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Файл:Age endocrinology. Study aid for students of medical universities
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significantly higher than those recommended in the standards. Therefore, it can be
concluded from these works that large doses of vitamin D administered without
indication may be harmful.
The role of calcium in muscle contractions is beyond doubt. However,
randomized clinical trials have not shown the effect of calcium supplements on
muscle strength in young female and male athletes. In addition, in older women,
taking yogurt fortified with vitamin D (200 IU) and calcium (400 mg) twice daily did
not increase walking speed.
12.2. VITAMIN D AND COGNITIVE FUNCTIONS
Evidence that VDR is also expressed in the central nervous system and that the
central nervous system is itself capable of synthesizing calcitriol through the
expression of 25-hydroxylase and 1α-hydroxylase has suggested that vitamin D may
play a role in maintaining and improving cognitive function.
Rats with AD and low levels of vitamin D lost their cognitive abilities faster
than the control group. Moreover, mice with low levels of vitamin D have increased
production of amyloid-β (Aβ), the formation of amyloid plaques, as is commonly
seen in patients suffering from AD. In transgenic mice that spontaneously accumulate
Aβ and suffer from AD, a diet supplemented with cholecalciferol can reduce amyloid
plaque formation by increasing amyloid clearance and improve cognitive function.
The mechanisms by which vitamin D reduces Aβ accumulation and amyloid
plaque formation are not well understood. It has been suggested that vitamin D
increases the clearance of Aβ across the blood-brain barrier, increasing its outflow
from the brain, both genomically and non-genomically. Moreover, it was shown in
cultures of cortical neurons in vitro that vitamin D is directly involved in the
production of Aβ and can suppress its expression. A number of genes that play a role
in the pathogenesis of AD contain a vitamin D response element in their sequences.
These genes are not activated if vitamin D deficiency occurs during growth.
However, it has not been proven that hypovitaminosis D during growth can affect
cognition in adulthood.
Despite evidence from in vitro and animal models, the effect of vitamin D on
cognitive function remains unclear. This relationship is thought to be complex and
mediated through the interaction of vitamin D with other hormones such as estrogen
and insulin. Transcriptome analysis of the neocortex in healthy and AD mice showed
that vitamin D treatment affects inflammation, immune response, neurotransmission,
vascular and hormonal changes, suggesting pleiotropic effects of vitamin D.
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A number of studies have shown that lower levels of vitamin D are associated
with cognitive decline in patients suffering from cognitive impairment. In addition, in
older adults presenting with memory deficits without a diagnosis of dementia,
hypovitaminosis D has been associated with lower mental flexibility. On the other
hand, a number of researchers have not found any evidence that hypovitaminosis D
can cause cognitive deficits in middle or later age.
However, due to the heterogeneity of the analyzed groups and the methods used
to assess cognitive functions, it is difficult to conduct a comparative analysis of studies.
Data on the relationship of vitamin D and cognition obtained in animal and
human studies have sparked interest in analyzing the possibility of using vitamin
supplements to prevent cognitive decline. However, it is difficult to compare the
results of various scientific works due to the fact that the study protocols used
(patient groups, vitamin D preparations, treatment regimens from a single dose to 18
weeks) are largely heterogeneous, do not clearly understand the role of vitamin D in
the pathogenesis and treatment of dementia So, Dhesi J. K. et al. (2004) used
ergocalciferol as a single intramuscular injection of 600,000 IU, Przybelski R. et al.
(2008) used oral ergocalciferol 50,000 IU three times a week for four weeks, Dean
A.J. et al. (2011) — oral cholecalciferol 5000 IU daily, while Pettersen J. A. et al.
(2017) used oral cholecalciferol at two different doses of 4000 IU and 400 IU daily
for 18 weeks. In addition, the size, age composition (old and young), social status
(living at home in the family and in nursing homes) of the groups were different. The
vitamin D status of the people included in the study also differed: in the study by
Dhesi J.K. et al. (2004) patients were only vitamin D deficient, while in other studies
they were deficient and not. In addition, the design of the studies is different: two
studies used a placebo-controlled group, while others did not.
