The severe acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2) infection and the climacteric woman

Abstract

The severe acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2) infection has affected millions of individuals worldwide, causing high mortality rates and severe physical sequelae, with a negative impact on society, economy, health care, lifestyle and personal relationships. Studies have confirmed this infection has sex and age differences in terms of disease severity and immune response, with a particular relationship with the anti-Müllerian hormone, a marker of aging, and estradiol, a marker of ovarian function. Postmenopausal women seem to present a more severe infection as compared to premenopausal ones. Estradiol protects the vascular system, mediating with the renin–angiotensin–aldosterone system, whereas testosterone enhances the levels of angiotensin-converting enzyme and the transmembrane protease serine-type 2, thus delaying viral clearance in men as compared to women. This new infection will stay among us, transforming our social, economic and daily lifestyle, and hence medical and health care as well as the use of menopause hormone therapy will need redefining, considering both preventive and curative perspectives.

摘要

冠状病毒2感染导致的严重急性呼吸综合症（SARS-CoV-2）已影响全球数百万人, 造成高死亡率和严重的身体后遗症, 对社会、经济、保健、生活方式和个人关系产生负面影响。研究证实, 这种感染在疾病严重程度和免疫反应方面存在性别和年龄差异, 与衰老标志物抗苗勒管激素和卵巢功能标志物雌二醇有特殊的关系。与绝经前女性相比, 绝经后女性似乎感染更为严重。雌二醇可保护血管系统, 介导肾素-血管紧张素-醛固酮系统, 而睾酮可提高血管紧张素转化酶和跨膜蛋白酶丝氨酸2型的水平, 因此与女性相比, 延迟了男性的病毒清除。这种新的感染将留在我们中间, 改变我们的社会、经济和日常生活方式, 因此, 从预防和治疗的角度考虑, 医疗和保健以及绝经激素疗法的采用都需要重新定义。

Keywords:

• SARS-CoV-2
• COVID-19
• menopause
• sex difference
• mortality
• ovarian hormones
• climacteric
• lockdown

The coronavirus 2 (SARS-CoV-2), causing the severe acute respiratory syndrome, belongs to a group of RNA-virus that also includes the type 1 SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS). The SARS-CoV-2 has infected millions of individuals worldwide in a few months, causing high mortality rates and severe physical sequelae. The pandemic has also had a negative impact on society, economy, health care (users and providers), lifestyle and personal relationships. Basal health status, sex, age, lifestyle, immune status, and current co-morbidities may determine the evolution of the infection and related complications. However, it seems that all humans have a major genetic risk of severe SARS-CoV-2 susceptibility which is present in a genomic segment inherited from the Neanderthals and currently present in 50% of people from South Asia and 16% of people in Europe¹. Therefore, this characteristic might explain the high contagiousness or dissemination all over the world.

The initial publications from China regarding the SARS-CoV-2 infection and the coronavirus disease 2019 (COVID-19) pointed out sex and age differences in terms of disease severity and immune response, being related to the anti-Müllerian hormone, a marker of aging, and estradiol, a marker of ovarian function. Males have worse clinical outcome when compared to women and postmenopausal women worse than premenopausal women. In addition, an inverse correlation between the inflammatory response and cytokine changes related to ovarian function has been observed, as the prognosis for postmenopausal women is worse than for those with normal menstrual function². Although the sex gap after SARS-CoV-2 infection was evident in China, the higher mortality rates found for men were initially attributed to the higher smoking rates found among them. However, mortality rates were also higher in men as compared to women from different European countries or from New York City^3,4.

Different study models/approaches have confirmed that the SARS-CoV-2 infection also has an age-related factor, including higher rates of positive cases, greater disease severity and higher mortality rates among men as compared to women across the lifespan^4,5. It seems that women produce stronger immune responses to the SARS-CoV-2 infection than men⁶. The sex difference in immune response may be related to the sexual chromosomes, several genes, gonadal hormones, and the microbiome that will be expressed by an exaggerated release of pro-inflammatory cytokines/chemokines. Testosterone has inhibitory properties on the immune system, both on cytokine production and lymphocyte proliferation^7,8.

