The Silent Sabotage
How COVID-19 May Have Hijacked Your Hormones
With every article and podcast episode, we provide comprehensive study materials: References, Executive Summary, Briefing Document, Quiz, Essay Questions, Glossary, Timeline, Cast, FAQ, Table of Contents, Index, Polls, 3k Image, and Fact Check.
They told you it was a respiratory virus. A bad flu, they sometimes whispered, before quickly pivoting to the next crisis. You wore your mask, you maybe got your shots, and you tried to move on. But what if the story they told you was only the first, most visible layer of a far more insidious attack? What if, while your lungs recovered (or didn’t), a silent sabotage was unfolding deep within, in the intricate dance of your hormones?
Forget the breathless headlines about variants. The real long-term fallout of this pandemic might be lurking in the delicate balance of your endocrine system – the very network that governs everything from your energy levels and mood to your metabolism and immune response. And the early whispers from the scientific community are less about a fleeting illness and more about a potential rewiring of your fundamental biology.
The data, increasingly difficult to ignore, paints a disturbing picture. It turns out SARS-CoV-2 isn’t just content to inflame your airways; it’s a master manipulator of your hormonal landscape. As one recent review chillingly titled "Endocrine dysregulation in COVID-19: molecular mechanisms and insights" lays bare, the virus appears to have a particular fondness for messing with your stress response.
Remember all that talk about the body’s fight-or-flight mechanism kicking in during infection? Well, that involves cortisol, a key stress hormone produced by your adrenal glands. Initially, it seemed straightforward: infection triggers inflammation, the adrenals get the signal, and cortisol levels rise. But here’s where the narrative takes a sinister turn. The review highlights a phenomenon known as “pseudo-Cushing’s syndrome,” where cortisol surges even when the usual trigger, ACTH, is behaving normally. It's like your body’s stress alarm is blaring for reasons your central command system doesn’t even understand, leaving your adrenal glands potentially less responsive in the long run. Plasma analyses suggest this erratic cortisol production could be linked to disturbances in calcium signalling and the activity of a protein called GNAS, both critical players in hormonal regulation and even the integrity of your tiny blood vessels.
But the hormonal havoc doesn’t end with cortisol. The researchers uncovered something even more unsettling: a syndrome resembling endocrine resistance. Think of it like this: your body’s cells start to ignore the hormonal signals that are supposed to guide them. This isn’t just a theoretical concern. The study found different patterns of this resistance depending on the severity of the initial infection.
In milder cases, there was elevated activity of EGFR and MMP9, along with increased expression of survival factors like Bax and Bcl2. These are pathways intimately involved in cell growth and survival. Chronic activation of EGFR, as the review points out, can throw off the normal hormonal balance and reduce sensitivity to hormonal signals. MMP9, an enzyme involved in tissue remodelling, could further complicate things by altering the environment around hormone receptors. It’s like the virus flipped a switch, telling your cells to prioritize growth and survival at the expense of responding to your body’s usual hormonal commands.
But the picture in severe cases is even more alarming. Here, the research points to the involvement of IGFR-I and enhanced NOTCH signaling alongside altered expression of Bcl2, AKT1, and MAPK8. These are deep-seated changes in cellular signaling. IGFR-I, a receptor for insulin-like growth factors, promotes cell growth and survival. Enhanced NOTCH signaling is crucial in cell fate and survival. Combined with altered levels of proteins that regulate cell death (like Bcl2) and survival pathways (like AKT1 and MAPK8), the researchers suggest this creates a cellular environment that is resistant to the normal cues, including those from hormone therapies. It's as if the virus has not just disrupted communication but actively reprogrammed the cellular response, potentially leading to long-term metabolic and other hormonal issues.
Consider the implications. We're not just talking about feeling a bit off. We're talking about the very mechanisms that regulate your body's internal environment being potentially hijacked. The study itself notes that these insights suggest potential endocrine targets for therapeutic interventions, a tacit acknowledgment that this is a significant and potentially treatable problem.
And the tendrils of this hormonal disruption reach further than just stress and growth. The review highlights that SARS-CoV-2 has been detected in endocrine tissues, suggesting a direct assault on these vital organs. It also notes the growing body of evidence pointing to altered glucose metabolism, thyroid dysfunction, and adrenal insufficiency in severe COVID-19. The virus can even interfere with the renin-angiotensin-aldosterone system (RAAS), impacting blood pressure and electrolyte balance. And let’s not forget the potential impact on sex hormones, with low testosterone linked to more severe COVID in men.
The researchers' own work, utilizing advanced plasma proteomics, revealed further concerning trends. They observed and predicted three key categories of endocrine effects: calcium dysregulation that may lead to hormonal hypersecretion; novel actions of the guanine nucleotide binding protein (GNAS); and fluctuations in circulating growth factors. Calcium ions are critical messengers in cellular signaling, including hormone receptor pathways. Disruptions here can have far-reaching consequences on everything from muscle function to vascular integrity.