Goodwill AM et al. (2017) in a systematic review noted that 314 patients did
not find significant improvements in cognitive function with vitamin D
supplementation. On the other hand, the Pettersen study J. A. et al. (2017) showed the
effect of high doses of cholecalciferol (4000 IU/day) on improving visual memory in
the elderly with low vitamin D levels.
In addition, a randomized, placebo-controlled clinical trial of vitamin D plus
calcium in healthy older women found that low-dose vitamin D (200 IU) and calcium
(400 mg) fortified yogurts eaten twice daily help maintain cognitive function.
Thus, although vitamin D may play a role in brain development and in the
maintenance of cognition, evidence from intervention studies is insufficient to indicate
that vitamin D supplementation, even at high doses, may be beneficial for patients with
cognitive impairment. Data on the combined use of calcium and vitamin D supplements
are insufficient to be included in recommendations. Further research is needed.
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13. BETACORONAVIRUSES
AND THE HUMAN ENDOCRINE SYSTEM: NEW DATA
In December 2019, in Wuhan, Hubei Province, China, a new deadly respiratory
disease was first described, the complications of which can be SARS and acute
respiratory distress syndrome with a relatively high risk of death for patients. In
March 2020, due to the rapid and large-scale spread of the infection in all countries,
WHO declared a pandemic of a new disease and called it COVID-19. The causative
agent of this disease is a new coronavirus called SARS-coronavirus 2 (SARS-CoV-2).
The SARS-Cov-2 virus belongs to the betacoronavirus genus, which includes
SARS-CoV-1 and MERS-CoV, which caused epidemics in 2002 and 2013,
respectively. SARS-CoV-2, according to a WHO report dated November 22, 2020, is
characterized by a high ability to spread — R0 of about 3.8 (1.4–6.49) and a
relatively low mortality rate of about 2.4 %, in contrast to MERS with an R0 < 1 and
a mortality rate of 34.4 % and SARS with an R0 of about 1.8 and a mortality rate of
10 %. Transmission from person to person occurs by airborne and contact routes,
although there is evidence of the possibility of transmission of the infection by air,
fecal or intrauterine routes. The mechanism of infection in SARS-CoV-1 and SARSCoV-2 is similar and occurs through the binding of the virus to angiotensinconverting enzyme type 2 receptors (ACE2) widely distributed in the human body,
with high expression in the tissues of the endocrine system, including the pituitary
gland, thyroid gland, adrenal glands, testicles and with the participation of the
TMPRSS2 protease and, to a lesser extent, cathepsins B (CTSB) and L (CTSL). On
the other hand, already at the beginning of the SARS, MERS and COVID-19
epidemics, it was obvious that hormonal and metabolic disorders can influence the
outcome of a viral disease. For example, diabetes mellitus is an important risk factor
for poor prognosis and high mortality. With regard to COVID-19 infection, available
evidence suggests that advanced age, old age, hypertension, obesity and diabetes
mellitus are significant risk factors for mortality. In addition, according to a number
of authors, Cushing's syndrome increases the risk of death, and adrenal insufficiency
prior to infection reduces the rehabilitation potential in patients with COVID-19.
Thus, the existing close relationship between COVID-19 and the endocrine system
has aroused the interest of endocrinologists in studying the infectious process and
developing ways of prevention and therapy for patients at high risk of developing
endocrine disorders.
