribing individualized treatments (4).

In conclusion, the use of sex hormone therapies can have benefits, but can also lead to adverse effects. Interactions in individuals with comorbidities must be carefully evaluated so that their risks do not outweigh the benefits.

GRANTS

This work was supported by MCTI Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq): Luciane H. Gargaglioni 407490/2018-3 and by São Paulo Research Foundation (FAPESP): Luciane H. Gargaglioni 2019/09469-8.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

L.H.G. and D.A.M. drafted manuscript; L.H.G. and D.A.M. edited and revised manuscript; L.H.G. and D.A.M. approved final version of manuscript.