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