GNAS, a protein involved in a range of endocrine functions, including the regulation of the thyroid, pituitary, gonads, and adrenal glands, also appears to be a key player in this viral endocrine sabotage. The researchers found GNAS to be significantly upregulated in their study, suggesting it could be contributing to hormonal imbalances and even endocrine resistance by interfering with hormone receptor signaling pathways. GNAS is even normally associated with cancer progression, a chilling parallel in the context of long-term cellular dysregulation.
The essay concludes with a stark reminder: conditions mimicking Cushing’s syndrome, characterized by excessive cortisol, have been observed in some COVID-19 patients, even without primary adrenal issues. This “Cushing’s-like syndrome” could be driven by direct viral infection, the inflammatory cytokine storm, or, ironically, the very glucocorticoid treatments used to combat severe COVID. But even when the exogenous steroids are withdrawn, the underlying hormonal dysregulation caused by the virus itself may persist.
So, while the world moves on, counting vaccine doses and infection rates, a deeper, more complex story is unfolding within the bodies of millions. A story of hormonal systems thrown into disarray, of cellular resistance to vital signals, of potential long-term consequences we are only beginning to grasp.
Are the lingering fatigue, the unexplained metabolic shifts, the anxiety that just won’t quit simply “long COVID”? Or are they the echoes of a silent endocrine storm, a testament to a virus that has burrowed deeper than we ever imagined, potentially leaving a lasting imprint on the very essence of our biological regulation?
The answers, as the researchers themselves admit, require much more investigation. But one thing is becoming increasingly clear: dismissing COVID-19 as solely a respiratory illness was a catastrophic oversight. The real battle for many may just be beginning, fought in the unseen arena of their own hormones. And ignoring this silent sabotage could have profound and lasting consequences for the health of a generation. It's time we started paying attention to the whispers coming from within. The endocrine system, once thought to be a bystander, may very well be the next frontier in understanding the true cost of this pandemic.
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STUDY MATERIALS
Briefing Document: Endocrine Dysregulation in COVID-19
Date: October 26, 2024 Source: Iosef C, Matusa AM, Han VKM and Fraser DD (2024) Endocrine dysregulation in COVID-19: molecular mechanisms and insights. Front. Endocrinol. 15:1459724. doi: 10.3389/fendo.2024.1459724
Executive Summary:
This review article examines the significant impact of SARS-CoV-2 infection on the endocrine system, with a primary focus on disruptions in cortisol signaling and the development of growth factor-induced endocrine resistance. The authors synthesize current research, including their own plasma proteomic studies, to elucidate the molecular mechanisms underlying these endocrine disturbances in both mild and severe COVID-19 cases. Key findings highlight elevated cortisol levels (sometimes independent of ACTH), calcium dysregulation, alterations in GNAS-regulated activities affecting vascular permeability, and the activation of receptor tyrosine kinase (RTK) pathways leading to endocrine resistance. The review concludes by emphasizing the potential of these insights for identifying therapeutic targets to improve outcomes for COVID-19 patients.
Main Themes and Important Ideas/Facts:
1. Significant Endocrine Impact of COVID-19:
While over 400,000 COVID-19 scientific reports exist, only a small fraction (~0.5%) specifically address its impact on the endocrine system.
Severe COVID-19 is associated with adverse endocrine outcomes, including altered glucose metabolism, thyroid dysfunction, and adrenal insufficiency.
SARS-CoV-2 has been detected in endocrine tissues, suggesting a direct viral effect.
The inflammatory processes post-infection can directly or indirectly affect endocrine tissues and their functions.
Key endocrine axes, including the hypothalamic-pituitary-adrenal (HPA) axis, renin-angiotensin-aldosterone system (RAAS), and the thyroid system, are affected by COVID-19.
Disturbance of RAAS can lead to electrolyte imbalances and hypertension.
Dysregulation of the HPA axis results in altered cortisol levels, ranging from adrenal insufficiency to elevated levels.
SARS-CoV-2 infection can alter thyroid function, manifesting as changes in TSH, FT4, and FT3 levels, and conditions like subacute thyroiditis.
Sex hormone levels can also be impacted, with low testosterone in men linked to more severe COVID-19 and higher testosterone in women associated with a stronger immune response.
2. Cortisol Signaling Dysregulation:
SARS-CoV-2 infection typically induces systemic inflammation, leading to the stimulation of the adrenal glands and elevated cortisol levels with normal ACTH.
The cytokine storm can also contribute to increased cortisol production.
In some cases, "pseudo-Cushing's syndrome" occurs, where cortisol levels rise independently of ACTH due to decreased adrenal gland responsiveness.
Plasma proteomic analyses suggest this may involve calcium dysregulation and GNAS-regulated activities, impacting microvascular permeability.
Some COVID-19 patients exhibit Cushing's-like symptoms, which can be due to:
Treatment with exogenous glucocorticoids (like Dexamethasone) for severe inflammation.