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Similarities Between SARS-CoV-2 and Other Beta Coronaviruses
Genome sequence analysis showed that SARS-CoV-2 belongs to the genus of
betacoronaviruses, which includes SARS-CoV-1 and MERS-CoV [1]. These
coronaviruses are enveloped RNA-stranded viruses with a large genome approaching
30 kb and include four structural proteins, namely the clubs (S), nucleocapsid (N),
envelope (E), and membrane (M) proteins.). The S protein is responsible for attaching
the virus to the receptor and fusion with the cell membrane. The N protein interacts
with viral RNA to form ribonucleoprotein. The E protein helps virion assembly and
turns on the action of ion channels; the M protein is involved in the assembly of new
viral particles. The SARS-CoV-2 genome is almost 80% similar to SARS-CoV-1 and
50 % to MERS-CoV. Moreover, SARS-CoV-2 proteins have a high degree of
homology (approximately 95 %) with SARS-CoV-1 proteins. Among viral proteins,
the S protein is the most important for infecting target cells, as it facilitates virus
entry. Entry of the virus depends on the binding of the S1 surface unit of the S protein
to the cellular receptor, which facilitates attachment of the virus to the surface of
target cells. In addition, entry requires priming of the S protein by cellular proteases,
which entails cleavage of the S protein at the S1/S2 and S2' site and allows viral and
cellular membrane fusion, a process driven by the S2 subunit. SARS-S employs
angiotensin-converting enzyme type 2 (ACE2) as an input receptor and uses the
cellular serine protease TMPRSS2 to prime the S-protein or, to a lesser extent,
cathepsins B (CTSB) and L (CTSL) [4, 6]. SARS-S and SARS-2-S share 76 % amino
acid identity and the SARS-2-S protein uses ACE2 for entry followed by TMPRSS2.
These data suggest that SARS-CoV-2 has the same target cells as SARS-CoV-1 [4].
On the other hand, MERS-CoV binds to dipeptidyl peptidase 4 (DPP4) to enter
human cells.
The effect of hormones on human susceptibility to coronavirus infection
Glucocorticoids and vitamin D
Scientists were interested in the question: can the treatment of patients with
COVID-19 with hormonal drugs affect the expression of ACE2 in tissues and, as a
result, the spread of the virus? To date, there is evidence that both vitamin D and
glucocorticoids can increase systemic expression of ACE2 receptors.
However, according to these data, such an increase in potential sites for virus
entry is only an obvious disadvantage and, rather, it is necessary to preserve the
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integrity of the parenchyma of various tissues, including endocrine glands. In fact,
binding of SARS-CoV-2 to human ACE2 reduces its expression, thereby causing
angiotensin II (Ang II) to be regenerated via the ACE enzyme. In turn,
overproduction of Ang II can stimulate cell growth, fibrosis, epithelial cell apoptosis,
generation of reactive oxygen species, and release of pro-inflammatory cytokines,
thereby enhancing the detrimental effect of infection. On the other hand, ACE2
cleaves Ang II to angiotensin 1-7 [Ang-(1-7)], which has a vasodilating effect,
lowering blood pressure by stimulating nitric oxide synthase (NOS). Counteracting
Ang II, Ang-(1–7) reduces fasting glycemia and glucose tolerance, stimulates β-cell
proliferation, prevents their apoptosis, and normalizes kidney function. The
ACE/ACE2 ratio is believed to have an important impact on the course of various
diseases, including diabetes mellitus, hypertension, nephropathy, as well as the
prognosis for patients with COVID-19.
Sex hormones
Although men and women have the same susceptibility to SARS-CoV-2, men
appear to be more severely affected and at risk of death regardless of age. Indeed,
some evidence indicates that TMPRSS2 expression in human tissues is regulated by
androgen receptor activity. It is reasonable to speculate that higher levels of
TMPRSS2 expression in males may contribute to more severe COVID-19 infection
compared to prepubertal women and children. Regarding this, Asselta R. et al. (2020)
analyzed genomic databases and found higher expression of TMPRSS2 mRNA in
lung samples from men compared to women (p = 0.029), while the level of ACE2
mRNA expression was not significantly different. This observation was confirmed by
Li M. Y. et al. (2020), while they failed to find any difference in the level of ACE2
expression between men and women of young and old age. However, further studies
are needed to confirm the possibility of the influence of different expression of
TMPRSS2 in men and women on the pathogenicity of the virus. In addition, it has
been hypothesized that CAG repeats of the androgen receptor gene that regulates
androgen sensitivity may also be associated with the severity of COVID-19 disease.
