Reflections and recommendations on the COVID-19 pandemic: Should hormone therapy be discontinued?

Since the COVID-19 pandemic outbreak, the extent of seriouscomplications and high rate of mortality has concerned all the healthauthorities worldwide. Death by COVID-19 is mainly due to acute re-spiratorydistresssyndrome(ARDS),althoughheartandmultipleorganfailure may contribute [1]. Underlying mechanisms are COVID-19-in-duced endothelial alteration, cytokine storm, inflammation, exudationin the lungs, and vessel occlusion.1. DifferencebetweensexesMortalitybyCOVID-19ishigherinmenthaninwomen.Amongtheadvocated reasons are a different exposure to risk factors such assmoking, reduced care of men about their health or different associa-tion with other morbidities. Nevertheless, a different expression ofACE2 may explain the different mortality between sexes. COVID-19disease progression is reduced by ACE2 enzyme expression in en-dothelial cells mainly at the lung and heart, where it exerts vasodi-lating, anti-inflammatory and anticoagulant effects [2]. ACE2 is codedby the X chromosome, of which men have only one, and ACE2 ex-pression in endothelial cells is stimulated by estrogens [2]. The possi-bility that thismechanisms accountsfor the lowermortalityof womenvs. men (Yi et al.) is sustained by the recent evidence that reducedmortality (−72 %) of fertile women vs. men is lost, at least in part, inthe postmenopausal years (−49.6 %) [3].2. HormonetherapyThese data lead to speculation that hormone therapy or even po-tentiating estrogen stimulus by exogenous estrogens may antagonizethe deadly progression of the disease. On the other hand, exogenousestrogens may increase coagulating factors and the risk of throm-boembolic events with a potential consequent increase in mortality.Hospitalized individuals with very severe COVID-19 disease have anactivated coagulation defined by high levels of D-dimers, products offibrin degradation, and when D-dimer levels are very high, antic-oagulants like heparin may reduce mortality [4]. In order to decreasethe risk of thromboembolic events a recent publication has re-commended that peri- and post-menopausal women immediatelywithdraw from exogenous hormone administration after becoming in-fected by COVID-19 [5]. This position stimulates some considerations.1) Thrombophilic states are not among the comorbidities that ac-celerate COVID-19 disease progression. To date, there is no reportdocumenting that the most thrombophilic state in woman life, i.e.pregnancy,orevenhormonalcontraceptiveuse[6],isassociatedwithaworst prognosis of COVID-19 infection. 2) Locally formed thrombi,consequenttomassiveendothelialdisruptionandlocalactivationoftheextrinsic coagulation cascade, rather than cloth emboli, appear to oc-cludelungvesselsofCOVID-19-infectedindividualsinthelaststageofdisease[4].Indeed,theevidencethatmanywomenwithoccludedlungvessels lack peripheral vein thrombosis challenges the theory of amassively increased thrombophilic condition [4]. Of the Virchowtriadexplainingbloodclotformation,i.e.increasedcoagulation,bloodstasisand altered endothelium, it is the third component that is highly pre-valent in COVID-19 individuals, the contribution of increased coagu-lation being unknown and probably negligible [4]. 3) The dose of he-parinusedinCOVID-19-infectedindividuals(80−100mg)exceedstheprophylacticdoseforthrombophilicstates.4)Aputativeincreasedriskof venous thrombosis due to increased synthesis of coagulation factorsis mainlylimited tothefirsttwo years oforal estrogenadministration,and up to now no study has reported a thrombophilic effect of trans-dermal estrogens [7]. 5) Perimenopausal women requiring hormonalcontraception are usually in their late forties and postmenopausalwomen start their hormone therapy for symptoms before 60 years ofage. In these years, mortality from COVID-19 is below 1 % [3], andthere is no report that it is higher in women on hormones.3. ConclusionsAt first sight, indications for COVID-19-positive individuals towithdraw from hormone therapy or oral contraceptives may seem awise recommendation, but it is not based on real data. It takes intoconsideration only one side of the coin, the procoagulant activity ofexogenousoralestrogens.ThiseffectforCOVID-19patientsislikelytheleast important. In these individuals, increased coagulation is con-sequent to massive endothelial disruption and to the activation of theextrinsic coagulation cascade, with no evidence that an increase incoagulating factors plays any role [4]. By contrast, the advice towithdraw from estrogens misses a consideration of the main effect ofestrogens, i.e. their ability to stimulate ACE2 enzyme expression, acritical factor in reducing mortality from COVID-19 [2].4. RecommendationsOn these bases, we suggest that advice for COVID-19-infectedwomen should be:a Hormone therapy or hormonal contraceptives [6] should be con-tinued, unless the woman is severely ill, a condition in which hor-monalbalanceisprobablynotsocrucial.Intheotherconditions,thepossibility that hormone withdrawal may accelerate COVID-19https://doi.org/10.1016/j.maturitas.2020.05.022Received 16 May 2020DOI of original article:https://doi.org/10.1016/j.maturitas.2020.05.021Maturitas 138 (2020) 76–770378-5122/ © 2020 Elsevier B.V. All rights reserved.T