This can lead to hypertension, glucose intolerance, and muscle weakness.
"[A] comprehensive understanding of the molecular and cellular mechanisms associated with both endogenous and exogenous glucocorticoids is crucial. This includes factors such as the timing of administration, dosage, duration of treatment, and specific formulations of these medications."
Endogenous hypercortisolism resulting from viral infection, possibly due to stress-induced HPA axis activation, cytokine-mediated stimulation of adrenal cortisol synthesis, or direct viral effects on adrenal glands.
Systemic ionic dysbalance, particularly potassium abnormalities, which can affect the HPA axis.
Dysregulated calcium signaling pathways, significantly impacted across COVID-19 datasets, involving GPCR (via GNAS), RTK (via PLCg and IP3R), and Voltage-Gated Calcium Channels (via Calmodulin).
GNAS protein's role in cAMP signaling, crucial for calcium regulation in association with PTH.
3. Endocrine Resistance:
COVID-19 exhibits a syndrome resembling endocrine resistance, governed by receptor tyrosine kinase (RTK) signaling pathways.
Mild COVID-19:Displays elevated activity of EGFR and MMP9.
Shows increased expression of survival factors like Bax and Bcl2.
"[C]hronic activation of EGFR, can alter the normal signaling balance within cells and potentially lead to reduced sensitivity to hormonal signals."
Elevated MMP9 may affect hormone receptor expression and function by degrading extracellular matrix components and releasing sequestered growth factors.
Severe COVID-19:Involves IGFR-I and enhanced NOTCH signaling.
Presents altered expression of Bcl2, AKT1, and MAPK8.
Enhanced IGF-IR signaling can increase cellular survival and proliferation, reducing the efficacy of hormone-based therapies.
Increased NOTCH signaling can lead to changes in cell fate and survival, making cells less responsive to apoptotic signals induced by hormone therapies.
Altered levels of Bcl2 (anti-apoptotic), AKT1 (survival, growth), and MAPK8 (stress response, apoptosis) contribute to an environment promoting cell survival and proliferation, hindering the effectiveness of hormone therapies.
Vascular dysfunction in COVID-19 can exacerbate endocrine pathology by affecting hormone delivery and signaling due to leaky blood vessels, inducing inflammation.
Alterations in calcium channel function and GNAS-controlled activities can disrupt vascular permeability, potentially inducing endocrine resistance by affecting intracellular signaling pathways crucial for hormonal responses.
Stress and inflammation from COVID-19 can induce amplified cellular survival, proliferation, and migration signaling, mirroring mechanisms of endocrine resistance.
4. Role of GNAS:
GNAS, a guanine nucleotide binding protein, is highlighted as potentially altering calcium homeostasis and vascular permeability.
It stimulates adenylate cyclase activity, controlling the production of several hormones and regulating endocrine glands.
GNAS signaling intersects with hormone action pathways like cAMP/PKA and MAPK.
Dysregulated GNAS activities, potentially linked to calcium balance and vascular permeability, could contribute to Cushing's-like syndrome.
GNAS functions downstream of several G protein receptors and alters the secretion of PTH, GHRH, ACTH, TSH, or gonadotrophins.
It can interact with CREB molecules and Proopiomelanocortin (PMOC), potentially influencing cortisol signaling in COVID-19.
GNAS activity might be associated with programmed cell death in COVID-19 due to overlapping growth factor signals affecting RAS signaling.
5. Comparative Proteomic Analysis:
The authors' group has conducted extensive plasma-targeted proteomics studies on COVID-19 patients.
Comparison with a study from Harvard Medical School (Filbin et al.) revealed similar changes in the cortisol signaling pathway.
Both studies analyzed patients with severe COVID-19 at similar time points post-admission.
While the studies used different Olink platforms with varying numbers of analyzed proteins, 201 markers were common between them, forming the basis for comparative analysis.
Clinical parameters were comparable across the studies.
6. Therapeutic Implications:
Insights into the complex interplay between COVID-19 and endocrine pathology, particularly endocrine resistance, suggest potential endocrine targets for therapeutic interventions.
Developing interventions aimed at preventing severe cases could be crucial.
The potential repurposing of EGFR inhibitors like nimotuzumab for COVID-19 treatment is being explored to modulate the immune response and reduce inflammation.
Methodological Limitations:
Very few studies are available for comparison, making the authors' data sets unique.
Confounding factors and publication biases may influence the results.
Patient numbers varied between the authors' study and the Harvard study, although recruitment was age- and sex-matched.
Conclusion:
COVID-19 significantly impacts the endocrine system through altered cortisol signaling and the development of endocrine resistance mechanisms. These changes involve complex molecular interactions, including calcium dysregulation, GNAS-regulated activities, and the activation of RTK pathways. Understanding these endocrine alterations is crucial for developing targeted therapeutic interventions to improve short- and long-term outcomes for COVID-19 patients. Future research should focus on further elucidating these mechanisms and exploring the potential of endocrine-targeted therapies.