According to this hypothesis, androgen receptors associated with androgenetic
alopecia, prostate cancer, benign prostatic hyperplasia, and polycystic ovary
syndrome may influence higher susceptibility to COVID-19 infection. Consistent
with these findings, a number of authors have reported disproportionately high
mortality among African American patients with COVID-19 who carry a shorter
CAG repeat variant in the androgen receptor gene. Indeed, men hospitalized for
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severe COVID-19 had a higher incidence of androgenetic alopecia. Finally,
Montololi M. et al. (2020) described the protective effect of antiandrogen therapy in
prostate cancer against SARS-CoV-2 infection. In accordance with this hypothesis, a
number of authors have proposed the use of antiandrogen therapy to reduce the
severity of the disease. However, rigorous prospective clinical studies are needed to
validate this strategy as an adjuvant therapy for COVID-19.
Moreover, both animal and human studies suggest that androgen suppression
leads to an increase in ACE2 expression, while it is unclear whether this effect leads
to an increased risk of severe infection or a protective effect of ACE2 protein
overexpression (discussed previously). Moreover, androgens and estrogens can
influence the immune antiviral response in opposite ways, and the frequency of
adverse reactions to both vaccines and antivirals is higher in women than in men,
which must be taken into account when choosing tactics.
The impact of coronaviruses on the endocrine system
Studies of the distribution of the ACE2 protein in human tissues have identified
potential routes of infection and suggested the pathogenetic consequences of SARSCoV-1 and SARS-CoV-2 infection. These data indicate maximum expression of
ACE2 in lung tissues, enterocytes of the small intestine and lower expression in
testicles, thyroid, adipose tissue, ovaries, and endothelium. In addition, ACE2 has
been found in the adrenal glands, prostate, pituitary, and hypothalamus. Lazartigues
E. et al. (2020) confirmed the expression of ACE2 and TMPRSS2 mRNA in the
endocrine tissue in both men and women, confirming the hypothesis that the
endocrine system is damaged during a viral infection in both sexes [15]. Finally,
since TMPRSS2 has been identified in extracellular vesicles, it is reasonable to
speculate that this protease may reach other tissues outside of its expression sites,
thereby promoting the spread of SARS-CoV-2 infection.
Pathological studies performed in patients infected with SARS-CoV-1 or
SARS-CoV-2 demonstrate varying degrees of endocrine tissue damage, including
direct cell damage due to virus entry and replication, vasculitis, arterial and venous
thrombosis, hypoxic cell damage, systemic immune response and cytokine storm.
In particular, thrombosis of small vessels of various organs was more common
in patients with COVID-19 than in patients with SARS. From this point of view, this
specific pathogenetic effect of COVID-19 may affect highly vascularized organs such
as endocrine glands, and in particular those that have a very dense vasculature,
including the pituitary gland.
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Coronaviruses and the hypothalamus/pituitary gland
In patients with SARS due to SARS-CoV-1 and the presence of neurological
symptoms, the expression of ACE2 receptors in the hypothalamus/pituitary gland was
found, which led to the assumption that beta-coronavirus infection can affect the
central nervous system and, as a result, the hypothalamus and pituitary. The site of
entry into the central nervous system for SARS-CoV-1 and SARS-CoV-2 has not yet
been determined and may be either indirect through the bloodstream or direct through
the cribriform plate. Moreover, a number of researchers suggest that betacoronavirus
infection may cause a general depression of the hypothalamic/pituitary axis
associated with the systemic effect of the infection and hypoxia in infected patients.
