Menopausal hormone therapy and postcovid syndrome: new realities

Introduction

The sudden onset of the COVID-19 pandemic has drastically changed lifestyles and created fundamentally new health risks for the population. Along with the maintenance of high morbidity rates, the immediate and long-term consequences of a new coronavirus infection are becoming increasingly important [1-3]. Globally, the outcomes and complications caused by the SARS-CoV-2 virus have yet to be fully determined. In this regard, various aspects of women's health protection both during illness and in the post-COVID period become relevant for obstetricians and gynecologists.

The ICD-10 already has new sections that include codes U09.9 (post COVID-19 condition) and U08 (COVID-19 personal history), with code U08.9 recommended for reporting “an earlier episode of confirmed or probable COVID-19, which affects the human health, and the person no longer gets sick with COVID-19” [4].

Despite the limited observation period, there is no doubt that COVID-19 can occur in a wide range of clinical manifestations, from an asymptomatic disease to the development of lethal outcomes [5]. A variable factor of novel coronavirus infection is also the duration of symptoms associated with SARS-CoV-2. Factors that correlate with the duration of certain manifestations of COVID-19 are of interest to scientists around the world. When monitoring patients since the onset of the pandemic, the number of reports of prolonged symptoms of COVID-19 coronavirus infection, the so-called “long COVID”, gradually increases. However, its prevalence and the ability to predict a protracted course in the early stages of the disease are still being studied [6].

 “Long COVID” and/or post-COVID syndrome are a set of symptoms that develop in one month or more after the acute phase of COVID-19 disease [7, 8, 9]. When interviewed, patients with “long COVID” reported symptoms lasting from 28 days to several months. “Long COVID” was characterized by such symptoms as fatigue, headache, shortness of breath, and anosmia. The probability of their development increased with age, body mass index, and was significantly higher in females [10]. Other persistent symptoms included cognitive and psychiatric disorders, chest and joint pain, palpitations, myalgias, smell and taste disorders, cough, gastrointestinal and cardiac diseases [11]. In terms of pathogenesis, “long COVID” can be caused by long-term tissue damage (for example, lungs, brain, and heart) and pathological inflammation (for example, as a result of virus persistence, development of immune dysregulation, and autoimmunity) [12]. Viral infection induces an aggressive immunologic response, and the impact of symptomatic or asymptomatic COVID is still being studied. Recent research data indicate numerous autoimmune complications in patients who have had COVID, which can affect internal organs, the musculoskeletal system, the nervous system, and skin [13].

Risk factors associated with the duration of clinical manifestations in current publications are female sex, a large number of early symptoms (five or more), early dyspnea, previous psychiatric disorders, and specific biomarkers (for example, D-dimer, C-reactive protein, and lymphocyte count), although the authors emphasize that additional studies are required to substantiate them [14]. The risk of long-term consequences is associated with skin, respiratory, cardiovascular, musculoskeletal, psychiatric, neurological, and renal lesions in those patients who survived the acute phase of the disease [15].

Female sex is a risk factor for post-COVID syndrome

The global research data indicate that post-COVID syndrome is a predominantly female disease since its development is more often observed in women. According to preliminary research findings, in addition to the female sex, age, comorbidities, obesity, and the severity of the acute period of the disease are also associated with “long COVID” [16]. However, it has been revealed that the severity of the acute phase of the disease is not associated with an increased risk of post-COVID syndrome, while female sex, older age, and active smoking increase its duration [17].

Some studies show that post-COVID syndrome often develops in patients with asymptomatic and mild severity of the disease, but its pathogenesis in this group of patients is not completely clear. The probability of an alternative course of COVID-19 that develops in genetically predisposed individuals with a stronger immune response, in which cells of the nervous system are predominantly affected, is allowed, possibly with the presence of an autoimmune component that may resemble chronic fatigue syndrome, or autoimmune dysautonomia [18]. These studies emphasize that women have a genetically stronger immune response; therefore, female sex combined with anosmia in asymptomatic or mild disease may be a predictive factor for the increased probability of post-COVID syndrome development, which may be induced by autoimmune damage of neurons, glia, and cerebral vessels [19].