Quiz & Answer Key
Quiz
Describe the initial endocrine response observed in many COVID-19 patients concerning cortisol and ACTH levels. What are the potential mechanisms driving these changes?
Explain the concept of "pseudo-Cushing's syndrome" in the context of COVID-19. What factors might contribute to this phenomenon?
According to the review, what role might calcium dysregulation and GNAS-regulated activities play in COVID-19 pathology? What downstream effects are suggested?
Contrast the endocrine resistance-like syndromes observed in mild versus severe cases of COVID-19, specifically mentioning the key signaling pathways and molecules involved.
How might elevated activity of EGFR and MMP9 contribute to endocrine resistance in mild COVID-19 cases?
What are the implications of enhanced IGF-IR and NOTCH signaling, along with altered Bcl2, AKT1, and MAPK8 expression, in the context of endocrine resistance in severe COVID-19?
Why is GNAS considered a potentially important protein in the context of COVID-19-related endocrine dysregulation? What endocrine glands and hormones might its activity influence?
Explain how SARS-CoV-2 infection and the resulting inflammation can disrupt calcium homeostasis. What are the potential consequences of this disruption on vascular permeability and endocrine function?
Describe the potential link between the use of exogenous glucocorticoids for COVID-19 treatment and the development of Cushing's syndrome-like features.
How did the researchers compare their findings with those from the Harvard University database? What were some of the similarities and differences in their approaches and findings regarding cortisol signaling?
Answer Key
Many COVID-19 patients exhibit elevated cortisol levels with normal adrenocorticotropic hormone (ACTH) levels. This is likely due to systemic inflammation and the cytokine storm stimulating the adrenal glands directly. Illness-induced stress can also contribute to increased cortisol production.
Pseudo-Cushing's syndrome in COVID-19 refers to elevated cortisol levels that occur independently of ACTH stimulation. This can happen when the adrenal glands become less responsive to ACTH, potentially involving calcium dysregulation and GNAS-regulated activities affecting microvascular permeability.
Calcium dysregulation and altered GNAS activity are suggested to contribute to hormonal hypersecretion and disruptions in calcium homeostasis. These changes can impact cell proliferation, metabolism, tight junctions, cell movement, and ultimately the regulation of microvascular permeability, potentially leading to endocrine resistance.
Mild COVID-19 is associated with elevated EGFR and MMP9 activity, along with increased expression of survival factors like Bax and Bcl2. Severe COVID-19, conversely, involves enhanced IGFR-I and NOTCH signaling, with altered expression of Bcl2, AKT1, and MAPK8, indicating different mechanisms of potential endocrine resistance.
Elevated EGFR activity can disrupt the normal signaling balance within cells and interfere with hormone receptor pathways, leading to reduced sensitivity to hormonal signals. Increased MMP9 can degrade extracellular matrix components and growth factor receptors, altering the cellular microenvironment and contributing to endocrine resistance.
Enhanced IGF-IR signaling promotes cell growth and survival, potentially bypassing or interfering with hormone receptor signaling. Increased NOTCH signaling can alter cell fate and survival, making cells less responsive to apoptotic signals. Altered Bcl2, AKT1, and MAPK8 levels further contribute to cell survival and proliferation, promoting endocrine resistance.
GNAS is a G protein alpha subunit involved in cAMP signaling and the regulation of calcium levels, crucial for the function of several endocrine glands, including the thyroid, pituitary, gonads, and adrenal glands. Its altered activity could affect hormone receptor signaling pathways and contribute to endocrine resistance.
SARS-CoV-2 can directly infect endocrine tissues and trigger inflammatory processes that disrupt calcium signaling pathways. Dysregulated calcium homeostasis can increase vascular permeability, altering the microenvironment of hormone-sensitive cells and potentially contributing to endocrine resistance and impaired hormone delivery.
The use of exogenous glucocorticoids, such as dexamethasone, to combat inflammation in severe COVID-19 can lead to Cushing's syndrome-like features, including hypertension, glucose intolerance, and muscle weakness, mimicking the effects of excessive endogenous cortisol.
The researchers compared their plasma proteomic data from severe COVID-19 patients with a publicly available dataset from Harvard University. Both studies showed similar changes in the cortisol signaling pathway. However, they used different Olink platforms, analyzing a different number of proteins, but identified a subset of common differentially expressed proteins for comparative analysis.
Essay Questions
Discuss the multifaceted ways in which SARS-CoV-2 infection can lead to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and altered cortisol levels. Consider direct viral effects, inflammation, and potential long-term consequences.
Critically analyze the concept of endocrine resistance in the context of COVID-19. Compare and contrast the molecular mechanisms implicated in mild and severe cases, and discuss the potential implications for therapeutic interventions.