SARS-CoV-1 and hypothalamus/pituitary gland
At autopsy in patients with SARS-CoV-1, in situ hybridization revealed the
expression of the SARS-CoV-1 RNA polymerase gene in pituitary cells. In 2005
Gu J. et al. (2005) used real-time polymerase chain reaction to detect the sequences
of the SARS genome in the cytoplasm of neurons of the cerebral cortex and
hypothalamus in 8 patients who died from SARS infection. In addition, an autopsy
study of the pituitary in five patients with SARS aged 24 to 51 showed a decrease in
cells producing TTH, ACTH, STH and damage to focal cells. However, as suggested
by Wei L. et al. (2010), the decrease in ACTH-, TTH- and STH -positive pituitary
cells could be associated with the administration of glucocorticoids. On the other
hand, the number and immunoreactivity of cells producing prolactin (PRL), LH and
FSH increased. This data is consistent with other studies describing elevated levels of
PRL, LH, FSH, and decreased testosterone levels in men with SARS infection. In
addition, Leow M. K. et al. (2005) in 61 people who had had SARS, when studying
the hormonal status within 3 months after recovery, twenty-four patients (39.3 %)
were found to have various degrees of hypocorticism, twelve of them (83.3 %)
clearly had central genesis, as evidenced by concomitant low levels of ACTH.
Notably, patients with pre-existing endocrine disorders were excluded from the
study, and endocrine changes were detected and compensated for within one year of
recovery from SARS.
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SARS-CoV-2 and hypothalamus/pituitary gland
The presence of SARS-CoV-2 in the CNS was first reported by Zhou L. et al.
(2020) who found SARS-CoV-2 in the cerebrospinal fluid of patients with COVID-
19. Therefore, it is reasonable to assume that during the acute phase of the systemic
inflammatory response, the blood-brain barrier may become more permeable,
allowing the virus to enter the central nervous system, hypothalamus, and pituitary
gland. A study in 40 patients with moderate COVID-19 compared to 54 healthy
controls showed significant reductions in GH and insulin-like growth factor-binding
protein 3 (IGFBP-3). To better understand the impact of COVID-19 on highly
vascularized endocrine glands, the common extrapulmonary microthrombosis
characteristic of COVID-19, in contrast to SARS-CoV-1, should be considered.
Therefore, this specific pathogenetic effect of COVID-19 may also affect the
functioning of the hypothalamus and pituitary gland, organs with a rich vascular
network. However, further research is needed to confirm hypothalamus/pituitary
involvement during COVID-19 infection.
Coronaviruses and the thyroid gland
A number of data suggest that both SARS-CoV-1 and SARS-CoV-2 can
influence the structure and function of the thyroid gland.
SARS-CoV-1 and the thyroid gland
A 2006 study assessed the structure of thyroid tissue in five SARS-Cov
patients. The autopsy showed a violation of the follicular architecture with varying
degrees of damage to the follicular cells and increased interfollicular fibrosis.
Moreover, patients with SARS completely lacked calcitonin-producing cells, which
did not match the control group. The Tunel test showed a high level of apoptosis in
all patients with SARS, both in the follicular epithelium and in the interfollicular
region. Thyroid function studies showed that the levels of TTH, free T3, and free T4
in patients with SARS were significantly lower than in the control group. In these
patients, the level of free T3 was inversely proportional to the severity of the disease.
In particular, in patients with SARS, serum free T3 and T4 levels decreased by 94 %
and 46 %, respectively, during the acute phase and by 90 % and 38 % during the
recovery phase. A large degree of morphological damage and the number of
apoptotic follicular cells explain the decrease in serum levels of T3 and T4 in patients
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with SARS. In contrast, the decrease in TTH levels in patients with SARS cannot be
explained by destruction of the follicular epithelium, since low levels of T3 and T4
may lead to higher TTH levels.
According to Leow MK et al. (2005), SARS can cause hypophysitis and, as a
result, central hypothyroidism, central hypocorticism. In addition, the toxic effect of
SARS on hypothalamic cells producing thyrotropin releasing hormone (TRH) cannot
be excluded. Another hypothesis explaining this thyroid hormonal background is a
low T3 syndrome associated with both severe lung infection followed by hypoxemia
and concomitant administration of high doses of glucocorticoids.