When studying the phenotypes of post-COVID syndrome, it has been revealed that among patients hospitalized with post-COVID syndrome, 75% were women; their average age at the time of admission was 46 years. In women, the phenotype associated with fatigue prevailed, while in men – the phenotype associated with dyspnea. Among the laboratory parameters, the most significant was the increase in interleukin-6, which occurred in 69% of hospitalized women [20].

Other studies have compared groups of patients with “long COVID” by age. It has been defined that persistent symptoms of post-COVID syndrome were more often observed in older people who were hospitalized for COVID-19 [21].

Metabolic dysfunction (for example, obesity, insulin resistance, and diabetes mellitus) is known to be a predisposing risk factor for severe acute COVID-19, but evidence is emerging that this factor, when combined with a chronic inflammatory state, may also predispose patients to post-COVID syndrome [22]. This fact is also confirmed by other studies, the authors of which argue that lipid disorders and obesity are age-independent risk factors for the development of post-COVID syndrome, suggesting that metabolic changes determine the risk of an unfavorable clinical course of COVID-19 at all stages [23].

Therefore, considering the epidemiology and pathogenesis of post-COVID syndrome, the category of women of menopause age, especially those with metabolic dysfunction, deserves special attention.

MHT multifaceted protective effect

With the onset of menopause, a number of physiological changes occur in the female body, which can induce undesirable consequences on the part of various organs and systems. During the perimenopause, neurotransmitter imbalance gradually occurs, which ultimately leads to sleep disorders, anxiety, depression, migraine, and dementia. There is also dependence between the level of endogenous estrogen and cognitive impairment [24]. Higher estrogen levels have been shown to promote good sleep, but the relationship between endogenous sex hormones and depressive symptoms is still inconclusive [25].

Postmenopausal women gradually develop osteoporosis, sarcopenia, metabolic syndrome, type 2 diabetes mellitus, and obesity. Approximately 50% of menopausal women are overweight, of which 25% are obese. Obesity contributes to the development of various complications, in particular such as hypercoagulability and thrombosis. Therefore, in the era of COVID-19, there is a pre-existing thrombotic risk in obese women. Since obesity and other comorbidities that exist in menopausal women cannot be cured in a short time, clinicians should be aware of such complementary associations and strive to provide the best comprehensive approach to the treatment (and possible prevention) of long-term post-COVID syndrome [26].

The vast majority of symptoms of the menopausal period are associated with progressive, up to absolute, estrogen deficiency. It is for this reason that menopausal hormone therapy (MHT) is generally recognized as pathogenetic therapy for menopausal disorders. Over the past years, MHT has proven its efficiency and safety in treating various symptoms of menopause, as well as has shown a significant effect in the prevention of “older age diseases”, which determine the duration and quality of life [27][28].

It is known that the timely start of MHT can reduce the risk of cardiovascular disease and type 2 diabetes, positively affecting glucose metabolism, insulin resistance, and abdominal fat deposition. When taken orally, estrogens, being absorbed in the intestines and entering the liver, reach a supraphysiological concentration, under the influence of which there is an increase in the synthesis of high-density lipoproteins and the elimination of low-density lipoproteins from the bloodstream.

However, the use of MHT can theoretically induce such undesirable consequences as venous thromboembolic complications (VTECs). Among gynecologists and doctors of other specialties, discussions are still ongoing about the safety of using MHT in general, not to mention the possibility of its use during the COVID-19 pandemic. On the one hand, in addition to many positive pharmacological effects and improvement of women’s life quality, MHT contributes to the prevention of cardiovascular diseases associated with progressive impairment of the vascular endothelium against the background of estrogen deficiency in postmenopausal women. On the other hand, there are concerns about the possible risks of VTECs during MHT, especially in combination with hypercoagulability characteristic of COVID-19 and sometimes a rather long post-COVID period [29-31].

It is known that in COVID-19, vascular endothelial lesions develop in three ways. First, the cytopathic effect of the virus is realized when it binds to the ACE2 receptors of endotheliocytes. Second, during a “cytokine storm”, the vessels are involved in an inflammatory reaction, accompanied by the attachment of immune system cells to the site of damage and aggregation of blood corpuscles. Third, there is a picture of systemic vasculitis with the appearance of antiphospholipid antibodies, which aggravate the tendency to form blood clots both in small and medium-sized vessels, and in large vessels with the development of subsequent complications.