Evaluate the significance of calcium signaling and GNAS-controlled activities in the development of endocrine dysregulation and potential pseudo-Cushing's syndrome in COVID-19 patients. How might these molecular changes contribute to the observed clinical manifestations?
Considering the overlap between growth factor signaling pathways and hormone receptor pathways, discuss how SARS-CoV-2-induced alterations in growth factor signaling (EGFR, IGF-IR, NOTCH) might contribute to endocrine resistance and affect the efficacy of hormonal therapies.
Based on the information provided, propose potential endocrine targets for therapeutic interventions aimed at improving short- and long-term outcomes for COVID-19 patients. Justify your choices based on the described molecular mechanisms of endocrine dysregulation.
Glossary of Key Terms
Adrenal Glands: Endocrine glands located above the kidneys that produce hormones such as cortisol and aldosterone.
Adrenocorticotropic Hormone (ACTH): A hormone produced by the pituitary gland that stimulates the adrenal glands to produce cortisol.
Cortisol: A steroid hormone produced by the adrenal glands, involved in stress response, immune function, and metabolism.
Cytokine Storm: An excessive and uncontrolled release of pro-inflammatory cytokines in the body, often observed in severe infections like COVID-19.
Endocrine Resistance: A condition where hormone-sensitive cells become less responsive to the effects of hormones or hormone-based therapies.
Growth Factors: Naturally occurring substances capable of stimulating cellular growth, proliferation, and differentiation. Examples include EGFR and IGF-1.
GNAS (Guanine Nucleotide-binding protein Gs subunit alpha): A gene encoding a protein involved in various signaling pathways, including hormone receptor signaling and calcium regulation.
Hypothalamic-Pituitary-Adrenal (HPA) Axis: A complex neuroendocrine system that regulates stress response through the hypothalamus, pituitary gland, and adrenal glands.
Receptor Tyrosine Kinases (RTKs): A class of cell surface receptors that initiate intracellular signaling cascades upon binding to their ligands, involved in cell growth, survival, and differentiation. Examples include EGFR and IGF-IR.
Systemic Inflammation: Inflammation affecting the entire body, often characterized by elevated levels of inflammatory markers in the blood.
Vascular Permeability: The capacity of blood vessel walls to allow the passage of molecules and cells. Increased permeability can contribute to inflammation and tissue damage.
Pseudo-Cushing’s Syndrome: A condition characterized by clinical features resembling Cushing's syndrome (excess cortisol) but without primary adrenal or pituitary pathology.
EGFR (Epithelial Growth Factor Receptor): A receptor tyrosine kinase that plays a role in cell proliferation, survival, and differentiation.
MMP9 (Matrix Metalloproteinase 9): An enzyme involved in the breakdown of the extracellular matrix, potentially influencing growth factor and hormone receptor availability.
IGF-IR (Insulin-like Growth Factor Receptor I): A receptor tyrosine kinase that mediates the effects of insulin-like growth factors, involved in cell growth and metabolism.
NOTCH Signaling: A cell signaling pathway involved in cell fate determination, proliferation, and differentiation.
Bcl2: An anti-apoptotic protein that inhibits programmed cell death (apoptosis).
AKT1: A protein kinase involved in cell survival, growth, and metabolism, part of the PI3K/Akt signaling pathway.
MAPK8 (JNK, Stress-Activated Protein Kinase): A protein kinase involved in stress responses and can influence apoptosis and cell proliferation.
Calcium Dysregulation: An imbalance in the normal levels and regulation of calcium ions within cells and the body.
Plasma Proteomics: The large-scale study of proteins in blood plasma.
Angiotensin-Converting Enzyme 2 (ACE2) Receptor: A receptor on the surface of many cell types that serves as the primary entry point for SARS-CoV-2.
Renin-Angiotensin-Aldosterone System (RAAS): A hormonal system that regulates blood pressure, fluid balance, and electrolyte balance.
Thyroid-Stimulating Hormone (TSH): A hormone produced by the pituitary gland that stimulates the thyroid gland.
Free Thyroxine (FT4) and Free Triiodothyronine (FT3): The active thyroid hormones in the bloodstream.
Growth Hormone/Insulin-like Growth Factor (GH-IGF-1) Axis: A hormonal system involved in growth and metabolism.
Gonadotropin-Releasing Hormone (GnRH) Axis: A hormonal system that regulates reproductive function.
Exogenous Glucocorticoids: Synthetic corticosteroids, such as dexamethasone, administered as medication.
Hypercortisolism: A condition characterized by abnormally high levels of cortisol.
Electrolyte Disorders: Imbalances in the levels of electrolytes (e.g., potassium, sodium) in the body.
Epithelial Sodium Channels (ENaC): Ion channels found in the membranes of some cells that facilitate the transport of sodium ions.
Furin: A protease enzyme hijacked by SARS-CoV-2 for viral entry.
G Protein-Coupled Receptor (GPCR): A large family of cell surface receptors that transduce signals via G proteins.