SARS-CoV-2 and the thyroid
Yao x. H. et al. (2020) at autopsy of the thyroid gland in three patients who
died from SARS-CoV-2 did not reveal changes in follicular cells in the presence of
severe interstitial lymphocytic infiltration. Immunohistochemistry and PCR analysis
failed to detect SARS-CoV-2 in thyroid tissue. These results differ from those
reported in patients with SARS-CoV-1, although the overall clinical data of patients
in both studies were similar. A number of studies have been devoted to the analysis
of changes in thyroid function associated with SARS-CoV-2. Thus, Chen M. et al.
retrospectively analyzing a group of 50 patients with SARS-CoV-2 found that the
degree of reduction in TTH and total T3 levels is positively associated with the
severity of COVID-19 infection in the absence of previously known thyroid disease
and the use of drugs that affect thyroid function. After recovery, there were no
significant differences in TTH concentration with the control group.
Chen T. et al. (2020) in a study of 274 SARS-CoV-2 patients found that TTH
and free T3 concentrations were significantly lower in deceased patients (n 113) than
in recovered patients (n 161), while free T4 levels were statistically did not differ. In
all patients, the risk of death correlated with thyroid hormone levels. These data were
confirmed by further studies, in particular Gao W. et al. (2020) found that free T3
levels were significantly lower in patients with severe COVID-19 disease, and free
T3 levels below 3.10 pmol/L predicted a high risk of death regardless of all other
causes. In addition, Li T. et al. (2020) showed that moderately symptomatic COVID19 patients experienced a drop in TTH and free T3 levels and an increase in
parathyroid hormone (PTH) levels from days 1 to 10 of illness, with concomitant
decreases in vitamin D, calcium, and albumin. The decrease in TTH and free T3
levels in patients with COVID-19, similar to those observed in patients with SARS,
may be associated with a euthyroid pathology syndrome caused by both hypoxemia
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and glucocorticoid treatment. Khoo B. et al. (2020) observed a moderate decrease in
TTH and free T4 on admission to the hospital and normalization of thyroid function
after discharge in a large group of patients. However, Chen M. et al. (2020)
hypothesized the possibility of a selective transient dysregulation of the pituitary due
to either a direct cytotoxic effect of the virus at the pituitary level or an indirect effect
through the activation of pro-inflammatory cytokines. This version was supported by
the observation of low TTH values during COVID-19 infection in 34 % (17/50) of
patients. On the other hand, this thought is not consistent with concurrently normal
free T4 levels.
A number of scientists have described direct damage to the thyroid tissue with
COVID-19: patients were worried about neck pain radiating to the jaw, general
weakness. On ultrasound: multiple diffuse hypoechoic areas with reduced vascularity.
Lab Findings: High levels of both free T4 and free T3, undetectable low serum TTH
levels. All these data point to a typical subacute thyroiditis. Interestingly, symptoms
of thyroiditis appeared in patients with mild COVID-19, without a history of thyroid
disease, after the disappearance of respiratory symptoms in the background of a
negative smear for the virus, with the exception of two cases of subacute thyroiditis at
the same time as a positive smear.
In addition, Lania A. et al. (2020) in a retrospective analysis of thyroid
hormone and serum interleukin-6 (IL-6) levels in 287 patients with COVID-19
admitted to intensive care units, found that 58 patients (20.2 %) had thyrotoxicosis
(overt in 31 cases), in 15 (5.2 %) — hypothyroidism (obvious in 2 cases), in 214
(74.6 %) — euthyroidism. Multivariate logistic regression analysis showed that
thyrotoxicosis was positively associated with higher levels of IL-6 (odds ratio 3.25,
95 % confidence interval 1.97–5.36; p < 0.001).
These observations can be explained as follows: (1) high expression of ACE2
and TMPRSS2 in the thyroid promotes COVID-19 attack and cytolysis, thereby
triggering an autonomic inflammatory process that progresses after resolution of
COVID-19; (2) the systemic immune response to SARS-CoV-2 infection can cause
thyroid damage with subsequent thyrotoxicosis.
Coronaviruses and adrenal glands
A number of scientists suggest a possible link between SARS or COVID-19
infections and primary and secondary adrenal insufficiency due to direct viral
damage, the action of a systemic inflammatory response, general hypoxia and
glucocorticoid therapy.
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