Information addressing the menopausal status and SARS-CoV-2 infection is limited; hence, understanding of the effect of estradiol on the immune response to this infection is lacking or preliminary. Gersh et al.⁹ advocate the convenient use of estradiol due to its anti-inflammatory properties and its effects over the renin–angiotensin–aldosterone system and anti-viral response biochemical mediators^9–11. For instance, estradiol protects the vascular system, mediating with the renin–angiotensin–aldosterone system, whereas testosterone enhances angiotensin-converting enzyme and the transmembrane protease serine-type 2 levels, thus delaying viral clearance in men as compared to women. Despite this, there are no studies reporting estrogen administration during the COVID-19 outbreak. On the other hand, estrogen receptors may be damaged or down-regulated. The antiestrogen tamoxifen may act through estrogen receptors and, as a P-glycoprotein inhibitor (independent of its effects at the receptor level), it may suppress T-cell functions and interferon release, increasing the severity of the SARS-CoV-2 infection¹². There is a need to monitor risk/benefits in women under menopause hormone therapy (MHT) or those receiving tamoxifen due to breast cancer.

Upon COVID-19 admission to an intensive care unit or suspicion of the infection, it is appropriate to stop estrogen or antiestrogen treatments and proceed to use low-molecular weight heparin until full mobilization capacity is restored. It is recommended to change from oral MHT to transdermal estradiol, associated or not with natural progesterone. However, the re-initiation of MHT should be performed under strict follow-up protocols and with complete information about risk/benefits and the use of low-molecular weight heparin. It cannot be denied that, during the COVID-19 pandemic, physical activity has been limited, potentially increasing weight gain and the risk of thromboembolic events, especially among women using MHT. Therefore, the prophylactic use of low-molecular weight heparins is a convenient measure.

Hamer et al.¹³ studied lifestyle factors and the risk of hospitalization in a large cohort of adults in which there were 760 cases of COVID-19. After adjusting the population for age, sex, smoking, obesity and physical inactivity, smoking and obesity were related to the disease while alcohol was not. Therefore, lifestyle is a modifiable protective factor against COVID-19.

Zhao et al.¹⁴ compared the burden of mental health before and during the initial days of the COVID-19 outbreak in order to identify vulnerable groups by sociodemographic factors. They found that, during the COVID-19 outbreak, as compared to years 2016 and 2017, stress level increased by 28.3%, anxiety prevalence increased by 42.3% and depression symptoms and unhappiness increased two-fold. The increases in stress level were significantly higher among older and less educated individuals. Quarantine reduces social connection, thus creating self-worries and that of family members which further increases the risk of depression, anxiety and stress among individuals. Arpino et al.¹⁵ reported that nearly 50% of individuals aged 50 or more felt sad or depressed more frequently than usual during the COVID-19 lockdown. During the lockdown, older individuals who maintained or increased non-physical contacts with non-co-resident individuals were at a lower risk of presenting perceived depressive feelings as compared to those who reduced non-physical contacts. The beneficial effect of non-physical contacts was stronger for intergenerational relationships and the effects were similar by gender and stronger among individuals aged 70 or more than those not living alone before the start of the lockdown.

The meta-analysis of Bueno-Notivol et al.¹⁶ found a pooled 25% prevalence of depression for the period from January to May 2020, which was nearly seven times higher than the global prevalence of depression observed in 2017 (3.4%). During the accumulated months of the pandemic, there have been limitations in social interactions and public events that negatively affected mental health. The lack of effective treatments against the SARS-CoV-2 infections produced fear, extreme anxiety and sleep disorders.

The presence of co-morbidities and changes in social and lifestyle factor may also affect COVID-19 clinical evolution and related mortality as well as immunological responses. The most common co-morbidities observed among non-hospitalized individuals with SARS-CoV-2 infection are hypertension, chronic pulmonary disease, kidney disease, excessive body weight and depression⁴. These conditions may require appropriate management or treatment adjustments.

Another aspect worth mentioning during lockdown is the overall increase in intimate partner violence (IPV), observed among well and less educated populations. Due to COVID-19 lockdown and movement restriction, people were confined to their homes (in many cases living crowded in small households), with advocates expressing concern about a potential increase in IPV. Although stay-at-home orders were intended to protect the public and prevent widespread infection, this situation left many IPV victims trapped at home with their abusers^17,18. Confinement may have dramatic consequences, increasing IPV and continued mistreatment, and even femicides, especially in communities with lower socioeconomic income and sexist culture or poor access to medical information.

The SARS-CoV-2 will stay among us, transforming our social, economic and daily lifestyle. Medical and health care will need to define clinical interventions and preventive measures considering various scenarios and gender/sex differences. The role of MHT in young and postmenopausal women should be re-defined from a new perspective, considering both preventive and curative interventions. As humans we are bound always to face throughout our history extraordinary and unique challenging events such as the 14th century Black Death epidemic or the ‘meeting of two worlds’ after the discovery of America by Columbus, when microbes were interchanged among the Old and New Worlds. There is a need to take immediate precautions in order not to send the coronavirus out of earth!

Potential conflict of interest

The author reports no conflicts of interest.

Source of funding

Nil.