Cyclic Adenosine Monophosphate (cAMP): A second messenger involved in various cellular processes, including hormone action.
Phospholipase C Gamma (PLCg): An enzyme involved in calcium signaling pathways.
Inositol 1,4,5-Trisphosphate Receptor (IP3R): A calcium channel found in the endoplasmic reticulum membrane.
Voltage-Gated Calcium Channel (CaV1): A type of ion channel that allows calcium ions to enter cells in response to changes in membrane potential.
Calmodulin: A calcium-binding protein that activates various kinases and other proteins.
Adenylate Cyclase: An enzyme that catalyzes the production of cAMP.
Protein Kinase A (PKA): A protein kinase whose activity is dependent on cAMP levels.
Mitogen-Activated Protein Kinase (MAPK) Pathways: Signaling pathways involved in cell growth, differentiation, and stress responses.
Angiotensin I (AGT1): A peptide hormone in the renin-angiotensin system.
Melanocortin Receptors (MC2R): Receptors that bind melanocortins, including ACTH.
TREK1: A type of potassium channel.
Phospholipase C (PLC beta): An enzyme involved in signaling pathways, including the regulation of the endothelial barrier.
CREB (cAMP Response Element-Binding Protein): A transcription factor that can be activated by cortisol signaling.
Cytochrome P450 (CYP) System: A family of enzymes involved in the metabolism of various molecules, including cortisol.
Protein Kinase C (PKC): A family of protein kinases involved in various signaling pathways.
Calcium/Calmodulin-Dependent Protein Kinase (CaMK): A protein kinase activated by calcium and calmodulin.
Proopiomelanocortin (PMOC): A precursor protein that is cleaved to produce various hormones, including ACTH.
RAS and KRAS: Small GTPase proteins involved in cell signaling pathways, often dysregulated in cancers.
GNG7 (Guanine nucleotide-binding protein G subunit gamma): A component of heterotrimeric G proteins involved in signal transduction.
Apoptosis: Programmed cell death.
Endothelial Dysfunction: Impaired function of the endothelium, the inner lining of blood vessels.
Thrombosis: The formation of blood clots inside blood vessels.
Bioinformatics Pipeline: A series of computational tools and analyses used to process biological data.
Meta-analysis: A statistical technique used to combine the results of multiple independent studies.
Fold Change (FC): The ratio of the expression level of a gene or protein in one condition compared to another.
Comorbidities: The presence of multiple health conditions in a patient.
Sepsis: A life-threatening condition caused by the body's overwhelming response to an infection.
Timeline of Main Events
Early Stages of the COVID-19 Pandemic: Obesity and diabetes are identified as risk factors for severe COVID-19 infection and become extensively studied.
Ongoing Observations (Throughout the Pandemic):SARS-CoV-2 is detected in endocrine tissues.
Severe COVID-19 is typically characterized by respiratory distress, low blood oxygen, need for ventilation, and/or multi-organ dysfunction.
Patients with severe COVID-19 are increasingly recognized to experience adverse endocrine outcomes, including altered glucose metabolism, thyroid dysfunction, and adrenal insufficiency.
Disturbances in the renin-angiotensin-aldosterone system (RAAS) due to SARS-CoV-2 infection affect aldosterone and renin levels, leading to electrolyte disturbances and hypertension.
SARS-CoV-2 infection leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in cortisol levels, with some patients exhibiting adrenal insufficiency or elevated cortisol levels.
The ACE2 receptor, the entry point for SARS-CoV-2, expressed in endocrine tissues like adrenal glands and pancreas, is implicated in endocrine homeostasis disturbance.
Thyroid function is altered in some COVID-19 patients, with changes in TSH, FT4, and FT3 levels, and reports of subacute thyroiditis or non-thyroidal illness syndrome.
COVID-19 may impact sex hormone levels, with low testosterone in men linked to more severe disease and higher testosterone in women associated with a stronger immune response.
The insulin system is impacted by targeting insulin-like growth factors (IGFs) and their shared receptor tyrosine kinases (RTKs), leading to hyperglycemia, insulin resistance, and new-onset diabetes in some patients, particularly those with severe COVID-19.
The growth hormone/insulin-like growth factor (GH-IGF-1) axis and the gonadotropin-releasing hormone (GnRH) axis may also be affected.
Some current and recovered COVID-19 patients exhibit features resembling Cushing’s syndrome.
Treatment of severe COVID-19 with exogenous glucocorticoids like Dexamethasone can lead to Cushing’s syndrome-like features.
Endogenous hypercortisolism may persist in some COVID-19 patients due to stress, cytokine stimulation, or direct viral effects on adrenal glands.
Electrolyte disorders, particularly potassium abnormalities, are frequently reported in COVID-19, potentially due to altered epithelial sodium channels (ENaC) activity and the effect of the SARS-CoV-2 envelope (E) protein on cation channels.