It has been noted that the propensity for a severe disease course of COVID-19, including the development of VTECs, is higher in men than in women [32][33]. This is due to the fact that androgen receptor activity is important for the transcription of the transmembrane serine protease 2 (TMPRSS2) gene, the expression of which is necessary for the activation of the SARS-CoV-2 spike protein, virus entry and spread in the body of the infected “host”. However, estrogen (17β-estradiol) has been shown to have antiviral activity against influenza, hepatitis C, SARS, and SARS-CoV-2 viruses. Its immunomodulatory effects in SARS-CoV-2 infection are currently being actively investigated in various laboratories around the world. Estrogen has been recently shown to have an anti-SARS-CoV-2 effect, which manifests itself in the suppression of TMPRSS2 expression in various cell lines [34][35].

Considering the physiological factors that protect the female body from the severe consequences of COVID-19, it should also be noted that estradiol and progesterone allow reducing the innate immune inflammatory response, while increasing immune tolerance and antibody production [36]. Therefore, the risk of developing immune dysregulation, which serves as a trigger for the “cytokine storm” and its long-term negative consequences, is reduced [37].

Estrogens are considered to be a key player in immunological response development and have a multifaceted protective effect on the vascular endothelium [35]. Prerequisites are being created for the use of MHT in women, including in the post-COVID period [38][39]. According to the research results available to date, MHT in the presence of concomitant factors potentially increases the risk of thromboembolic diseases, especially when taken orally, while when taken transdermally in standard therapeutic doses, it does not exceed the initial population risk. Therefore, it is recommended to apply an individual approach to the use of MHT, which is especially important for patients with obesity and post-COVID syndrome, given the positive effect of MHT on metabolic parameters. As a rule, the lowest effective dose of estrogen should be used and the transdermal route of administration should be preferred to minimize the iatrogenic risk of VTECs. In addition, in the context of reducing risks in recent years, all professional communities recommend the use of metabolically neutral progestogens, such as micronized progesterone, dydrogesterone, or transdermal norethisterone, in combination with estrogens.

Studies have also revealed that postmenopausal women, who were diagnosed with COVID-19, experienced more pronounced symptoms of estrogen deficiency, which is a significant reason for considering the use of MHT in the post-COVID period [40].

MHT in BMD: indicate impossible to refuse. Where a comma should be put?

Another aspect of the use of MHT is oncological risks, primarily in relation to the mammary gland. During the menopausal transition and in early postmenopause, the state of benign mammary dysplasia (BMD) often worsens, which, according to the modern paradigm, induces and reflects the individual risk of breast cancer [41]. In the context of the ongoing COVID-19 pandemic, the number of risk factors of BMD expectedly increases: more than 30% of patients hospitalized with COVID-19 have cognitive impairment, depression, and anxiety, which persist for several months after the discharge from hospital [42]. A long-term stressful situation is inextricably linked with neuroendocrine disorders; therefore, frustrating situations occupy a significant place among the causes of BMD development [43]. Modern studies confirm the theory of the influence of immune system disorders on the development of breast diseases; persistent chronic infection is involved in BMD pathogenesis [44]. During the menopausal transition, the body has a very modest opportunity for recovery. The appointment of MHT to such patients not only improves the quality of life but also helps to cope with stressful situations due to the positive effect of estrogens and progesterone on cognitive functions. It should be remembered that MHT is not contraindicated in BMD, especially if combinations of estradiol with micronized progesterone or dydrogesterone are used [41].

Conclusion

Summarizing the above, it should be recognized that today, during the COVID-19 pandemic, doctors providing care to middle-aged women, primarily obstetricians and gynecologists, will inevitably have to pay closer attention to the age-related aspects of the health of women in peri- and postmenopause, since the severity of chronic diseases associated with aging is often exacerbated by COVID-19 and/or post-COVID syndrome [45][46]. Despite the risk of thromboembolic complications when prescribing MHT to peri- and postmenopausal women who have undergone COVID-19, the favorable effect of estrogens on the vascular endothelium and the immune response is undeniable. However, in the context of the ongoing pandemic, there are still many open questions related both to the appointment of MHT and the study of additional mechanisms of autoimmunity, protection of the vascular wall and the coagulation system, which creates prerequisites for further research.