Dysregulated calcium signaling pathways are significantly observed across COVID-19 datasets, involving GPCR/GNAS/PTHR, Growth factor RTK/PLCg/IP3R/PI3, and Voltage-Gated Calcium Channel/Calmodulin pathways.
Vascular dysfunction in COVID-19 is associated with endocrine pathology, potentially leading to endothelial dysfunction, increased vascular permeability, and thrombosis, affecting hormone delivery and signaling.
Past Four Years (Leading up to the Publication): The authors' research group has performed extensive plasma-targeted proteomics studies on COVID-19 patients using Olink technology.
Comparative Studies:The authors' group and a group from Harvard Medical School (Filbin et al.) demonstrated similar changes in the cortisol signaling pathway in COVID-19.
A comparative analysis highlighted the activation of the angiotensin I (AGT1) 1/AT1 receptor system.
Findings in Mild COVID-19: Elevated activity of EGFR and MMP9, along with increased expression of survival factors like Bax and Bcl2, are observed and linked to potential endocrine resistance.
Findings in Severe COVID-19: Involvement of IGF-IR, enhanced NOTCH signaling, and altered expression levels of Bcl2, AKT1, and MAPK8 are observed, suggesting mechanisms for endocrine resistance.
Methodological Comparison (Between the Authors' Study and Filbin et al.'s Study):Both studies analyzed patients with severe COVID-19 at similar time points post-admission.
Filbin et al. studied a larger cohort with COVID-negative controls using the Olink Explore 1536 platform.
The authors (Iosef et al.) studied a smaller cohort with healthy controls using the Olink Explore 3072 platform, allowing for the analysis of more proteins.
Despite different numbers of differentially expressed proteins, 201 markers were common between the two studies, forming the basis for comparative analysis.
Publication Date: 22 October 2024.
Submission and Acceptance Dates: Received 04 July 2024, Accepted 01 October 2024.
Cast of Characters:
Cristiana Iosef: Affiliated with the Children’s Health Research Institute, Lawson Health Research Institute, and the Department of Pediatrics, Western University (London, ON, Canada). One of the lead authors of this review, involved in conceptualization, data curation, formal analysis, investigation, methodology, software, visualization, and writing.
Andrei M. Matusa: Affiliated with the Children’s Health Research Institute (London, ON, Canada). Co-author involved in software, visualization, and writing.
Victor K. M. Han: Affiliated with the Children’s Health Research Institute, Lawson Health Research Institute, and the Department of Pediatrics, Western University (London, ON, Canada). One of the corresponding authors and a lead author, involved in conceptualization, funding acquisition, resources, supervision, and writing.
Douglas D. Fraser: Affiliated with the Children’s Health Research Institute, Lawson Health Research Institute, and the Department of Pediatrics, Western University (London, ON, Canada). One of the corresponding authors and a lead author, involved in conceptualization, funding acquisition, investigation, methodology, resources, supervision, validation, and writing.
Jeff M. P. Holly: Affiliated with the University of Bristol (United Kingdom). The editor of this review.
Dana Manuela Savulescu: A science and medical writer (Canada). One of the reviewers of this review.
Avraham Ishay: Affiliated with the Technion Israel Institute of Technology (Israel). One of the reviewers of this review.
Shacham EC and Ishay A: Authors of a study examining immune activation resulting from chronic endogenous glucocorticoid excess in Cushing's syndrome and how coronavirus infection might improve outcomes for COVID-19 patients treated with glucocorticoids.
Filbin MR et al. (Harvard Medical School): Authors of a study whose plasma proteomic data on severe COVID-19 patients was used for comparison with the authors' data.
Zhou S et al.: Authors of a study that also found GNG7 and GNAS proteins to play a role in the progression of COVID-19.
FAQ
What are the main ways COVID-19 affects the endocrine system?
COVID-19 infection significantly impacts the endocrine system through several mechanisms, including stimulating the adrenal glands leading to elevated cortisol levels, potentially causing a condition resembling Cushing's syndrome (either due to stress, inflammation, or direct viral effects), and inducing endocrine resistance. The virus can also affect glucose metabolism, thyroid function, adrenal sufficiency, and sex hormone levels. Furthermore, it can disrupt the hypothalamic-pituitary-adrenal (HPA) axis, the renin-angiotensin-aldosterone system (RAAS), and the thyroid system.
How does COVID-19 lead to elevated cortisol levels?
SARS-CoV-2 infection triggers systemic inflammation and illness-induced stress, which stimulate the adrenal glands to produce more cortisol. This typically occurs with normal levels of adrenocorticotropic hormone (ACTH). Additionally, the cytokine storm associated with severe COVID-19 can independently stimulate cortisol production. In some cases, cortisol levels may rise even when the adrenal glands become less responsive to ACTH, a phenomenon termed "pseudo-Cushing’s syndrome."
What is "pseudo-Cushing's syndrome" in the context of COVID-19, and what might cause it?
"Pseudo-Cushing’s syndrome" in COVID-19 refers to elevated cortisol levels that occur independently of ACTH stimulation, suggesting a reduced responsiveness of the adrenal glands to ACTH. Plasma proteomic analyses indicate that this phenomenon may involve calcium dysregulation and altered activities of the GNAS protein, which can ultimately impact the regulation of microvascular permeability and adrenal function.
How does COVID-19 contribute to endocrine resistance?
COVID-19 can induce a syndrome resembling endocrine resistance through the activation of receptor tyrosine kinase (RTK) signalling pathways. In mild cases, this is associated with elevated activity of EGFR and MMP9, along with increased expression of survival factors like Bax and Bcl2. In more severe cases, IGF-IR and enhanced NOTCH signalling are involved, along with altered expression of Bcl2, AKT1, and MAPK8. These changes can make cells less responsive to hormonal signals and therapies by activating alternative survival and growth pathways.
What roles do calcium dysregulation and GNAS protein play in COVID-19-related endocrine issues?
Dysregulated calcium signalling, involving receptors like GPCR (acting through GNAS), RTK, and Voltage-Gated Calcium Channels, is significantly observed in COVID-19. GNAS, a protein involved in cAMP signalling, is crucial for regulating calcium levels and is associated with the function of various endocrine glands. Alterations in GNAS activity and calcium homeostasis can lead to hormonal hypersecretion, disruptions in vascular permeability, and potentially contribute to both elevated cortisol levels and endocrine resistance.
How do growth factor signalling pathways differ between mild and severe COVID-19 cases concerning endocrine resistance?
In mild COVID-19, elevated activity of EGFR and MMP9, along with increased survival factors like Bax and Bcl2, are prominent. EGFR activation can interfere with hormone receptor pathways, while MMP9 can alter the cellular microenvironment affecting hormone receptor function. In severe COVID-19, the involvement of IGF-IR and enhanced NOTCH signalling, alongside altered levels of Bcl2, AKT1, and MAPK8, creates an environment favouring cell survival and proliferation, further promoting resistance to hormone therapies.
What is the significance of the angiotensin I/AT1 receptor system in the context of COVID-19 and endocrine function?
Comparative analysis of plasma proteomic data highlights the activation of the angiotensin I/AT1 receptor system in COVID-19. Angiotensin II, a product of this system, is involved in maintaining blood pressure, fluid and electrolyte balance, and can stimulate aldosterone secretion from the adrenal cortex. In COVID-19, the ACE enzyme, which converts angiotensin I to II, is a target for the virus, potentially leading to vasoconstriction, altered cardiac function, and kidney dysfunction, thereby impacting endocrine homeostasis.
What are the potential therapeutic implications of understanding COVID-19-related endocrine dysregulation?
Understanding the complex interplay between COVID-19 and endocrine pathology, particularly the mechanisms of cortisol dysregulation and endocrine resistance, suggests potential endocrine targets for therapeutic interventions. Strategies aimed at modulating cortisol signalling, addressing calcium and GNAS-related disruptions, and overcoming growth factor-induced endocrine resistance could improve short- and long-term outcomes for COVID-19 patients. Further research into these mechanisms may guide the development of more effective and targeted treatments.
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A C T H S D F G H J K L P O I U Y T
S E T S I S E R Z X C V B N M Q W E
D F G H J K L O I U Y T R E W Q A S
R T Y U I O P A S D F G H J K L Z X
E W Q A S D F G H J K L Z X C V B N
N M Q W E R T Y U I O P A S D F G H
O I U Y T R E W Q A S D F G H J K L
C V B N M Q W E R T Y U I O P A S D
R T Y U I O P A S D F G H J K L Z X
I W Q A S D F G H J K L Z X C V B N
N M Q W E R T Y U I O P A S D F G H
E I U Y T R E W Q A S D F G H J K L
P V B N M Q W E R T Y U I O P A S D
S T Y U I O P A S D F G H J K L Z X
U W Q A S D F G H J K L Z X C V B N
D M Q W E R T Y U I O P A S D F G H
O I U Y T R E W Q A S D F G H J K L
C V B N M Q W E R T Y U I O P A S D
U S H I N G S U D O E P Z X C V B N
T W Q A S D F G H J K L Z X C V B N
E M Q W E R T Y U I O P A S D F G H
I I U Y T R E W Q A S D F G H J K L
N V B N M Q W E R T Y U I O P A S D
A T Y U I O P A S D F G H J K L Z X
L W Q A S D F G H J K L Z X C V B N
Words to Find:
ACTH
ADRENAL
AKT1
BCL2
CALCIUM
CORTISOL
EGFR
ENDOCRINE
GNAS
IGFRI
INSULIN
MAPK8
MMP9
NOTCH
PROTEOMICS
PSEUDOCUSHINGS
RAAS
RESISTANCE
TESTOSTERONE
THYROID